COST Action CM0803 - u-szeged.hu · P09 Cell Penetrating Properties and Conformational Analysis of...

COST Action CM0803

Foldamers: building blocks, structure and function

Szeged, Hungary

Academy House, Szeged (Somogyi u. 7.) 24 – 26th September 2009

Organising Committee:

Prof. Ferenc Fülöp chair

Prof. David Aitken vice-chair

Prof. Rosa M. Ortuño

Prof. Andrew J. Wilson

Dr. Tamás A. Martinek

Local organiser:

University of Szeged, Institute of Pharmaceutical Chemistry

Sponsors

COST

BioBlocks Kft.

Sanofi Aventis

Chair of the Management Committee: Prof. Ferenc Fülöp [email protected] http://www.pharm.u-szeged.hu/gyki

mailto:[email protected]

http://www.pharm.u-szeged.hu/gyki

CONTENT

Wellcome from the chair of the Organising Committee ................................................................. I Institute of Pharmaceutical Chemistry, University of Szeged, Hungary .................................... III Locations............................................................................................................................................ V Program.............................................................................................................................................. 1 MC Meeting ........................................................................................................................................ 2 WG1: Foldamer building blocks ...................................................................................................... 4

Methodology for the Asymmetric Synthesis of -amino Acids ........................................................ 6 Fluorinated β-amino acids: new synthetic strategies ...................................................................... 7 Lipase-catalysed direct strategies for the preparation of enantiopure β-amino acids..................... 8 Synthesis of carbocyclic and heterocyclic β-amino acid derivatives............................................... 9 Conformationally restricted - and -amino acids as constituents in foldamers:

Synthesis and application as organocatalysts and as ligands for Neuropeptide Y............... 10 New constrained bicyclic amino acid through diversity oriented synthesis (DOS):

synthesis and molecular recognition properties .................................................................... 11 4-Membered ring -amino acids: synthesis of building blocks and some

insight into the folding of their oligomers............................................................................... 12 WG2: Foldameric secondary structures and controlled self-assembly .................................... 13

Effects of Substituted Proline Residues and Terminal Functional Groups on the Stability of the Polyproline II Structure .......................................................... 14

Carboproteins: Carbohydrate-templated designer proteins .......................................................... 15 Conformational Control: New Atropisomers and Long-Range Communication............................ 16 Structure and self-assembling of chiral cyclobutane β-peptides................................................... 17 Folding and self-assembling with urea-based oligomers .............................................................. 18 Foldamer stability in Trp cage miniproteins................................................................................... 19

WG3: Functional foldamers............................................................................................................ 20 FOLDAPPI : Designing foldamers as new drug entities................................................................ 21 Oxazolidin-2-ones based foldamers.............................................................................................. 22 A fresh perspective on sugar amino acids: structure, disorder and application............................ 23 From sheet-forming peptides to positive cooperativity in folded asymmetric catalysts ................ 24 Helically folded capsules based on aromatic oligoamide foldamers............................................. 25 DNA-binding polyamides in nanoarchitectures ............................................................................. 26

Posters ............................................................................................................................................. 27 P01 Aromatic oligoamide inhibitors of protein-protein interactions .............................................. 29

P02 The effect of bicyclic residue on -peptide helical secondary structures.............................. 30 P03 Regio- and stereoselective 1,3-dipolar cycloaddition of nitrile oxides to ethyl

cis- or trans-2-aminocyclopent-3-enecarboxylates....................................................... 31 P04 Enzymatic hydrolysis of hydroxylated alicyclic β-amino esters............................................. 32 P05 Efficient syntheses of hydroxy-substituted β-aminocyclohexanecarboxylic acids ................ 33 P06 Morpholine-based scaffolds for the generation of reverse-turn mimetics ............................. 34 P07 Self-assembling of a bicyclic and chiral urea: a combined experimental

and computational study............................................................................................... 35 P08 New chiral multifunctional cyclobutane dendrimers .............................................................. 36 P09 Cell Penetrating Properties and Conformational Analysis of

Functionalised Oligoprolines......................................................................................... 37

P10 Stereoselective synthesis and transformations of the enantiomers of apopinene-based β-amino acids................................................................................... 38

P11 An improved enzymatic method for the preparation of valuable β-arylalkyl- β-amino acid enantiomers.......................................................................... 39

P12 Effects of side-chain topology and entropy on the self-organization of β-peptides ................................................................................................................. 40

P13 β-Peptides and novel “hybrid” ,β-peptoids: scaffolds for multivalent ligand display ........... 41

P14 Effect of azapeptide building blocks: stable peptide foldamers in water............................... 42 P15 Synthesis of orthogonally protected piperidine and azepane

-amino ester enantiomers ........................................................................................... 43

P16 Circular dichroism investigation of novel “hybrid” ,β-peptoids ............................................ 44

P17 Redox-Dependent Disulfide Formation in SAP30L Co-repressor Protein Studied by ESI FT-ICR Mass Spectrometry..................................................... 45

P18 Intramolecular Enolate-Imine Cyclisation Reactions for the Synthesis of β-Amino Acids............................................................................................................... 46

P19 When a random coil is coiled: critical evaluation of coiled-coil vs. disordered cross-predictions......................................................................................... 47

P20 Compliance of protein structural ensembles with experimental NMR data .......................... 48 P21 Structural evaluation of potential ligands targeting GLP-1 receptor ..................................... 49

Author index .................................................................................................................................... 50 Participants in alphabetical order.................................................................................................. 52 Szeged .............................................................................................................................................. 56

Brief history of the city of sunshine................................................................................................ 56 Some sights and attractions in Szeged......................................................................................... 59

Sponsors .......................................................................................................................................... 62 COST............................................................................................................................................. 62 Sanofi Aventis................................................................................................................................ 63 BIOBLOCKS Kft................................................................................................................................ 64

COST Foldamers: building blocks, structure and function I

24 – 26th September 2009

Wellcome from the chair of the Organising Committee

WELLCOME FROM THE CHAIR OF THE ORGANISING COMMITTEE

Some year ago I have suggested starting a conference series on betas. The suggestion started with the following sentences “The interest in -amino acids and their derivatives has increased exponentially in the past decade and this has become a hot topic in synthetic and medicinal chemistry. Some of the -amino acids exhibit their own pharmacological activity, while many can be found in important drugs; a number of their derivatives are currently being investigated in clinical studies. These compounds can serve as building blocks in peptide chemistry, in drug research, and in natural product, heterocyclic and combinatorial chemistry, just to mention a few of the important areas. Their structures, especially in peptide foldamers tend to be unique; their use in the future can be expected to be wide-ranging.”

The conference series did not begin straight away, but instead I had a chance to organise a section entitled “Enantioselective synthesis of β-amino acids” in the frame of 16th INTERNATIONAL CONFERENCE ON ORGANIC SYNTHESIS 11-15 June 2006 Merida, Mexico. The speakers of this afternoon were: Giuliana Cardillo (Università degli Studi di Bologna, Italy) "Unusual β-Amino Acids: Synthesis and Application; Norbert De Kimpe, (Ghent University, Belgium) "Synthesis and rearrangements of β-aminocyclo-propanecarboxylic acid derivatives"; Claudio Palomo Nicolau (Universidad del País Vasco, Spain) "Catalytic Enantioselective Synthesis of β-Amino acids"; David J. Aitken, (Université Blaise Pascal, France) "Total Synthesis of Cyclotheonamide C: Focus on the -Oxo-β-Amino acid Moiety"; Rosa M. Ortuño (Universitat Autónoma de Barcelona, Spain) "Cyclobutane Containing β-Amino Acids: Stereoselective Synthesis and Incorporation Into Highly Rigid β -Peptides"; Peter Spiteller (Technische Universität München, Germany) " β-Amino Acids in Nature"; Ferenc Fülöp, (University of Szeged, Hungary) "Synthesis of cyclic β-amino acids: toolkits to construct foldamers". As you see most of the speakers are present in the conference and joining the Cost project.

We all believed that the section was very successful and the speakers decided to continue this work in the frame of a joint project. Since we were all from Europe it was logical and desirable to start a Cost framework.

The engine of the project writing was Tamás A. Martinek; a young and extremely talented colleague (who in the meantime became Associate Professor). The project took shape over the course of several discussions, and soon evolved towards the use of betas for the formation of foldamers. Finally the project title is Functional peptidomimetic foldamers: from unnatural amino acids to self-assembling nanomaterials. The main objective of the Action is to develop peptidomimetic foldamers into a technology platform in drug discovery and biomedical applications. The goal is to relay the ideas, pharmacophore models and requirements among the potential biomedical applications (e.g., inhibition of protein-protein interactions, self-assembling nanostructured drug delivery systems, functional biomimetic materials, etc.), to the laboratories involved in foldamer design and synthesis, and the researchers who are continuously extending the pool of homologated

II Foldamers: building blocks, structure and function COST


Wellcome from the chair of the Organising Committee

amino acids. This parallel top-down and bottom-up information handling is expected to boost the application oriented foldamer research in Europe.

We are all happy to join the Cost CM0803 Action, and organize conferences, meetings in the fields, educate PhD students, visit each other’s laboratories and much more. We very much hope that the final outcome will be very positive, and that by getting to know each other better we can create even stronger connections, create new EU projects, etc.

Prof. Ferenc Fülöp chair of Cost CM0803

Kick-off meeting participants on 18th May 2009 in Brussels (from left to right): Andy Wilson, Knud J. Jensen, Claudia Tomasini, Norbert Sewald, David Aitken, Ferenc Fülöp, András Perczel, Norbert De Kimpe, Rosa M. Ortuño, Tamás A. Martinek, George Fleet, Ivan Huc

COST Foldamers: building blocks, structure and function III


Institute of Pharmaceutical Chemistry, University of Szeged, Hungary

INSTITUTE OF PHARMACEUTICAL CHEMISTRY, UNIVERSITY OF SZEGED, HUNGARY


History. In Szeged, the subject Pharmaceutical Chemistry was initially taught at the Institute of Chemistry, Ferencz József University of Sciences. This institute was later divided up. Professor Tibor Széki became head of one of the new departments, and lectured on both Organic Chemistry and Pharmaceutical Chemistry. In 1938, Professor Győző Bruckner took over the Institute of Organic and Pharmaceutical Chemistry. In 1947, the Institute of Pharmaceutical Chemistry was set up as a separate institute, headed by Professor Dénes Kőszeg, who had lectured on this subject since 1935. At that time, the drug compounds included mainly inorganic molecules, and the education and research therefore concentrated on the preparation and analysis of these compounds. Professor Elemér Vinkler, who had earlier lectured on organic drug compounds, headed the Institute between 1963 and 1979. Professor Vinkler was a professional in organic chemistry and dealt with organic sulphur compounds in his research work. Hence, the research profile changed to synthetic preparative organic chemistry from 1964. In this way, the research and education were harmonized with the international trends: at that time, it was obvious that mainly organic compounds would be applied in the therapy. Between 1979 and 1998, when Professor Gábor Bernáth was the Head of the Department, the research and education profile moved further towards the synthetic organic chemistry of saturated heterocyclic compounds, and an up-to-date stereochemical approach was emphasized in the graduate education too. Since 1998, the present head, Professor Ferenc Fülöp has been leading studies on the saturated heterocycles, enzymatic resolutions, cyclic -amino acids and the synthesis of di- and trifunctional compounds. During the past 35 years, the Institute of Pharmaceutical Chemistry has been the center of research and education in Pharmaceutical and Organic Chemistry in Southern Hungary.

Present activities. The Institute currently provides lectures on Pharmaceutical Chemistry, on Organic Chemistry on Qualitative Chemical Analysis, and Introduction to Chemical Drug Research.

Synthetic organic chemistry, drug research and the structural analysis of the synthesized compounds have been the main research profile of the Institute of Pharmaceutical Chemistry, University of Szeged for the last two-three decades, which includes the following topics:

(1) Developments of new selective (both diastereo- and enantioselective) procedures for the preparation of difunctional compounds (e.g. -lactams, -amino acids, 1,2- and 1,3-amino alcohol and 1,3-amino phenol derivatives) by using conventional ex-chiral-pool methods and enzymatic kinetic resolutions;

(2) Studies on the applications of 1,2- and 1,3-difunctional compounds in the preparation of heterocyclic compounds, -peptides and potentially bioactive molecules;

(3) Developments of various possibilities for the further hydroxy or amino functionalizations of carbo- or heterocyclic -amino acid derivatives;

(4) Application of enantiopure di- and trifuctional compounds in organocatalytic asymmetric transformations;

(5) Structural analysis of -peptide foldamers by using NMR spectroscopy;

(6) Analysis of conformational and ring-chain equilibria of saturated heterocycles by spectroscopic and theoretical methods;

(7) Computational chemistry, computer-aided drug design.

The Institute gained a great experience in the field of drug research made in long-term collaborations with various pharmaceutical companies both from Hungary and from Europe (e.g. Richter, Chinoin, Hungary; Biotie, Finland; Acros, Belgium; Bioblocks, USA). Numerous compounds, prepared in the Institute, proved to possess beneficial pharmacological activities.


IV Foldamers: building blocks, structure and function COST


Institute of Pharmaceutical Chemistry, University of Szeged, Hungary

The Institute possesses a ca. 4000-membered diverse compound library collected from the substances prepared during the preparative organic chemical research work performed in the Institute in recent years. The library contains various derivatives of 1,2- and 1,3-difunctional compounds (amino acids, amino alcohols, hydroxy acids, etc.) with acyclic, carbocyclic (both aromatic and alicyclic) and heterocyclic skeleton. Differently saturated 1,3-heterocyclic derivatives obtained by the cyclizations of the difunctional compounds are also included. The structure and >95% purity of the members of the compound library are determined by NMR spectroscopy and MS spectrometry.

The Institute has very good abilities for the organic synthetic work. There are 5 well-equipped laboratories for preparative organic chemical research (one of them has been established for enzymatic reactions) and an instrument centre for the structural analysis of the prepared compounds (400, 500 and 600 MHz NMR, GC-LC-HRMS, IR and UV spectrometers, polarimeter, GC and HPLC instruments, with chiral columns).

The teaching staff:

Prof. Ferenc Fülöp PhD., DSc., Head of Department, Corresponding Member of the Hungarian Academy of Sciences

Dr. László Lázár PhD., associate professor Dr. Enikő Forró PhD., associate professor Dr. Tamás A. Martinek PhD., associate professor Dr. Zsolt Szakonyi PhD., associate professor Dr. Loránd Kiss PhD., lecturer Dr. Márta Fábiánné Palkó PhD., lecturer Dr. Ferenc Miklós PhD., research assistant Dr. István Szatmári PhD., research assistant Dr. Zita Zalán PhD, assistant lecturer 2 residents and 13 PhD students working in these laboratories.

COST Foldamers: building blocks, structure and function V


Locations

LOCATIONS

8. Votive Church, Saint Dömötör Tower and National Pantheon (Dóm square)

1. University of Szeged, Faculty of Pharmacy, Institute of Pharmaceutical Chemistry (MC meeting, Eötvös street 6) 9. Ferenc Móra Museum (Roosevelt square 1)

2. Academy House (The place of the conference, Somogyi street 7)

10. The Somogyi Library (Dóm square) 11. The City Hall of Szeged (Széchenyi square 10-11)

3. “Sótartó” Roosevelt Square Fishermen's (Dinner for the MC members, Roosevelt square)

12. Anna Medical, Thermal and Experience Bath, (Tisza Lajos boulevard 24)

13. Reök Palace (Regional All Arts Centre, Tisza Lajos boulevard 56) 4. Novotel Hotel Szeged**** (Maros street 1)

5. Hotel Matrix** (Zárda street 8) 14. Heroes' Gate (Aradi vértanúk square) 6. Port 15. The Szeged National Theatre 7. “Öreg Kőrössy” Fishermen's Restaurant

(Conference dinner, Szeged, Felső Tisza-part 336, by ship)

COST Foldamers: building blocks, structure and function 1


Program

PROGRAM

Szeged, Hungary 24 – 26th September 2009

24th September (Thursday)

12:00 Arrival (direct bus and/or taxi transfer will be organized from the airport) Registration (Academy House Lobby)

17:00-19:00 MC meeting (Faculty of Pharmacy, Room V)

19:00 Dinner for the MC members (Roosevelt Square Fishermen's)

25th September (Friday)

9:00-9:05 Ferenc Fülöp: Opening remarks for the conference

9:05-12:05 Session WG1: Foldamer building blocks

10:15-10:45 Coffee break and networking

12:05-14:00 Lunch and Poster session for all the WGs

14:00-16:40 Session WG2: Foldameric secondary structures and controlled self-assembly

17:50 Meeting at the Novotel Hotel

18:00 Transfer to the restaurant and conference dinner

19:00 Conference dinner (“Öreg Kőrössy” Fishermen's Restaurant)

26th September (Saturday)

9:00-12:10 Session WG3: Functional foldamers


12.10-12:20 Closing remarks

12:20 Lunch

Departure (bus transfer to Budapest or to the Airport)

2 Foldamers: building blocks, structure and function COST

Session WG1 24 – 26th September 2009

MC Meeting

MC MEETING

Chair: Prof. Ferenc Fülöp ([email protected])

Faculty of Pharmacy, Room V Eötvös street 6

24th September (Thursday) 17:00-19:00 MC Meeting

Participants:

Prof. Ferenc Fülöp chair HU University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: 36 62 545564; e-mail: [email protected]

Prof. David Aitken vice-chair, WG1 coordinator FR Université Paris-Sud, France ICMMO, Bat.420, Université Paris-Sud, 15 rue Georges Clemenceau, 91405 Orsay cedex, France; tel: +33613205838; e-mail: [email protected]

Dr. Tamás A. Martinek STSM coordinator HU University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: +3662545768; e-mail: [email protected]

Prof. Rosa M. Ortuño WG2 coordinator ES Universitat Autonoma de Barcelona Universitat Autonoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; tel: 34 93 408 2699; e-mail: [email protected]

Prof. Andrew J. Wilson WG3 coordinator UK University of Leeds School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK; tel: +44 (0)1133431409; e-mail: [email protected]

Dr. Steven Bull UK University of Bath University of Bath; tel: 01225 862655; e-mail: [email protected]

Prof. Norbert De Kimpe BE Ghent University Coupure links 653, B-9000 Ghent, Belgium; tel: 32-9-264.59.51; e-mail: [email protected]

Prof. Santos Fustero ES Universidad de Valencia. Facultad de Farmacia. Dpto. Química Orgáncia Avda Vicente Andrés Estellés s/n 46100-BURJASST (Valencia) Spain; tel: +34 963544279; e-mail: [email protected]

Dr. Gilles Guichard FR Institut Européen de Chimie et de Biologie 2 rue Escarpit - 33170 Pessac, France; tel: 06 63 75 78 34; e-mail: [email protected]


24 – 26th September 2009 Session WG1

MC Meeting

Prof. Knud J. Jensen DK University of Copenhagen IGM, KU-LIFE, Thorvaldsensvej 40, DK-1871 Frederiksberg, Denmark; tel: +45 3533 2430; e-mail: [email protected]

Prof. András Perczel HU Eötvös Loránd University 1117 Budapest, Pázmány Péter s. 1/A; tel: +36-1-3722500 ext. 1653; e-mail: [email protected]

Prof. Oliver Reiser GE University of Regensburg Universitätsstr. 31; tel: +499419434631; e-mail: [email protected]

Prof. Claudia Tomasini IT Università di Bologna Dipartimento di Chimica Ciamician - Università di Bologna - Via Selmi 2 - 40126 bologna - Italy; tel: +39-0512099596; e-mail: [email protected]

Prof. Pirjo Vainiotalo FI University of Joensuu Univ. Joensuu, Department of Chemistry, PO Box 111, 80101 Joensuu, Finland; tel: +358505224345; e-mail: [email protected]

Dr. Jänis, Janne FI University of Joensuu, Department of Chemistry P.O. Box 111, FI-80101 Joensuu, Finland; tel: +358-13-2513356; e-mail: [email protected]

Dr. Erwan Arzel COST science officer BE COST; 149 avenue Louise; 1050 Brussels; Belgium; tel: 003225333817; e-mail: [email protected]

Prof. Abraham H. Parola DC rapporteur IL Ben-Gurion University of the Negev; Department of Chemistry; The Faculty of Natural Sciences, Ben-Gurion University, P.O. Box; 653, Beer Sheva, Israel, 84105; tel: 97286472454, +972528795945; fax: +97286472943; e-mail: [email protected]



WG1: Foldamer building blocks

WG1: FOLDAMER BUILDING BLOCKS

Coordinator: DAVID AITKEN ([email protected])

Oral presentations: room 103-104 of the Academy House

Somogyi street 7

25th September (Friday) 9:05-12:05 Session WG1

09.05-09.15 David Aitken: Introduction to session WG1 Laboratoire de Synthèse Organique et Méthodologie, Institut de Chimie Moléculaire et des Matériaux d’Orsay (CNRS – UMR 8182), Université Paris–Sud 11, 15 Rue Georges Clemenceau, 91405 Orsay, France e-mail: [email protected]

09:15-09:35 Steve D. Bull: Methodology for the asymmetric synthesis of -amino acids Department of Chemistry, University of Bath, Bath, BA2 7AY, UK. e-mail: [email protected]

09:35-09:55 Santos Fustero: β-amino acids and related homologues Departamento de Química Orgánica, Universidad de Valencia, E-46100 Burjassot, Spain, and Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain, e-mail: [email protected]

09:55-10:15 Enikő Forró: Lipase-catalysed direct strategies for the preparation of enantiopure β-amino acids Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, Eötvös street 6, Hungary, e-mail: [email protected]


10:45-11:05 Norbert De Kimpe: Synthesis of carbocyclic and heterocyclic β-amino acid derivatives Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium, e-mail: [email protected]

11:05-11:25 Oliver Reiser: Conformationally restricted -amino acids as cons-tituents in foldamers: Synthesis and application as organocatalysts and as ligands for Neuropeptide Y Institut für Organische Chemie, Universität Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany, e-mail: [email protected]




mailto:[email protected]%1Eszeged.hu






11:25-11:45 Antonio Guarna: New constrained bicyclic , β, and / amino acids: synthesis and molecular recognition properties Department of Organic Chemistry "Ugo Schiff", University of Florence, Polo Scientifico e Tecnologico, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Florence, Italy e-mail: [email protected]

11:45-12:05 Valérie Declerck: 4-Membered ring -amino acids: synthesis of building building blocks and some insight into the folding of their oligomers Laboratoire de Synthèse Organique et Méthodologie, Institut de Chimie Moléculaire et des Matériaux d’Orsay (CNRS – UMR 8182), Université Paris–Sud 11,15 Rue Georges Clemenceau, 91405 Orsay, France, e-mail: [email protected]






METHODOLOGY FOR THE ASYMMETRIC SYNTHESIS OF -AMINO ACIDS

Steven D. Bull

Department of Chemistry, University of Bath, University of Bath, BA27AY, UK.

Methodology employing chiral lithium amide species or chiral Lewis acids for the asymmetric synthesis of haloaryl--amino acids,1 -pyridyl--amino acids,2 bis- and tris--amino acid scaffolds,3 and cyclic and bicyclic--amino acids4 will be described.

We will also describe a practically useful three component coupling method for determining the enantiomeric excess of chiral amines by NMR spectrosocopy that can be used to rapidly analyse the enantiopurity of -amino acid derivatives produced in asymmetric processes. 5,6

1 S. D. Bull, S. G. Davies, S. Delgado-Ballester, P. M. Kelly, L. J. Kotchie, M. Giannotti, M. Laderas, A. D.

Smith, J. Chem. Soc., Perkin Trans 1, 2001, 3112. 2 S. D. Bull, S. G. Davies, S. Delgado-Ballester, D. J. Fox, M. Giannotti, P. M. Kelly, C. Pierres, E. D. Savory,

A. D. Smith, J. Chem. Soc., Perkin Trans 1, 2002, 1858. 3 S. D. Bull, A. D. Smith, S. G. Davies, J. Chem. Soc., Perkin Trans 1, 2001,1858. 4 M. Koutsaplis, P. C. Andrews, S. D. Bull, P. J. Duggan, B. J. Fraser, P. Jensen, Chem. Commun., 2007,

3580. 5 Y. Perez-Fuertes, A. M. Kelly, A. L. Johnson, S. Arimori, S. D. Bull, T. D. James, Org. Lett., 2006, 8, 609. 6 A. M. Kelly, Y. Pérez-Fuertes, J. S. Fossey, S. D. Bull, T. D. James, Nature Protocols, 2008, 3, 210.




FLUORINATED β-AMINO ACIDS: NEW SYNTHETIC STRATEGIES

Santos Fustero

Departamento de Química Orgánica, Universidad de Valencia, E-46100 Burjassot, Spain, and Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, E-

46012 Valencia, Spain. E-mail: [email protected]

In nature, the great majority of molecules, including proteins, nucleic acids, and most biologically active compounds, contain nitrogen. For this reason, the development of new synthetic methods for the construction of nitrogenous molecules has defined the frontiers of organic synthesis since its inception. It is not surprising, then, that a concerted effort has been made over the past few decades to develop building blocks for this purpose. Another area of expansion in recent years has had to do with the discovery of the utility of fluorine-containing molecules, a recognition which comes from an awareness of their unique biomedical properties.1 Consequently, the development of new practical synthetic methods for the preparation of nitrogen-containing fluorinated chiral synthons, as well as the upgrade of existing ones, has received a considerable deal of attention.2 In particular, fluorinated amino acid derivatives have been found to exhibit a variety of biological properties while also being useful and versatile synthetic intermediates in organic synthesis. The full scope of our methodology in the synthesis of the various types of cyclic and acyclic fluorinated -amino acid derivatives will be discussed. Specifically, we are planning to synthesize in a diastereo- and enantioselective fashion derivatives 13 and 24 bearing a difluoro or trifluoromethyl unit in their structure. With this purpose, we will use techniques such as metathesis reactions both in the cross metathesis (CM) and ring closing metathesis version (RCM), organocatalysis and asymmetric synthesis based on the use of enantiomerically pure sulfoxides.

NH2

CO2HF

Fn

RF

R

NH2

CO2H

n=0-2

1 2

1 Müller, K.; Faeh, C.; Diederich, F. Science, 2007, 317, 1881-1886.

2 Fustero, S.; Sanz-Cervera, J. F.; Aceña, J. L.; Sánchez-Roselló, M. Synlett, 2009, 525-549.

3 a) Fustero, S.; Sánchez-Roselló, M.; Sanz-Cervera, J. F.; Aceña, J. L.; del Pozo, C.; Fernández, B.; Bartolomé, A.; Asensio, A.; Ramírez de Arellano, C. Org. Lett., 2006, 8, 4633-4636.

b) Fustero, S.; Sánchez-Roselló, M.; Aceña, J.L.; Fernández, B.; Asensio, A.; Sanz-Cervera, J. F.; del Pozo, C. J. Org. Chem., 2009, 74, 3414-3425.

4 a) Fustero, S.; del Pozo, C.; Catalán, S.; Alemán, J.; Parra, A.; Marcos, V.; García Ruano, J. L. Org. Lett., 2009, 11, 641-644. b) García Ruano, J. L.; Alemán, J.; Catalán, S.; Marcos, V.; Monteagudo, S.; Parra, A.; del Pozo, C.; Fustero, S. Angew. Chem. Int. Ed., 2008, 47, 7941-7944.





LIPASE-CATALYSED DIRECT STRATEGIES FOR THE PREPARATION OF ENANTIOPURE β-AMINO ACIDS

Enikő Forró

Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, Eötvös street 6, Hungary

Chiral -amino acids are of great interest, in view of their importance from both pharma-

ceutical and chemical aspects. They are used to prepare modified analogues of biolo-

gically active peptides, and peptides with well-defined three-dimensional, foldameric

structures,, natural products, drug candidates and heterocycles1.

Consequently, in the past few years a large number of selective syntheses have been

described for enantiopure -amino acid derivatives. A highly efficient and very simple

direct enzymatic method has been developed for the synthesis of enantiopure -amino

acids (e.g. cispentacin, benzocispentacin, 1,4-ethyl- and 1,4-ethylene-bridged cispentacin,

etc.) through the enzyme-catalysed enantioselective (E > 200) ring cleavage of

unprotected -lactams, yielding the ring-opened -amino acid and unreacted -lactam

enantiomers, which can be easily separated2.

NH

OR1

R2

lipaseH2O

NH2

COOHR1

R2 HN

O R1

R2

+

A direct enzymatic method for the synthesis of cis and trans -amino acid enantiomers

through the lipase-catalysed enantioselective hydrolysis (E usually > 100) of -amino

esters in organic media was recently discovered3.

NH2

COOEtR1

R2

lipaseH2O

NH2

COOHR1

R2

+

H2N

EtOOC R1

R2

In parallel, a new GC method has been developed for the enantioseparation of racemic

amino acids on a chiral column after a simple and rapid double derivatization (esterification

followed by N-acylation)4.

1 F. Fülöp, Chem. Rev., 2001, 101, 2181; F. Fülöp, T.A. Martinek, G.K. Tóth, Chem. Soc. Rev., 2006, 35, 323; L.

Kiss, E. Forró, F. Fülöp, Synthesis of carbocyclic β-amino acids, in Amino Acids, Peptides and Proteins in Organic Chemistry. Vol. 1 (Ed. A.B. Hughes) WILEY-VCH, Weinheim, 2009; T.A. Martinek, I.M. Mándity, L. Fülöp, G.K. Tóth, E. Vass, M. Hollósi, E. Forró, F. Fülöp, J. Am. Chem. Soc., 2006, 128, 13539; A. Hetényi, Z. Szakonyi, I.M. Mándity, É. Szolnoki, G.K. Tóth, T.A. Martinek, F. Fülöp, Chem. Commun., 2009, 177; I.M. Mándity, E. Wéber, T.A. Martinek, G. Olajos, G.K. Tóth, E. Vass, F. Fülöp, Angew. Chem. Int. Ed., 2009, 48, 2171; F. Fülöp, F. Miklós, E. Forró, Synlett, 2008, 1687.

2 E. Forró, F. Fülöp, Org. Lett., 2003, 5, 1209; E. Forró, F. Fülöp, Chem. Eur. J., 2006, 12, 2587; E. Forró, F. Fülöp, Adv. Synth. Catal., 2006, 348, 917.

3 E. Forró, F. Fülöp, PCT Pat. Appl. (2007), 28 pp. WO 2007/091110 A1; E. Forró, F. Fülöp, Chem. Eur. J., 2007, 13, 6397; G. Tasnádi, E. Forró, F. Fülöp, Tetrahedron: Asymmetry, 2008, 19, 2072; G. Tasnádi, E. Forró, F. Fülöp, Tetrahedron: Asymmetry, 2009, in press.

4 E. Forró, J. Chromatogr. A., 2009, 1216, 1025.




SYNTHESIS OF CARBOCYCLIC AND HETEROCYCLIC β-AMINO ACID DERIVATIVES

Sven Mangelinckx,a Lorand Kiss,b Erika Leemans,a Matthias D’hooghe,a Eva Van Hende,a Guido Verniest,a Sietske Peeters,a Tamara Meiresonne,a Ferenc Fülöp,b and

Norbert De Kimpea aDepartment of Organic Chemistry, Faculty of Bioscience Engineering,

Ghent University, Coupure Links 653, B-9000 Ghent, Belgium bInstitute of Pharmaceutical Chemistry, University of Szeged, Hungary

The synthesis of conformationally constrained carbocyclic and heterocyclic β-amino acids

is becoming increasingly important in synthetic, agricultural and pharmaceutical chemistry.

This attention results from the specific properties of these non-proteinogenic constrained

amino acids with respect to biological activity (antifungal, gametocidal, peptidase-

inhibition) and structural features (building blocks for structurally and functionally unique β-

peptides).

R1 EWG

EWG

R1

X

1X = Br, Cl; n = 0 - 1

R1 = AlkylEWG = COOR, CN

( )n

R2 R2

2X = Br, Cl; n = 0 - 1

R2 = AlkylP1 = Alkyl, Aryl, Tosyl, Sulfinyl

H

NP1

P2P3N

R3

3R3 = H, COOR, CH2OPMP

P2, P3 = H, Alkyl, Arylmethyl,Arylidene

Carbocyclic and heterocyclic-amino acid derivatives

X( )n

In this presentation, the development of diverse synthetic pathways towards new confor-mationally constrained carbocyclic (cyclopropanes and cyclobutanes) and heterocyclic (aziridines, azetidines and tetrahydrofurans) β-amino acid derivatives starting from electrophilic allylic halides 1, halogenated imines 2 and allyl amines 3 is disclosed. The presence of a constrained ring and/or functional groups in the synthesized β-amino acid derivatives allowed further study of ring opening reactions, ring transformations and functional group transformations.




CONFORMATIONALLY RESTRICTED - AND -AMINO ACIDS AS CONSTITUENTS IN FOLDAMERS: SYNTHESIS AND APPLICATION

AS ORGANOCATALYSTS AND AS LIGANDS FOR NEUROPEPTIDE Y

Florian Sahr, Silvia DePol, Chiara Zorn, Regis Delatouche, Andrea Bordess, Karin Guitot, Lucia Formicola, Oliver Reiser

Institut für Organische Chemie, Universität Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany

-Amino acids have proved to remarkably stabilize secondary structures in peptides. Especially -peptides were shown to mimick the privileged elements of -peptides such as helices, -turns or -sheets with considerably fewer residues compared to their -analogs. In order to combine the stabilizing properties of -amino acids and the functional variety displayed through the side chains of -amino acids in peptides, we investigated mixed -peptides, making use of cyclic cis-1,2-aminocarboxylic acids of type 1 and 2. Their stereoselective synthesis, incorporation into peptides and the application of the latter as organocatalysts and ligands for neuropeptide Y will be discussed. Furthermore, the extension of our studies to cyclic -amino acids such as 3 will be presented.




NEW CONSTRAINED BICYCLIC AMINO ACID THROUGH DIVERSITY ORIENTED SYNTHESIS (DOS): SYNTHESIS AND

MOLECULAR RECOGNITION PROPERTIES

Antonio Guarna

Department of Organic Chemistry "Ugo Schiff", University of Florence, Polo Scientifico e Tecnologico, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Florence, Italy ( e-mail

[email protected])

Since the early reports of Schreiber et al.1.Diversity-Oriented Synthesis (DOS) has become a new paradigm for developing large collections of structurally diverse small molecules to provide a larger array of the chemical space in drug discovery issues. The principles of DOS have evolved to the development of different cyclic structures through the build/couple/pair approach.2 Recently, we have developed a DOS strategy using amino acid and sugar derivatives as building blocks to access to chemical and geometrical generation of new constrained byciclic amino acids.3

functionalgrouppairing

Pairinggroups

Couplinggroups

Enantiopurebuildingblocks

Thanks to high number of stereocenters and functions of such compounds these new classes of constrained amino acids were applied in drug discovery programs and in molecular recognitions studies.

1 Schreiber, S. L. Science, 2000, 287, 1964-1969. 2 a) Comer, E.; Rohan, E.; Deng, L.; Porco J. A. Jr., Org. Lett., 2007, 9, 2123-2126. 3 Trabocchi, A.; Menchi, G.; Guarna, F.; Machetti, F.; Scarpi, D.; Guarna A. Synlett, 2006, 3, 331-353. Sladojevich,

F.; Trabocchi, A.; Guarna, A.; Org. Biomol. Chem., 2008, 6, 3328-3336. A. Trabocchi, D. Scarpi, A. Guarna Amino Acids, 2008, 34, 1-24, Lalli C., Trabocchi A., Sladojevich F. Menchi G. Guarna A. Chem. Eur. J., 2009, 15, 7871-7875.




4-MEMBERED RING -AMINO ACIDS: SYNTHESIS OF BUILDING BLOCKS AND SOME

INSIGHT INTO THE FOLDING OF THEIR OLIGOMERS

Valérie Declerck, David J. Aitken

Laboratoire de Synthèse Organique et Méthodologie, Institut de Chimie Moléculaire et des Matériaux d’Orsay (CNRS – UMR 8182), Université

Paris–Sud 11,15 Rue Georges Clemenceau, 91405 Orsay, France

-Peptides are amongst most thoroughly investigated peptidomimetic oligomers owing to their resistance to proteolytic degradation and to their possibility to adopt secondary structure like -peptides. In this respect, cyclic -amino acids, where both the and carbon atoms are part of the ring, are of particular interest since they are conformationally restricted. Oligomers of 5 and 6-membered ring -amino acids have proved to adopt regular structures such as sheets or helices. Our interest focuses on the extension of this field to include 4-membered ring -amino acids. In this presentation we will cover the historical development and expose our current activities in this area.

The need for an efficient and easy-to-handle access to cyclobutane -amino acids inspired development of a [2+2] photocycloaddition strategy, allowing access to all four stereoisomers of the parent structure. The procedure can be adapted to accommodate side chain moieties in various positions around the cyclobutane ring. We will present our current work dealing with the consequences of the replacement of a carbon atom of the 4-membered ring by the more conformationally-flexible nitrogen atom and also in the introduction of side chains with potential hydrogen bond donor or acceptor character.

We will also present some stimulating results concerning the folding preferences which prevail in 4-membered ring -amino acids and their oligomers.



WG2: Foldameric secondary structures and controlled self-assembly

WG2: FOLDAMERIC SECONDARY STRUCTURES AND CONTROLLED

SELF-ASSEMBLY

Coordinator: ROSA M. ORTUÑO ([email protected])


Somogyi street 7

25th September (Friday) 14:00-16:40 Session WG2

14:00-14:10 Rosa M. Ortuño: Introduction to session WG2 Departament de Química, Universidad Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain, e-mail: [email protected]

14:10-14:35 Grégory Upert: Effects of substituted proline residues and terminal functional groups on the stability of the polyproline II structure Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland, e-mail: [email protected]

14:35-15:00 Knud Jensen: Carboproteins: carbohydrate-templated designer proteins Nanobioscience IGM - Bioorganic Chemistry, University of Copenhagen, Faculty of Life Sciences, Thorvaldsensvej 40, DK-1871 Frederiksberg C, Denmark, e-mail: [email protected]

15:00-15:25 Jonathan Clayden: Conformational communication through helical peptide foldamers School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, email: [email protected]

15:25-15:50 Eric Da Silva: Structure and self-assembling of chiral cyclobutane β-peptides Departament de Química, Universidad Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain, e-mail: [email protected]

15:50-16:15 Gilles Guichard: Folding and self-assembling with urea-based oligomers Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux - CNRS UMR 5248, 2 rue R. Escarpit, 33607 Pessac, France, e-mail: [email protected]

16:15-16:40 András Perczel: Foldamer stability in Trp cage miniproteins Laboratory of Structural Chemistry and Biology, Institute of Chemistry, Eötvös Loránd University, Pázmány Péter sétány 1/A, H-1117 Budapest, Hungary, Protein Modelling Group MTA-ELTE, Institute of Chemistry Eötvös Loránd University, Pázmány Péter sétány 1/A, H-1117 Budapest, Hungary, e_mail: [email protected]










EFFECTS OF SUBSTITUTED PROLINE RESIDUES AND TERMINAL FUNCTIONAL GROUPS ON THE STABILITY OF THE

POLYPROLINE II STRUCTURE

Grégory Upert, Michael Kümin and Helma Wennemers*

Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland

The helical polyproline II (PPII) conformation is widespread in nature and important for protein-protein interactions (e.g. signal transduction processes) as well as for structural integrity (e.g. collagen)1. Factors like solvation and steric interactions between the pyrrolidine rings are known to influence the stability of the PPII helix2. We investigated the influence of 4-azidoproline (Azp) residues and the functionalisation of the termini. The conformational switch of oligoprolines from the PPII to the PPI helix, which can be easily monitored by CD-spectroscopy, was used as a measure to evaluate the conformational stability of the PPII structure.

PPII (favoured in water) PPI (favoured in n-PrOH)

Effect of Azp residues: (4R)Azp residues stabilize the PPII helix whereas (4S)Azp residues have a destabilizing effect3. These results support the importance of a n π* interaction for the stability of the PPII helix. Apart from its conformation directing effect the azido-groups also allow for derivatisation, rendering Azp containing oligoprolines attractive as molecular scaffolds3.

Effect of terminal functional groups: Peptides consisting of 12 proline residues with free or capped end-groups were examined. Significantly different tendencies to switch between the two helical conformations were found, which correlate nicely with the results of quantum chemical calculations. As in α-helical structures the macrodipole was found to influence the stability of the polyproline helices.

References

1 for examples see: a) M. V. Cubellis, F. Caillez, T. L. Blundell, S. C. Lovell, Proteins, 2005, 58, 880-892; b) B.

Bochicchio, A. Tamburro, Chirality, 2002, 14, 782-792; c) B. J. Stapley, T. P. Creamer, Protein Sci., 1999, 8, 587-595.

2 a) A. Rath, A. R. Davidson, C. M. Deber, Biopolymers (Pept. Sci.), 2005, 80, 179. b) T. P. Creamer, M. N. Campell, Adv. Protein Chem., 2002, 62, 263-282.

3 a) M. Kümin, L.-S. Sonntag, H. Wennemers, J. Am. Chem. Soc., 2007, 129, 566-567; b) L.-S. Sonntag, S. Schweizer, C. Ochsenfeld, H. Wennemers, J. Am. Chem. Soc., 2006, 128, 14697-14703.




CARBOPROTEINS: CARBOHYDRATE-TEMPLATED DESIGNER PROTEINS

Knud J. Jensen

Nanobioscience IGM - Bioorganic Chemistry University of Copenhagen, Faculty of Life Sciences

Thorvaldsensvej 40, DK-1871 Frederiksberg C, Denmark

De novo design and total chemical synthesis of proteins allows the preparation of novel biomolecules to address complex biological questions. It offers the prospect of designing proteins with new tailored properties. The development of highly efficient methods for coupling of unprotected peptides has placed the reliable chemical synthesis of proteins within reach of bioorganic chemistry. This lecture presents our efforts in the design and chemical synthesis of a novel class of chimeric model proteins, termed carboproteins, in which carbohydrates are used as templates in de novo design of proteins. Here, the template preoorganizes the secondary structure elements and directs the formation of a tertiary structure, thus achieving structural economy. The lecture describes our synthetic methodologies for solid-phase chemical synthesis of carboproteins and the biophysical characterization of helix bundle structures using CD spectroscopy and small-angle X-ray scattering.




CONFORMATIONAL CONTROL: NEW ATROPISOMERS AND LONG-RANGE COMMUNICATION

Jonathan Clayden

School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL [email protected]

Stereochemistry is in effect a form of binary information, and stereochemical control is a way of communicating that information from one point in a molecule to another. Communication over distances > 1 nm can be achieved provided molecular conformation is well controlled.1

ON

OO

N

NOPh

Me

HMe

ON

OO

N

ON

OO

N

R

OH

2

A B

CHORMgBr

chain of achiral amino acids

chiralcontroller

spectroscopicprobe

AB system62 bondsfromstereogeniccentre

2.5 nm

3.9 nm

3

1,23-stereoontrol

S

MeO

O O

94:6 er at C–S axis

MeO2S

[]D18 = –22.1 (c 1.16, CHCl3)t1/2

18(rac) = 130 minG‡

291K = 93.8 kJ mol–1

1

HN

Ph

NH

O

HN

ONH

NH

N

O

OH

OBnO

H

N

O

HNH

N

O

O

OH

OHNH

N

O

OH

Ha

Hb

n

We showed some years ago that a combination of steric and dipole effects allows the orientation of functional groups to be controlled,2 and we have exploited these effects in the stereocontrolled synthesis of a series of new families of atropisomers – most recently the biaryl sulfones 1.3 By identifying structures with well-defined conformational preferences – for example the polyamide 24 (in which the amides adopt an all-anti conformation) and the pseudopeptide 35 (which has strong helical preference) – we can synthesise molecules which offer the possibility of communication of stereochemical information over distances exceeding 2.5 nm, the typical thickness of a cell membrane. Progress and prospects in this area will be described.

References:

1 J. Clayden Chem. Soc. Rev., 2009, 38, 817-829. 2 J. Clayden and N. Vassiliou, Org. Biomol. Chem., 2006, 4, 2667-2678. 3 J. Clayden, J. Senior and M. Helliwell, Angew. Chemie Int. Ed., 2009, 48, 6270-6273. 4 J. Clayden, A. Lund, L. Vallverdú and M. Helliwell, Nature (London), 2004, 431, 966-971. 5 J. Clayden, A. Castellanos, J. Solà and G. A. Morris, Angew. Chemie Int. Ed., 2009, 48, 5962-5965.




STRUCTURE AND SELF-ASSEMBLING OF CHIRAL CYCLOBUTANE β-PEPTIDES

E. Da Silva, E. Torres, E. Gorrea, V. Branchadell and R. M. Ortuño*

Departament de Química, Universidad Autònoma de Barcelona, 08193 Bellaterra, Barcelona (Spain). E-mail: [email protected]

Cyclobutane β-aminoacid derivatives have been incorporated in different types of β-peptides adopting a preferential conformation in solution due to the formation of an intra-molecular hydrogen bond.1 The secondary structure of a series of cis-β-peptides (n = 2, 3, 4, 6, 8) has been investigated in solution by NMR techniques.2 Moreover, molecular modeling allowed us to suggest an aggregation model for self-assembling in which a parallel molecular arrangement is preferred and the conformation is similar to that observed in solution. All of them are prone to self-assemble producing nano-fibrils as evidenced by TEM, AFM, and SPFM tech-niques. Recently, a new study based on derivatives of cis- and trans-2-amino-cyclobutane-1-carboxylic acid incorporated in bis(cyclobutane) β-dipeptides have been synthesized. The predominance of eight-membered hydrogen-bonded rings has been manifested for (trans,trans)- and (trans,cis)-β-dipeptides while the formation of six-membered rings is preferred for the (cis,trans)-β-dipeptide similarly to the previously described (cis,cis)-diastereomer.3 In some cases, this confor-mational change can induce the formation of a stable and reversible gel involving nano-fibrillar structures (SEM technique).

1 Izquierdo, S.; Kogan, M. J.; Parella, T.; Moglioni, A. G.; Branchadell, V.; Giralt, E.; Ortuño, R. M.; J. Org. Chem.,

2004, 69, 5093; Izquierdo, S.; Rua, F.; Sbai, A.; Parella, T.; Alvarez-Larena, A.; Branchadell, V.; Ortuño, R. M.; J. Org. Chem., 2005, 70, 7963; Rua, F.; Boussert, S.; Parella, T.; Diez-Perez, I.; Branchadell, V.; Giralt, E.; Ortuño, R. M.; Org. Lett., 2007, 9, 3643.

2 Torres, E.; Gorrea, E.; Burusco, K. K.; Rúa, F.; Da Silva, E.; Nolis, P.; Boussert, S.; Díez-Pérez, I.; Dannenberg, S.; Izquierdo, S.; Giralt, E.; Jaime, C.; Branchadell, V.; Ortuño, R. M.; J. Org. Chem., 2009, submitted.

3 Torres, E.; Gorrea, Da Silva, E.; Nolis, P.; Branchadell, V.; Ortuño, R. M.; Org. Lett., 2009, 11, 2301.




FOLDING AND SELF-ASSEMBLING WITH UREA-BASED OLIGOMERS

Gilles Guichard

Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux - CNRS UMR 5248, 2 rue R. Escarpit, 33607 Pessac, France

Multiple approaches, at the interface between biology, synthetic organic and polymer chemistries have been developed to elaborate synthetic systems with protein-like structures and functions. The design of discrete oligomers (i.e. foldamers) with predictable and well-characterized folding patterns akin to naturally occuring helices, turns and linear strands has attracted considerable attention over the last decade.1 Non-natural aromatic and aliphatic oligoamide backbones have proven to be extremely well suited for the design of robust secondary structures as well as more sophisticated tertiary structural motifs. Concurrently, macrocyclic and linear oligoamides have been shown to be reliable building units for the fabrication of self-assembled nanostructures (e.g. nanotubes, nanospheres, fibrils,…).2-4 The reasons for the hegemony of the amide linkage lie in part in the relative ease of amide bond formation and in the robustness of H-bond interactions that help to stabilize folded conformations and to drive self-assembly. At first glance, the creation of oligomers with non-amide backbones, yet endowed with a potential to fold and self-assemble, rivalling that of oligoamides may appear especially difficult. To meet this challenge, a multitude of amide bond surrogates have been probed, some with success. Oligomers with a urea backbone, although they have so far received less attention than their amide counterparts, gradually made their name in the field. This presentation will essentially focus on the development of aliphatic urea-based oligomers with propensity to fold and/or to self assemble.

1 Hecht, S.; Huc, I. Foldamers: Structure, Properties, and Applications; Wiley, 2007. 2 Bong, D. T.; Clark, T. D.; Granja, J. R.; Ghadiri, M. R., Angew. Chem. Int. Ed., 2001, 40, 988-1011. 3 Gazit, E. Chem. Soc. Rev., 2007, 36, 1263-9. 4 Woolfson, D. N.; Ryadnov, M. G., Curr. Opin. Chem. Biol., 2006, 10, 559-567.




FOLDAMER STABILITY IN TRP CAGE MINIPROTEINS

András Perczel1,2, Petra Rovó1, Viktor Farkas2, András Láng1, Gábor K. Tóth3 1Laboratory of Structural Chemistry and Biology, Institute of Chemistry,

Eötvös Loránd University, Pázmány Péter sétány 1/A, H-1117 Budapest, 2Hungary, Protein Modelling Group MTA-ELTE, Institute of Chemistry

Eötvös Loránd University, Pázmány Péter sétány 1/A, H-1117 Budapest, Hungary, and 3Department of Medical Chemistry, Faculty of General Medicine, University of Szeged,

Dóm tér 8., H-6720 Szeged, Hungary

Abstract:

The 20-residue long, Trp cage miniproetin, NLYIQWLKDG GPSSGRPPPS, labeled as Tc5b by Neidigh and co-workers1 starts at the N-terminus by an alpha-helix (residues 2 to 9), continues by a 310-helix (or embedded -turns, residues 11-14) and concludes at its C-terminal by a poly-proline II helix, all structural subunits packed against the central Trp6. Beside the central hydrophobic core, the role of the structure stabilizing salt-bridge (Asp9 and Arg16) is also claimed as of central significance for stabilizing a protein like 3D-structure. Various spectroscopic methods (e.g. NMR, ECD) will be presented on how to analyses stability and foldamer interactions of both the natural and 15N-labelled Tc5b variants2.

Figure Superposition and secondary structure or foldamer distribution of several Trp cage miniprotein variants.

Keywords: structure and stability, salt-bridge, molecular trigger, Trp-cage miniprotein, NMR, ECD, optimized molecular folding, H-bonding network

References 1 Nat. Struct. Biol., 2002, 9, 425-430. 2 Hudáky, P. et. al. Biochemistry, 2008, 47, 1007-1016, Rovó P. 2009 unpublished.



WG3: Functional foldamers

WG3: FUNCTIONAL FOLDAMERS

Coordinator: ANDREW J. WILSON ([email protected])


Somogyi street 7

26th September (Saturday) 9:00-12:10 Session WG3

09:00-09:10 Andrew J. Wilson: Introduction to Session WG3 School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom and Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom; e-mail: [email protected]

09:10-09:40 Fred Denonne: FOLDAPPI: validating foldamers as new drug entities UCB Pharma, New Medicines. Chemin du Foriest, 1420 Braine-l’Alleud, Belgium, e-mail: [email protected]

09:40-10:10 Claudia Tomasini: Oxazolidin-2-ones based foldamers Dipartimento di Chimica “G. Ciamician”, Alma Mater Studiorum – Università di Bologna, Via Selmi 2 – 40137 Bologna, e-mail: [email protected]

10:10-10:30 Alison Edwards: A fresh perspective on sugar amino acids: structure, disorder and application Medway School of Pharmacy, Universities of Kent and Greenwich at Medway, Central Avenue, Chatham Maritime, Kent, ME4 4TB, United Kingdom, e-mail: [email protected]


11:00-11:20 Martin Smith: Positive cooperativity in folded asymmetric catalysts Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA UK, e-mail: [email protected]; http://msmith.chem.ox.ac.uk/

11:20-11:40 Yann Ferrand: Helically folded capsules based on aromatic oligoamide foldamers Institut Européen de Chimie Biologie - Université de Bordeaux 2, rue Robert Escarpit, 33607 Pessac, France, e-mail: [email protected]

11:40-12:10 Alex Heckel: DNA-binding polyamides in nanoarchitectures University of Frankfurt, Cluster of Excellence Macromolecular Complexes, Max-von-Laue-Str. 9, 60438 Frankfurt (M), Germany, e-mail: [email protected]

12:10-12:20 Closing remarks






http://msmith.chem.ox.ac.uk/






FOLDAPPI : DESIGNING FOLDAMERS AS NEW DRUG ENTITIES

Frédéric Denonne

UCB Pharma, New Medicines. Chemin du Foriest, 1420 Braine-l’Alleud, Belgium. [email protected]

The pharmaceutical industry currently uses mainly two kinds of molecules to interact with proteins and treat diseases. These are (i) small molecules with molecular weights around 500 Da and (ii) antibodies of several kDa. Put together, the limitations of these two entities only allow targeting 20% of known proteins. Middle-sized molecules obviously have a role to play there. Among them, foldamers are particularly attractive especially aromatic amide foldamers, which fold into rigid helixes suitable to be used as scaffolds to access large protein areas. The aim of the FOLDAPPI project is to block protein-protein interactions with this type of foldamers. Validation of this concept will be attempted with IL-4, a key regulator of the immune system for which no small molecule inhibitor of IL-4R has been reported so far. Modifying the interaction of IL-4 with its receptor is very important to control misguided immune reactions such as allergy and asthma.





OXAZOLIDIN-2-ONES BASED FOLDAMERS

Claudia Tomasini

Dipartimento di Chimica “G. Ciamician”, Alma Mater Studiorum – Università di Bologna Via Selmi 2 – 40137 Bologna, [email protected]

The essential requirement for an oligomer to be included in the foldamer family is to possess a well defined, repetitive secondary structure, imparted by conformational restrictions of the monomeric unit. In this connection we described the preparation and the conformational analysis of pseudopeptides containing the 4-carboxy oxazolidin-2-one unit: these compounds contain a cyclic urethane moiety, so that by coupling it with a carboxylic acid derivative an imido-type function is obtained.1 This latter group is characterized by a nitrogen atom connected to an endocyclic and an exocyclic carbonyl which tend to adopt the trans conformation. As a consequence of this locally constrained disposition effect, these imide-type oligomers are forced to fold in an ordered conformation, that can lead, in the solid state to the formation of fibers or platelets.2

N

O

O

O

O

1 (a) C. Tomasini, G. Luppi, M. Monari, J. Am. Chem. Soc., 2006, 128, 2410-2420. (b) F. Bernardi, M. Garavelli, M.

Scatizzi, C. Tomasini, V. Trigari, M. Crisma, F. Formaggio, C. Peggion, C. Toniolo, Chem. Eur. J., 2002, 8, 2516-2525.

2 (a) G. Angelici, G. Falini, H.-J. Hofmann, D. Huster, M. Monari, C. Tomasini, Angew. Chem. Int. Ed., 2008, 47, 8075-8078; (b) G. Angelici, G. Falini, H.-J. Hofmann, D. Huster, M. Monari, C. Tomasini, Chem. Eur. J., 2009, 15, 8037-8048.





A FRESH PERSPECTIVE ON SUGAR AMINO ACIDS: STRUCTURE, DISORDER AND APPLICATION

Alison A. Edwards

Medway School of Pharmacy, Universities of Kent and Greenwich at Medway, Central Avenue, Chatham Maritime, Kent, ME4 4TB, United Kingdom

Sugar amino acids (SAAs) can be employed as highly functionalised stereodiverse molecular scaffolds and are commonly utilised in peptidomimetics, primarily as dipeptide isosteres.1,2 The homo-oligomers of SAAs, known as carbopeptoids, have been extensively studied for foldamer preference i.e. oligomers that can adopt compact conformations in relatively short sequences.3 There is significant interest in novel foldamer systems which can mimic the range of secondary structures exhibited by proteins and also adopt novel conformations. A wealth of knowledge exists regarding protein structure, however there are many biologically active proteins which are intrinsically disordered - where all or part of their secondary structure is undefined.4,5 The “Disprot” database highlights the large number of proteins which fall into this category.4

An ordered secondary structure can be described as either a regular structure (e.g. an -helix) or an irregular structure where a single conformation is adopted that has no regularity (e.g. a static loop). In contrast, disordered structures occur when either dynamic switching occurs between ordered structures or the backbone is flexible and able to adopt a continuum of conformations. When highly ordered compact structures are present in foldamers, structural interpretation is readily achieved via X-ray crystallography and NMR studies. However, when foldamers adopt irregular, dynamic, flexible or ordered but extended conformations then there is decreased likelihood of successful structural interpretation. This is where the application of electronic circular dichroism (CD) and vibrational techniques, such as VCD (vibrational CD) and ROA (Raman optical activity),5 come into their own.

The biological significance of disordered peptidomimetic foldamers6 will be discussed and the use of available methods to identify conformational preference. Key aspects to consider for the design, preparation and application of foldamer related systems will be discussed with appropriate examples from sugar amino acids, peptoids, -peptides and amino sugar derivatives.

1 Edwards, A. A. et al. J. Comb. Chem., 2004, 6, (2), 230-238. 2 Jensen, K. J.; Brask, J. Biopolymers, 2005, 80, (6), 747-761. 3 Hill, D. J. et al. Chem. Rev., 2001, 101, 3893-4011. 4 Vucetic, S. et al. Bioinformatics, 2005, 21, 137-140. 5 Zhu, F. J. et al. J.f Mol. Biol., 2006, 363, (1), 19-26. 6 Dunker, A. K. et al. Curr. Op. Struct. Biol., 2008, 18, (6), 756-764.




FROM SHEET-FORMING PEPTIDES TO POSITIVE COOPERATIVITY IN FOLDED ASYMMETRIC CATALYSTS

Martin D. Smith

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA UK.

[email protected]; http://msmith.chem.ox.ac.uk/

As part of an ongoing investigation into the conformational propensities of -peptides,1,2 we have generated a non-peptidic reverse-turn that populates a hairpin conformation in the solid state and in solution. Exploitation of the well-defined conformational preferences of this construct enabled the generation of sheet-like materials that populate hydrogen bond

stabilized conformations. Both solid state and solution data indicate significant C-H…O hydrogen bonding in these materials, which is consistent with the postulated structural role of this interaction in proteins.3

CF3

N

O

NR1

O

SH

H

N

N

H

R2

R3

H

H

QuickTime™ and a decompressor

are needed to see this picture.

R1= tBu, R2, R3 = Et

Ph

NBoc

H OTBS

OiPr

PhCO2

iPrNHBoc

48 h, – 40ÞC, toluene

>99% ee97% yield

0.1 mol% loading

N

O

H

N

O

HH

N3

CF3

O

N

O

H

N

O

H

N3H

HH

HHH

We considered whether this turn-forming construct could be used to develop folded materials that demonstrate positively cooperative ligand-receptor binding. This effect could be exploited in the development of more efficient asymmetric catalysts that operate by hydrogen bonding, leading to the development of new transformations through the discovery of more active catalysts with lower loading, shorter reaction times and wider substrate scope. In designing these new catalysts, we reasoned that by analogy with ligand-protein binding, a series of non-covalent interactions within the catalyst structure could: (i) direct folding toward population of an ensemble of structured conformations, preorganizing the catalyst and minimizing the entropic cost of transition state binding and (ii) result in stronger intramolecular non-covalent interactions and cooperative ligand binding and hence greater stabilization of charged intermediates and transition states.4

1 M. K. Qureshi and M. D. Smith, Chem. Commun., 2006, 5006.

2 A. Kothari, M. K. Qureshi, E. Beck and M. D. Smith, Chem. Commun., 2007, 2814.

3 C. R. Jones, M. K. N. Qureshi, F. R. Truscott, S.-T. D. Hsu, A. J. Morrison & M. D. Smith, Angew. Chem. Int. Ed., 2008, 47, 7099.

4 C. R. Jones, D. Pantos, A. J. Morrison & M. D. Smith, Angew. Chem. Int. Ed., 2009, in press; DOI: 10.1002/anie.200903063.




HELICALLY FOLDED CAPSULES BASED ON AROMATIC OLIGOAMIDE FOLDAMERS

Yann Ferrand

Institut Européen de Chimie Biologie - Université de Bordeaux 2, rue Robert Escarpit, 33607 Pessac, France

A major trend both in chemistry and modern biology is the development of technologies that widen the structural and functional diversity of folded biopolymers beyond naturally occurring patterns. Over the last ten years, foldamers – synthetic oligomers or polymers possessing well-defined, bio-inspired, folded conformations in solution – have fundamentally shifted our knowledge of biopolymer folding in showing that molecular backbones chemically remote from those that nature uses are also able to adopt folded secondary motifs such as helices, turns and linear strands. More recently artificial tertiary and quaternary foldamer motifs have also been produced. Interest in foldamer research stems from the fact that, if protein and other biopolymer structures may be mimicked, their functions may be mimicked as well and even further expanded, paving the way to countless applications.

NN

O

H

-

--

N

We have recently proposed a unique design of helically folded capsules based on sequences of aromatic amino-acids which code for a large helix hollow in the center and a narrow helix diameter at the end of the sequence (Figure above, right). Preliminary proof of concept has been made for small guests in non polar solvents (eg. butanediol or D/L tartaric acid).1

References:

1 Bao C., Kauffmann B., Gan Q., Srinivas K., Jiang H., Huc I. Angew. Chem. Int. Ed., 2008, 47, 4153.




DNA-BINDING POLYAMIDES IN NANOARCHITECTURES

Alexander Heckel

University of Frankfurt, Cluster of Excellence Macromolecular Complexes, Max-von-Laue-Str. 9, 60438 Frankfurt (M), Germany

Polyamides consisting of pyrrole and imidazole fold into a double-crescent hairpin motif and bind strongly and sequence-specifically to double stranded DNA.1 We use these minor groove binders as a structural element (“sequence-specific glue”) for DNA nano-architectures – providing a second well-defined interaction that is orthogonal to the Watson-Crick base pairing.

In a first approach two different DNA-binding polyamides were connected by a long, flexible linker to form a divalent “strut”.2 Each side of the strut could recruit and bind a specific DNA sequence (1). As a test system we chose two small DNA circles3 carrying the respective binding site. It could be shown that the strut was strong enough to hold the two DNA rings together.2,4

In another approach we covalently coupled a polyamide (“anchor”) to an oligonucleotide. We ligated this DNA-polyamide hybrid into a double-stranded DNA circle that also carries the binding site for the polyamide. These circles self-assemble and form stable homodimeric complexes (2) that were imaged by atomic force microscopy (3).5

1 Hsu, C. F.; Phillips, J. W.; Trauger, J. W.; Farkas, M. E.; Belitsky, J. M.; Heckel, A.; Olenyuk, B. Z.; Puckett, J. W.;

Wang, C. C. C.; Dervan, P. B. Tetrahedron, 2007, 63, 6146-6151. 2 Schmidt, T. L.; Nandi, C.; Rasched, G.; Parui, P. P.; Brutschy, B.; Famulok., M.; Heckel, A. Angew. Chem. Int. Ed.,

2007, 46, 4382-4384. 3 Rasched, G.; Ackermann, D.; Schmidt, T. L.; Broekmann, P.; Heckel, A.; Famulok, M. Angew. Chem. Int. Ed., 2008,

47, 967-970. 4 Nandi, C. K.; Parui, P. P.; Schmidt, T. L.; Heckel, A.; Brutschy, B. Anal. Bioanal. Chem., 2008, 390, 1595-1603. 5 Schmidt, T. L.; Heckel, A. small, 2009, 5, 1517-1520.


24 – 26th September 2009 Posters

Posters

POSTERS

Poster session in room 3 (ground floor) of the Academy House

Somogyi street 7

Posters can be placed from 25th September morning after Registration and should be removed at the latest

on 26th September after lunch.

25th September (Friday) 12:05-14:30 Poster session for all the WGs

P01 Andrew J. Wilson School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom and Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom; [email protected]

P02 Éva Szolnoki Institute of Pharmaceutical Chemistry, University of Szeged, H-6720, Eötvös u.6., Hungary; [email protected]

P03 Melinda Nonn Institute of Pharmaceutical Chemistry, University of Szeged, H-6720, Eötvös u.6., Hungary; [email protected]

P04 László Schönstein Institute of Pharmaceutical Chemistry, University of Szeged, H-6720, Eötvös u.6., Hungary; [email protected]

P05 Gabriella Benedek Institute of Pharmaceutical Chemistry, University of Szeged, H-6720, Eötvös u.6., Hungary; [email protected]

P06 Andrea Trabocchi Department of Organic Chemistry "Ugo Schiff", University of Florence, Polo Scientifico e Tecnologico, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Florence, Italy; [email protected]

P07 Esther Gorrea Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona; [email protected]

P08 Raquel Gutiérrez-Abad Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona; [email protected]










Posters 24 – 26th September 2009

Posters

P09 Yvonne A. Nagel Department of Chemistry, University of Basel, St. Johanns- Ring 19, 4056 Basel, Switzerland; [email protected]

P10 Zsolt Szakonyi Institute of Pharmaceutical Chemistry, University of Szeged, H-6720, Eötvös u.6., Hungary; [email protected]

P11 Gábor Tasnádi Institute of Pharmaceutical Chemistry, University of Szeged, H-6720, Eötvös u.6., Hungary; [email protected]

P12 István M. Mándity Institute of Pharmaceutical Chemistry, University of Szeged, H-6720, Eötvös u.6., Hungary; [email protected]

P13 Sophie Faure Laboratoire SEESIB (UMR 6504 - CNRS), Clermont Université, Université Blaise Pascal, 24 avenue des Landais, 63177 Aubière, France. [email protected]

P14 Anasztázia Hetényi Institute of Pharmaceutical Chemistry, University of Szeged, H-6720, Eötvös u.6., Hungary; [email protected]

P15 Brigitta Kazi Institute of Pharmaceutical Chemistry, University of Szeged, H-6720, Eötvös u.6., Hungary; [email protected]

P16 A. A. Edwards Medway School of Pharmacy, Universities of Kent and Greenwich at Medway, Central Avenue, Chatham Maritime, Kent, ME4 4TB, United Kingdom. [email protected]

P17 Jänis, Janne University of Joensuu, Department of Chemistry; [email protected]

P18 Caroline Evans Department of Chemistry, University of Bath, Bath, BA2 7AY, UK. [email protected]

P19 Zoltán Gáspári Eötvös Loránd University, Institute of Chemistry, Structural Chemistry and Biology Laboratory [email protected]

P20 Zoltán Gáspári Eötvös Loránd University, Institute of Chemistry, Structural Chemistry and Biology Laboratory [email protected]

P21 Petra Rovó Eötvös Loránd University, Institute of Chemistry, Structural Chemistry and Biology Laboratory [email protected]
















Posters P01

P01 AROMATIC OLIGOAMIDE INHIBITORS OF PROTEIN-PROTEIN INTERACTIONS

Fred Campbell,a Jeff P. Plante,a,b Bara Malkova,b B. Tom Burnley,b Thomas A. Edwards,b Stuart L. Warrinera,b and Andrew J. Wilsona,b

aSchool of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom bAstbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom [email protected]

Protein-protein interactions (PPIs) play a pivotal role in diseased states and there is a

pressing need for synthetic agents that selectively target these interfaces.1 What is not

clear is how to do this using a small molecule, given that it

must cover 800-1100 Å2 of a protein surface and complement

the discontinuous projection of hydrophobic and charged

domains over a flat or moderately convex surface.1

‘Proteomimetics’2 replicate the spatial projection of key binding

residues from a secondary structural motif important in the

target PPIs and thus represent a possible solution.

Foldamers3,4,5 because of their well-defined conformational

properties and projection of functional groups are ideal

scaffolds to act as proteomimetics. In this presentation we will

discuss our initial studies on the solid-phase syntheses of N-

alkylated aromatic oligoamides derived from p-aminobenzoic

acid (Figure 1). We will also present preliminary screening

results that show these compounds act -helix mimetics and

inhibit the p53-hDM2 protein-protein interaction – an important

ancer target.

c

1 44, 4130-4163. Yin, H.; Hamilton, A. D. Angew. Chem. Int. Ed., 2005, 2 J. Am. Chem Orner, B. P.; Ernst, J. T.; Hamilton, A. D.3

. Soc., 2001, 123, 5382-5383.

78. 6 Murray, J. K.; Gellman, S. H. Pept. Sci., 2007, 88, 657-686.

Gellman, S. H. Acc. Chem. Res., 1998, 31, 178-190. 4 Huc, I. Eur. J. Org. Chem., 2004, 17-29. 5 Li,, Z.-T.; Hou, J.-L.; Yi, H.-P. Chem. Asian J., 2006, 1, 766-7

N

CO2H

N

O

HN

O

R3

R2

R1

Figure 1. Tr imer ic Nalkylated aromat ic

oligoamide scaff olds




P02 Posters

P02 THE EFFECT OF BICYCLIC RESIDUE ON -PEPTIDE HELICAL SECONDARY STRUCTURES

Éva Szolnoki, Zsófia Hegedüs, Zsolt Szakonyi, Tamás A. Martinek, Ferenc Fülöp

Institute of Pharmaceutical Chemistry, University of Szeged, H-6720, Eötvös u.6., Hungary

β-Peptides with cyclic side-chains are able to form stable helical secondary structures.1 The five membered ring containing trans-ACPC and trans-APC residues have a strong nucleating effect for H12 helix.2

Recently we have reported a new monoterpene-derived, β-amino acid building block (2-amino-6,6-dimethyl-bicyclo[3.1.1]heptane-3-carboxylic acid; ABHC), the bicyclic analog of ACHC.3 Incorporation of this bulky residues with trans relative backbone configuration in the peptide chain, cause steric repulsions between the side-chains in position i-(i+3) and are able to form the H12 helix as well. β-peptide homooligomers containing up to five ABHC residues, unambiguously adopt stabile H12 helix.4

Our present aim was to determine the structure-induced effect of ABHC residues in the presence of open-chain β3-amino acid residues in the sequence.

For this purpose, oligomers contain-ing trans-ABHC and β3-homoserine with three different motifs were synthesized and structurally charac-terized. We concluded that numbers and positions of ABHC monomers play key role in formation of H12

helix. If the number of β3-homoserine is increased, its H14-stabilizing effect can be observed. This could be a novel approach to rationally design H12 helical foldamers.

1 J. J. Barchi, X. Huang, D. H. Appella, L A. Christianson, S. R. Durell, S. H. Gellman, J. Am. Chem. Soc., 2000, 122,

2711-2718. 2 F. Fülöp, T. A. Martinek, G. K. Tóth, Chem. Soc. Rev., 2006, 35, 323-334. 3 Z. Szakonyi, T. A. Martinek, R. Sillanpää, F. Fülöp, Tetrahedron: Asymmetry, 2008, 19, 2296-2303. 4 A. Hetényi, Z. Szakonyi, I. M. Mándity, É. Szolnoki, G. K. Tóth, T. A. Martinek, F. Fülöp, Chem. Commun., 2009,

177-179.

H2N COOH

H2N COOH

H2N COOH

H2N COOH



Posters P03

P03 REGIO- AND STEREOSELECTIVE 1,3-DIPOLAR CYCLOADDITION OF NITRILE OXIDES TO ETHYL cis- OR

trans-2-AMINOCYCLOPENT-3-ENECARBOXYLATES

Melinda Nonn, Loránd Kiss, Enikő Forró, Ferenc Fülöp

Institute of Pharmaceutical Chemistry, University of Szeged, H-6720, Eötvös u.6., Hungary

Alicyclic -amino acids have received significant interest in recent years because of their occurrence in many pharmacologically important compounds.1 Isoxazolines, are versatile intermediates for the synthesis of a variety of bioactive compounds.2 The 1,3-dipolar cycloaddition of nitrile oxides to alkenes is a widely used, efficient method for the synthesis of isoxazolines.3

NH

O COOEt

NHRN

O

R' R S

SR

(+/-)

COOEt

NHR

ON

R

S

R

R

R'

R = Boc, COPh; R' = Me, Et

COOEt

NHR

ON

R S

R

R'

SCOOEt

NHRN

O

R'

R

SS

R

Recently we have synthetized novel isoxazoline-fused cispentacin regio- and stereo-isomers by 1,3-dipolar cycloaddition of nitrile oxides to protected cis-2-aminocyclopent-3-ene carboxylates.4 Since the reactions were not selective the aim of this work was to execute a selective 1,3-dipolar cycloaddition to ethyl cis- or trans-2-aminocyclopent-3-enecarboxylates. The reactions were regio- and stereoselectively performed when the trans--amino esters were reacted with nitrile oxides generated from primary nitroalkanes with Boc2O, while the cis--amino esters were reacted with nitrile oxides generated from primary nitroalkanes with phenylisocyanate. The compounds were also prepared in enantiomerically pure form.

1 Kiss, L.; Forró, E.; Fülöp, F. Synthesis of carbocyclic amino acids. Amino Acids, Peptides and Proteins in Organic

Chemistry. Vol. 1, Ed. A. B. Hughes, Wiley, Weinheim, 2009, 367. 2 Kozikowski, A. P.; Tapadar, S.; Luchini, D. N.; Kim, K. H.; Billadeau, D. D. J. Med. Chem., 2008, 51, 4370. 3 Nair, V.; Suja, T. D. Tetrahedron, 2007, 63, 12247. 4 Kiss, L.; Nonn, M.; Forró, E.; Sillanpää, R.; Fülöp, F. Tetrahedron Lett., 2009, 50, 2605.



P04 Posters

P04 ENZYMATIC HYDROLYSIS OF HYDROXYLATED ALICYCLIC β-AMINO ESTERS

László Schönstein, Enikő Forró, Loránd Kiss, Ferenc Fülöp

Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös street 6, Hungary

Hydroxylated β-amino acids represent a valuable class of amino acids, because they are important key elements of many biologically relevant compounds. For example taxol and taxotere having a hydroxylated β-amino acid residue in their structure are effective clinically available chemotherapeutic agents for the treatment of cancer diseases1. Among the cyclic analogues several hydroxylated β-amino acid derivatives have antibiotic (e.g. oryzoxymycin2) or antifungal activities, and are building blocks for pharmaceutically impor-tant natural substances such as fortamine, chryscandin, pentopyranamine, gougerotin and blasticidin3. The cyclic, conformationally restricted β-amino acids have been reported as building blocks in the construction of novel peptides4. The hydroxylated β-amino acids might be interesting components for the synthesis of potential biologically active peptides having also a relevant contribution in their secondary structure.

Our aim in the present work was to develop an enzymatic route for the synthesis of enantiopure hydroxylated β-amino acids through enzyme-catalysed hydrolysis of racemic hydroxylated alicyclic β-amino esters. The earlier extensive investigations on enzymatic hydrolysis of alicyclic β-amino esters2 suggested the possibility of the lipase-catalysed enantioselective hydrolysis of β-amino esters (±)-1 - (±)-3 in an organic solvent. Extensive enzyme screening was performed for the hydrolysis of the model compound (±)-1 in diisopropyl ether, using water as nucleophile. We also analysed the effects of solvent, temperature and the different quantity of water added to the reaction mixture on the enantioselectivity and reaction rate.

NHBoc

COOEtHO EtOOC

BocHN

OH

NHBoc

COOHHOCAL-B

t-BuOMe60°C

(±)-1 4 5

NHBoc

COOEtHO

NHBoc

COOEtHO

NHBoc

HO

(±)-1 (±)-3(±)-2

H2O

COOEt

High enantioselectivity (E = 65) was observed when the CAL-B (Candida antarctica lipase B)-catalysed hydrolysis of (±)-1 was performed with H2O (0.5 equiv.) in t-BuOMe at 60 °C. The produced -amino acid 4 (ee = 85%) and unreacted -amino ester 5 (ee = 92%) could be easily separated, through an organic solvent-water extraction.

1 D. G. I. Kingston, D. J. Newman, Curr. Opin. Drug Disc. Dev., 2007, 10, 130. 2 E. Forró, F. Fülöp, Chem. Eur. J., 2007, 13, 6397. 3 L. Kiss, E. Forró, F. Fülöp, Synthesis of carbocyclic β-amino acids. Amino Acids, Peptides and Proteins in Organic

Chemistry. Vol. 1, Ed. A.. B. Hughes, Wiley, Weinheim, 2009, 367. 4 F. Fülöp, T. A. Martinek, G. K. Tóth, Chem. Soc. Rev., 2006, 35, 323-334.



Posters P05

P05 EFFICIENT SYNTHESES OF HYDROXY-SUBSTITUTED -AMINOCYCLOHEXANECARBOXYLIC ACIDS

Gabriella Benedek, Márta Palkó, Edit Wéber, Tamás A. Martinek, Enikő Forró, Ferenc Fülöp

Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6., Hungary

β-Amino acids and their derivatives are found in a large number of natural products. Some representatives (e.g. cispentacin) exhibit antifungal activity.1 The hydroxy-functionalized β-amino acids play an important role in medicinal chemistry because of their occurrence in many biologically relevant compounds.2

Our present aim was to prepare new dihydroxy-substituted β-amino acids with a cylcohexane skeleton by diastereoselective dihydroxylation, starting from β-lactams 1,4, via aminocarboxylates 2a,b and 5a,b, both in racemic and enantiopure form.

NH

O

NH

O

COOEt

NHBoc

COOH

NH2

COOEt

NHBoc

COOH

NH2

HO

HO

HO

OH

1 2a: cis2b: trans

3a: 1S,2R,4R,5S3b: 1R,2R,4R,5S

4 5a: cis5b: trans

6a: 1R,2R,3S,4R6b: 1S,2R,3S,4R

Oxidation of N-Boc-protected esters 2a,b and 5a,b with a catalytic amount of OsO4 and 4-methylmorpholine N-oxide as the stoichiometric co-oxidant,3 selectively afforded N-Boc protected dihydroxy esters, as single diastereomers in good yields. Subsequent hydrolysis by microwave irradiation in H2O at 150 °C for 1 h resulted in (1S,2R,4R,5S)- and (1R,2R,4R,5S)-2-amino-4,5-dihydroxycyclohexanecarboxylic acids (3a,b) and (1R,2R,3S,4R)- and (1S,2R,3S,4R)-2-amino-3,4-dihydroxy-cyclohexanecarboxylic acids (6a,b).4

1 Fülöp F., Chem. Rev., 2001, 101, 2181. 2 Palkó M.; Kiss L.; Fülöp F. Curr. Med. Chem., 2005, 12, 3063. 3 Benedek, G.; Palkó, M.; Wéber, E.; Martinek, T. A.; Forró, E.; Fülöp, F. Eur. J. Org. Chem., 2008, 3724. 4 Wang, G.; Li, C.; Li, J.; Jia, X. Tetrahedron Lett., 2009, 50, 1438.



P06 Posters

P06 MORPHOLINE-BASED SCAFFOLDS FOR THE GENERATION OF REVERSE-TURN MIMETICS

Andrea Trabocchi, Antonio Guarna

Department of Organic Chemistry "Ugo Schiff", University of Florence, Polo Scientifico e Tecnologico, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Florence, Italy

Morpholine-based turn mimetics

-Turns play a crucial role in proteins and bioactive peptides due to their ability to induce folding and generate compact structures, and they are often involved in molecular recog-nition processes. Also, -turn structures have been recently proposed as effective organo-catalysts in a variety of transformations, suggesting the development of turn mimetics as an opportunity for advances in catalysis and organic synthesis. Many turn mimetics have been developed so far, consisting in the replacement of the i+1-i+2 central dipeptidic sequence of the turn and able to preserve the intramolecularly hydrogen-bonded ten-membered pseudo-cycle. Also, a strong interest is focused on proline-mimetics, as among the naturally occurring amino acids proline is often observed at the i+1 position of -turn structures, generating a trans amide bond with the preceding amino acid at position i.

During last years we have been developing new bicyclic scaffolds containing the mor-pholine ring from the combination of amino acid and carbohydrate derivatives,1 which have been used as mimetics of the central dipeptidic sequence of a common beta-turn. Also, we recently reported a new method for the synthesis of enantiopure Fmoc-protected mor-pholine-3-carboxylic acid from dimethoxyacetaldehyde and serine methyl ester through a short and practical synthetic route,2 and the conformational analysis of peptides containing morpholine-3-carboxylic acid (Mor) as an unexplored proline surrogate.3 Herein is presented an overview of diverse scaffolds containing the morpholine nucleus as reverse turn promoters, and their conformational analysis by NMR and molecular modeling.

1 A. Trabocchi, G. Menchi, F. Guarna, F. Machetti, D. Scarpi, A. Guarna, Synlett, 2006, 331–353. 2 F. Sladojevich, A. Trabocchi and A. Guarna, J. Org. Chem., 2007, 72, 4254–4257. 3 A. Trabocchi, F. Sladojevich and A. Guarna, Chirality, 2009, 21, 584–594.



Posters P07

P07 SELF-ASSEMBLING OF A BICYCLIC AND CHIRAL UREA: A COMBINED EXPERIMENTAL AND COMPUTATIONAL

STUDY

Esther Gorrea, Eric Da Silva, Vicenç Branchadell, Rosa M. Ortuño

Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain, email: [email protected]

The bicyclic and chiral urea 1, recently synthesized in our laboratory, presents a high tendency to self-assemble.

N

HN

O

OO

1

The X-Ray structural analysis of this species in the solid state shows a hydrogen-bonding network where each one of the molecules are involved in the formation of two hydrogen bonds.

On the other hand, NMR and IR spectra show the presence of intermolecular aggregation in solution. The formation of these aggregates has been theoretically studied through DFT calculations. The results show that at least three molecules are necessary to obtain an aggregation pattern similar to that observed in the solid state.

.

X-Ray diffraction DFT calculations



P08 Posters

P08 NEW CHIRAL MULTIFUNCTIONAL CYCLOBUTANE DENDRIMERS

Raquel Gutiérrez-Abad, Ona Illa, Rosa M. Ortuño*

Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain, email: [email protected]

Dendrimers are highly-branched molecular (nano)architectures of well defined size and number of terminal groups. These molecules have potential applications as biomaterials, drugs or hosts.

In the present work, new chiral multifunctional cyclobutane dendrimers have been synthesized through a convergent approach. This synthetic methodology, which consists in the attachment of pre-synthesized dendrons to the core, leads to dendrimers of monodisperse molecular weight which are easier to purify.

In our laboratory 1,3,5-trisubstituted benzenes have been used as cores, whereas a multifunctional cyclobutane γ,ε-aminoacid has been used as a dendron. According to the type of the core’s substituting group three different kinds of dendrimers have been obtained:

NH

NH

OHN

O O

O

OMeH

H

O

MeO

H

H

O OMe

OtBuO

tBuO

O OOtBu

H H

N-centered amides C=O-centered amides

Ureas

Structural properties of these molecules are under study.1

1 Aguilera, J.; Gutierrez-Abad, R.; Mor, A.; Moglioni, A. G.; Moltrasio, G. Y.; Ortuño, R.M. Tetrahedron: Asymmetry,

2008, 19, 2864-2869.



Posters P09

P09 CELL PENETRATING PROPERTIES AND CONFORMATIONAL ANALYSIS OF FUNCTIONALISED

OLIGOPROLINES

Yvonne A. Nagel and Helma Wennemers*

Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland

Our interest in oligoprolines as well-defined molecular scaffolds1 led us to explore the ability of appropriately functionalised oligoprolines to translocate through cell membranes. Towards this goal fluorescein labelled amphiphilic oligoprolines were prepared that bear guanidinium and amino groups in every first and third position.2 Compounds with different chain length as well as different charge densities were prepared and compared to reference oligopeptides without defined helical structure. Thus, the influence of the primary structure as well as the secondary structure, determined by CD spectroscopy, on cellular uptake were investigated. Different concentrations and incubation times on live non-fixed HeLa cells were analysed by confocal microscopy. To gain information about the location of delivery, a counter staining was carried out with Hoechst 33342. To quantify the cell penetrating properties FACS experiments were performed and the toxicity of the oligoproline derivatives was evaluated by MTT assays.

N N N

O O O

NH2

O

n = 2, 3, 4

NH

O

OH

COOH

O

O

NH

NH2H2N

NH

NH2H2N

CF3CO2 CF3CO2

1 a) M. Kümin, L.-S. Sonntag, H. Wennemers, J. Am. Chem. Soc., 2007, 129, 566-567; b) L.-S. Sonntag, S.

Schweizer, C. Ochsenfeld, H. Wennemers, J. Am. Chem. Soc., 2006, 128, 14697-14703. 2 For other related CPPs see: a) I. Geisler, J. Chmielewski, Chem. Biol. Drug. Des., 2009, 73, 39-45; b) B. A. Smith,

D. S. Daniels, A. E. Coplin, G. E. Jordan, L. M. McGregor, A. Schepartz, J. Am. Chem. Soc., 2008, 130, 2948-2949.



P10 Posters

P10 STEREOSELECTIVE SYNTHESIS AND TRANSFORMATIONS OF THE ENANTIOMERS OF

APOPINENE-BASED -AMINO ACIDS

Zsolt Szakonyi1, Reijo Sillanpää2, Ferenc Fülöp1 1Institute of Pharmaceutical Chemistry, University of Szeged,

H-6720 Szeged, Eötvös utca 6, Hungary; 2Department of Chemistry, University of Jyväskylä, POB 35, 40351 Jyväskylä, Finland

In the recent years, both racemic and enantiopure -amino acids have proved to be excellent building blocks in the synthesis of 1,3-heterocycles, -peptide oligomers and chiral catalysts.1 Our former results revealed that a tertiary carbon next to the amino group on monoterpene skelet decreased the reactivities of the synthons relative to those containing a secondary carbon next to the functional groups.

Our present aim was the preparation and some transformations of a new family of monoterpene-based chiral -lactams and -amino acid derivatives derived from (-)- and (+)-apopinene, in order to eliminate the disadvantageous steric effect of the 2-methyl substituent on the pinane ring system.

(-)- and (+)-apopinene was synthetized from commercially available (-)-myrtenal and (+)--pinene. Chlorosulfonyl isocyanate addition to apopinene furnished monoterpene-fused -lactams in highly regio- and stereospecific reactions.2

NH2 . HCl

COOR

R = H, Me, Et; X = O, S; R1, R2 = H, OMe, Cl; R3 = Et, Pr, tBu, Ph; R4 = tBu, CH2Ph

NH2 . HCl

COOR

NH

O1 2 3 4

HN

COOEt

HN

X

R1

R2N

O

R3

O

HN

R4

R = H

NHFmoc

COOH7 6 5

-Lactam 2 were easily converted to the -amino acid and its protected derivatives 3-5. The base-catalyzed isomerization of the cis-amino ester afforded the corresponding trans-amino acid enantiomers. -Amino esters 3 and 4 were transformed to urea and thiourea derivatives possessing remarkable MDR reversing effect.2

(1R,2R,3S,4R)-Amino acid 3 was reacted with aldehydes and isocyanides under different connditions to prepare enantiomeric -lactams via U-4C-3CRs with high diastereoselec-tivities.3

1 F. Fülöp, T.A. Martinek, G.K. Tóth, Chem. Soc. Rev., 2006, 35, 323-334, and references cited therein 2 Z. Szakonyi, F. Fülöp, PCT: WO 2008/059299 A1. 3 Z. Szakonyi, R. Sillanpää, F. Fülöp, Mol. Div., 2009, DOI 10.1007/s11030-009-9143-y.



Posters P11

P11 AN IMPROVED ENZYMATIC METHOD FOR THE PREPARATION OF VALUABLE β-ARYLALKYL--AMINO

ACID ENANTIOMERS

Gábor Tasnádi, Enikő Forró, Ferenc Fülöp

Institute of Pharmaceutical Chemistry, University of Szeged, 6720 Szeged, Eötvös u. 6., Hungary

Due to their well-documented significance, β-amino acids are currently at the focus of pharmaceutical research.1 Recently, we developed an efficient enzymatic pathway for the preparation of β-amino acid enantiomers through the lipase-catalysed ring-opening of carbocyclic2a and 4-aryl-substituted β-lactams.2b Then, we extended that method to 4-arylalkyl-substituted β-lactams, but low enantioselectivities (E ≤ 12) were observed, and gram-scale resolutions were performed in two steps, which caused low yields (≤ 36%).3 Later, we published the highly selective (E > 100) lipase-catalysed hydrolysis of carboxyclic β-amino esters,4a which method was successfully extended to β-aryl-4b and β-heteroaryl4c-β-amino esters.

Here, we report the lipase-catalysed hydrolysis of β-arylalkyl-β-amino esters (±)-1 - (±)-3 in an organic media. This method proved to be more suitable for the preparation β-arylalkyl-β-amino acid enantiomers than that for the ring-opening of the corresponding lactams.3 Moreover, compound 3b, the building block of the new antidiabetic drug JANUVIATM, was for the first time prepared in an enzymatic way according to the best of our knowledge.

n NH2

COOEt

(±)-1, n = 1, R1 = R2 = R3 = H

(±)-2, n = 2, R1 = R2 = R3 = H

(±)-3, n = 1, R1 = R2 = R3 = F

R1

R2

R3

n NH2

COOEt

R1

R2

R3

nH2N

HOOC

R1

R2

R3

+

1a, 2a, 3a 1b, 2b, 3b

t-BuOMe or i-Pr2OS R

H2Olipase PS IM

45 °C

High enantioselectivities (E ~ 200) were observed when the hydrolyses were performed in t-BuOMe or in i-Pr2O at 45 °C using lipase PS IM (Burkholderia cepacia) as a catalyst with 0.5 equiv. of H2O. Products could be easily separated and were isolated in good enantiomeric excesses (≥ 96%) and yields (≥ 42%).

1 (a) F. Fülöp, Chem. Rev., 2001, 101, 2181-2204; (b) F. Fülöp, T. A. Martinek, G. K. Tóth, Chem. Soc. Rev., 2006, 35, 323-

334. 2 (a) E. Forró, F. Fülöp, Org. Lett., 2003, 5, 1209-1212; (b) E. Forró, T. Paál, G. Tasnádi, F. Fülöp, Adv. Synth. Catal., 2006,

348, 917-923. 3 G. Tasnádi, E. Forró, F. Fülöp, Tetrahedron: Asymmetry, 2007, 18, 2841-2844. 4 (a) E. Forró, F. Fülöp, Chem. Eur. J., 2007, 13, 6397-6401; (b) G. Tasnádi, E. Forró, F. Fülöp, Tetrahedron: Asymmetry,

2008, 19, 2072-2077; (c) G. Tasnádi, E. Forró, F. Fülöp, Tetrahedron: Asymmetry, 2009, 20, 1771-1777.



P12 Posters

P12 EFFECTS OF SIDE-CHAIN TOPOLOGY AND ENTROPY ON THE SELF-ORGANIZATION OF β-PEPTIDES

István M. Mándity1, Lívia Fülöp2, Elemér Vass3, Gábor K. Tóth2, Tamás A. Martinek1, Ferenc Fülöp1

1Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged,Eötvös u. 6, Hungary

2Department of Medical Chemistry, University of Szeged, H-6720 Szeged,Dóm t. 8, Hungary

3Institute of Chemistry, Department of Organic Chemistry, Eötvös Loránd University, H-1117 Budapest, Pázmány P. s. 1/A, Hungary

The -peptide foldamers are among the most interesting models of the artificial polymers. The importance of -peptides in chemistry and biology is warranted by the fact that they have important biological applications.1 Relationship has been established between the backbone chirality pattern and the prevailing secondary structure,2 which underlines the role of stereochemical control in the β-peptide foldamer design.3 Important challenges are to investigate (i) the effect of the side-chain topology on the secondary structure and (ii) the effect of the entropic behaviour of the side-chain on the association property of foldamers.

In this work, β-peptides have been constructed with alternating backbone configuration having cyclohexene, cyclohexane and norbornene side chains (Fig. 1). The cyclohexene

and cyclohexane based foldamers form the known H10/12 helix, but the peptide with norbornene side-chains exhibits an interesting unprecedented circular secondary structure. Furthermore, the peptides with conformationally rigid cyclohexane and norbornene side-chains form vesicule-like nanostructure. We concluded that the residual side-chain flexibility is major factor in inhibition of the self-association due to entropic reasons.

1 C. M. Goodman, S. Choi, S. Shandler, W. F. DeGrado, Nat. Chem. Biol., 2007, 3, 252-262. 2 T. A. Martinek, I. M. Mándity, L. Fülöp, G. K.; Tóth, E. Vass, M. Hollósi, E. Forró, F. Fülöp, J. Am. Chem. Soc.,

2006, 128, 13539-13544. 3 I. M. Mándity, E. Wéber, T. A. Martinek, G. Olajos, G. K. Tóth, E. Vass, F. Fülöp, Angew. Chem. Int. Ed., 2009, 48, 2171-2175.

NHO

NH

n

NHO

NHHN

n

O

NHO

NHHN

n

NHO

NHHN

n

Nanostructure Secondary structure

NHO

NH

n

NHO

NHHN

n

O

NHO

NHHN

n

NHO

NHHN

n

Nanostructure Secondary structure

Figure 1. Models studied and their self organization propensities



Posters P13

P13 -PEPTIDES AND NOVEL “HYBRID” ,β-PEPTOIDS: SCAFFOLDS FOR MULTIVALENT LIGAND DISPLAY

M. Barra,a T. Hjelmgaard,a C. Caumes,a E. De Santis,b A. A. Edwards,b O. Roy,a S. Faure,a C. Taillefumiera

a Laboratoire SEESIB (UMR 6504 - CNRS), Clermont Université, Université Blaise Pascal, 24 avenue des Landais, 63177 Aubière, France.

b Medway School of Pharmacy, Universities of Kent and Greenwich at Medway, Central Avenue, Chatham Maritime, Kent, ME4 4TB, United Kingdom.

Polyvalent protein-carbohydrate interactions play an essential role in numerous biological events. Therefore, the design of multivalent compounds that bind to a multivalent target has become a new focus of interest in the last decade.1 The more common approach is the attachment of a large number of monovalent sugar ligands (identical or different) onto a selected scaffold (polymers, oligomers, dendrimers or membranes). The latter should fulfil several criteria: ease of synthesis, bioavailability and absence of toxicity. Moreover, the flexibility, size, and shape of the scaffold may contribute to binding.

In our ongoing research, we seek to develop novel well defined and organized peptidomimetic platforms2 for presentation of bioactive carbohydrate ligands that evade peptide disadvantages such as a short half-life, rapid metabolism, immunogenicity and poor bioavailability. Herein, we present the synthesis and conformational studies of -peptides (which are known for their folding propensities) and novel “hybrid” ,-peptoids3 conveniently functionalized for rapid anchoring of carbohydrates.

-Peptide plateforms

O

Sugar

O

RHN NH

NH

CO2R'

O

O

SugarO

Sugar

RHN NH

NH

CO2R'

O OR'' R'' R''

n = 0,2,4

Asparticacid

n = 0,2,4

Sugar = Tn (GalNAc), mannose

Click chemistry

Conformational studies: NMR, CD, IR

Peptide coupling

Novel “hybrid” ,-peptoids

O

NN

n = 1-5

R''

R'

O

R' and R'' = (S)--Methylbenzyl, (CH)2OBn, (CH)2OH, CH2C CH

OtBu

OIterative solution-phase synthesis

Conformational studies: NMR, CD

1 Mammen, M.; Choi, S.-K.; Whitesides, G. M., Angew. Chem. Int. Ed., 1998, 37, 2754-2794. 2 Roy, O; Faure, S.; Thery, V.; Didierjean, C.; Taillefumier, C. Org. Lett., 2008, 10, 921-924. 3 Hjelmgaard, T.; Faure, S.; Caumes, C.; De Santis, E.; Edwards, A. A.; Taillefumier C., Org. Lett., 2009, ASAP.



P14 Posters

P14 EFFECT OF AZAPEPTIDE BUILDING BLOCKS: STABLE PEPTIDE FOLDAMERS IN WATER

Anasztázia Hetényi,a, b Gábor K. Tóth,b Csaba Somlai,b Elemér Vass,cTamás A. Martinek,a Ferenc Fülöpa

aInstitute of Pharmaceutical Chemistry and bDepartment of Medical Chemistry, University of Szeged, Szeged, Hungary, cInstitute of Chemistry, Eötvös Loránd University,

Budapest, Hungary

Foldamers stabilized by long-range H-bonding interactions constitute a thoroughly studied class of materials mimicking proteins and are currently attracting considerable interest.1 There are two major approaches to the modification of natural α-amino acid building blocks. First, homologation of the amino acid residues, which results in aliphatic (β- and γ-peptides)2 and aromatic oligoamide foldamers.3 Second, replacement of the amide moiety with functional groups capable of forming a strong H-bonding network leads to intriguing foldameric oligoureas4 and azapeptides.5

Because of the promising biomedical applications, the stabilization of foldamers in aqueous medium is a great current challenge and various methods have been proposed.6 All these approaches utilize either the side-chains or the chain termination to attain an energetically favourable construction, which increases the stability in the H-bond-destroying water.

Azapeptide residues potentially offer stronger H-bonding networks in the backbone, and they can therefore serve as secondary structure-stabilizing building blocks. NMR, VCD, ECD and molecular modelling results revealed that the incorporation of the 1-aminoproline (aza-ACPC) monomers into the β-peptide chains leads to well-defined secondary structures, including H12 and H10/12 helices, which are well soluble and exceptionally stable in water.

1 P. Le Grel, G.Guichard, in Foldamers: Structure, properties and applications: foldamers based on remote

intrastrand interactions. Eds: S. Hecht, I. Huc), Wiley-VCH, 2007, pp 35–74. 2 D. Seebach, D. F. Hook, A. Glattli, Biopolymers, 2006, 84, 23–37. 3 C. Li, G. T. Wang, H. P. Yi, X. K. Jiang, Z. T. Li, R. X. Wang, Org. Lett., 2007, 9, 1797–1800. 4 A. Violette, M. C. Averlant–Petit, V. Semetey, C. Hemmerlin, R. Casimir, R. Graff, M. Marraud, J. P. Briand, D.

Rognan, G. Guichard, J. Am. Chem. Soc., 2005, 127, 2156–2164. 5 P. Le Grel, A. Salaun, M. Potel, B. Le Grel, F. Lassagne, J. Org. Chem., 2006, 71, 5638–5645. 6 a) J. A. Kritzer, J. Tirado–Rives, S. A. Hart, J. D. Lear, W. L. Jorgensen, A. Schepartz, J. Am. Chem. Soc., 2005,

127, 167–178; b) M. Rueping, Y. R. Mahajan, B. Jaun, D. Seebach, Chem. Eur. J., 2004, 10, 1607–1615; c) R. P. Cheng, W. F. DeGrado, J. Am. Chem. Soc., 2002, 124, 11564–11565.



Posters P15

P15 SYNTHESIS OF ORTHOGONALLY PROTECTED PIPERIDINE AND AZEPANE -AMINO ESTER

ENANTIOMERS

Brigitta Kazi, Loránd Kiss, Enikő Forró, Ferenc Fülöp

Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6., Hungary

As a consequence of their biological effects, the conformationally constrained alicyclic β-amino acids have generated great interest among chemists and biochemists. These compounds are found in many natural products, β-lactams or antibiotics. 1

The incorporation of conformationally restricted β-amino acids into biologically active peptides has aroused considerable interest in the preparation of peptide-based drug molecules.2 β-Amino acids containing a heteroring have also received significant attention as a result of their biological potential.3 One of the largest groups involves heterocyclic β-amino acid derivatives with one N-atom in the ring.

Our aim was to develop a route for the synthesis of the diastereomers of six- and seven-membered β-aminocarboxylates with an N-atom in the ring.4

COOEt

NHBoc

COOEt

NHBoc

HO

HOBnN

COOEt

NHBoc

COOEt

NHBoc

HO

HO

COOEt

NHBoc

BnNCOOEt

NHBoc

BnNCOOEt

NHBoc

nn n

cis 1a 2atrans 1b

cis 3a 4atrans 3b

cis 5a 6atrans 5b 6b

n=1: 1,3,5n=2: 2,4,6

7 8 9 10

The synthetic approach was based on dihydroxylation of the olefinic bond, followed by oxidative ring cleavage and ring closure by reductive cyclization. OsO4-mediated dihydroxylation resulted in cis-functionalized dihydroxy -amino esters. The diol derivatives were oxidized with NaIO4, and the resulting dialdehyde was subjected to reductive ring closure with benzylamine in the presence of NaCNBH3, which furnished the desired heterocyclic -amino esters.

1 Kiss, L.; Forró, E.; Fülöp, F. Synthesis of carbocyclic β-amino acids. Amino Acids, Peptides and Proteins in

Organic Chemistry. Vol. 1, Ed. A. B. Hughes, Wiley, Weinheim, 2009, 367. 2 a) Fülöp, F.; Martinek, T. A.; Tóth, G. K., Chem. Soc. Rev., 2006, 35, 323; b) Mándity, I. M.; Wéber, E.;

Martinek, T. A.; Olajos, G.; Tóth, G. K.; Vass, E.; Fülöp, F., Angew. Chem. Int. Ed., 2009, 48, 2171. 3 a) Porter, E. A.; Weisblum, B.; Gellman, S. H., J. Am. Chem. Soc., 2005, 127, 11516.; b) Simpson, G. L.;

Gordon, A. H.; Lindsay, D. M.; Promsawan, N.; Crump, M. P.; Mulholland, K.; Hayter, B. R.; Gallagher, T. J. Am. Chem. Soc., 2006, 128, 10638; c) Caputo, F.; Cattaneo, C.; Clerici, F.; Gelmi, M. L.; Pellegrino, S. J. Org. Chem., 2006, 71, 8467.

4 Kiss, L.; Kazi, B.; Forró, E.; Fülöp, F., Tetrahedron Lett., 2008, 49, 339.



P16 Posters

P16 CIRCULAR DICHROISM INVESTIGATION OF NOVEL “HYBRID” -PEPTOIDS

E. De Santis,a T. Hjelmgaard,b S. Faure,b C. Caumes,b C. Taillefumier,b A. A. Edwardsa a Medway School of Pharmacy, Universities of Kent and Greenwich at Medway,

Central Avenue, Chatham Maritime, Kent, ME4 4TB, United Kingdom. b Laboratoire de Synthèse et Etude de Systèmes d’Intérêt Biologique (UMR 6504 - CNRS),

Université Blaise-Pascal, Clermont-Ferrand II, Aubière, France

The spatial conformation of proteins and peptides plays an important role in their biological activity. The three-dimensional arrangement of the proteinogenic side chains and backbone is necessary for the appropriate display of pharmacophores and/or highly specific ligand-receptor binding. The ability of proteins to fold into a unique, stable, active conformation has promoted interest in the development of peptidomimetic backbones that resemble active conformations and offer therapeutic advantages, such as increased specificity and higher bioavailability.

Herein we present a circular dichroism (CD) investigation of novel “hybrid” α,β-peptoids1 to be used as pepidomimetic scaffolds to display bioactive carbohydrate ligands (Fig 1a). CD is an invaluable tool to assist the conformational analysis of these systems, due to complexity in the NMR arising from cis/trans isomerism and absence of X-ray crystallo-graphic data. The novel “hybrid” α,β-peptoid backbone exhibited two characteristic conformations. The CD spectra of the linear oligomers are consistent with a helical conformation.2,3 The cyclic oligomers showed a more planar conformation,4 which is more pronounced in cycles with an even number of repeating units. Analysis of families with different sequence patterns and different terminal protecting groups will give further insight into their conformational preference and the contribution of protecting groups to the observed conformation(s) (Fig 1b).

(a)

(b)

R-(αb-βp-αb-βp)-R’

R-(αOH-βp-αOH-βp)-R’

R-(αp-βp-αp-βp)-R’

Figure 1: (a) CD spectra of linear and cyclic α,β-peptoid octamers in MeCN (b) Different sequence patterns investigated3

1 Hjelmgaard, T.; Faure, S.; Caumes, C.; De Santis, E.; Edwards, A. A.; Taillefumier, C., Org. Lett., 2009, DOI:

10.1021/ol9015767. 2 Norgren, A. S.; Zhang, S. D.; Arvidsson, P. I., Org. Lett., 2006, 8, 4533-4536. 3 Wu, C. W.; Sanborn, T. J.; Zuckermann, R. N.; Barron, A. E., J. Am. Chem. Soc., 2001, 123, 2958-2963. 4 Huang, K.; Wu, C. W.; Sanborn, T. J.; Patch, J. A.; Kirshenbaum, K.; Zuckermann, R. N.; Barron, A. E.;

Radhakrishnan, I., ., J. Am. Chem. Soc., 2006, 128, 1733-1738.



Posters P17

P17 REDOX-DEPENDENT DISULFIDE FORMATION IN SAP30L CO-REPRESSOR PROTEIN STUDIED BY ESI FT-ICR MASS

SPECTROMETRY

Laitaoja, Mikko1; Jänis, Janne1; Viiri, Keijo2; Valjakka, Jarkko2; Lohi, Olli2; Permi, Perttu3; Pihjalamaa, Tero3; Vainiotalo, Pirjo1

1University of Joensuu, Department of Chemistry; 2University of Tampere, Institute of Medical Technology; 3University of Helsinki, Institute of Biotechnology

Introduction

Sin3a is a scaffold protein in a co-repressor complex that carries out histone deactylation, an important factor in transcriptional repression. Sin3a-associated protein SAP30L mediates DNA, protein and phospholipid binding of the complex and contains a novel N-terminal Cys3His-type (Cys29, Cys38, Cys74 & His77) zinc finger (ZnF) structure. ZnF motifs are known to be redox-active, playing an important role in signal transduction. We have characterized a redox-dependent disulfide formation in SAP30L by ultrahigh-resolution ESI FT-ICR mass spectrometry.

Methods

Recombinantly produced N-terminal ZnF motif (residues 25-92) of SAP30L was used. Mass spectrometry was performed with a Bruker APEX-Qe 4.7-T hybrid quadrupole–FT-ICR mass spectrometer. In-solution digestion was performed with trypsin and on-line digestion with a technique based on immobilized pepsin.

Results

In denaturing solution conditions (CH3CN/water) or upon chelation of Zn with 1,10-fenantroline SAP30L appeared as a reduced apo-form without bound Zn2+ cation. In non-denaturing solution conditions (10 mM NH4OAc pH 6.9) SAP30L bound one Zn2+ cation (holo-form) with a considerable change in a charge state distribution (CSD) towards lower charge states, indicating a folded polypeptide structure. A treatment with H2O2 resulted in the loss of zinc and a concomitant formation of two disulfide bridges, with CSD identical to that of the holo-form suggesting a native-like protein structure. The oxidized form of SAP30L was digested followed by electron capture dissociation (ECD) tandem mass spectrometry of the resulting peptides. The results unambiguously indicated disulfides between adjacent Cys29 and Cys30 as well as Cys38 and Cys74. Our results suggest that SAP30L contains a novel ZnF motif in which a non-coordinating Cys30 residue can participate in the redox-regulation of the protein. We are currently examining how different redox-states of SAP30L affect the DNA and phospholipid binding of the protein.



P18 Posters

P18 INTRAMOLECULAR ENOLATE-IMINE CYCLISATION REACTIONS FOR THE SYNTHESIS OF β-AMINO ACIDS

Caroline Evans, Steven D. Bull

Department of Chemistry, University of Bath, Bath, BA2 7AY, UK.

A novel methodology to enable the stereoselective synthesis of a range of β-amino acids will be reported.

Stereoselective 5-exo-trig and 6-exo-trig ring closure reactions, via an intramolecular nucleophilic attack of ester enolates onto chiral imines,1 result in the formation bicyclic β-lactam substrates with high levels of diastereoselectivity. The -lactams can then be hydrolysed to form the corresponding -amino acid.2

The effect of different chiral auxiliaries upon the diastereoselectivity of the β-lactam formation will be described.

1 Koutsaplis, M.; Andrews, P. C.; Bull, S. D.; Duggan, P. J.; Fraser, B. H.; Jensen, P., Chem. Commun., 2007, 3580-

3582. 2 Forro, E.; Fulop, F., Chem. Eur. J., 2006, 12, 2587-2592.



Posters P19

P19 WHEN A RANDOM COIL IS COILED: CRITICAL EVALUATION OF COILED-COIL VS.

DISORDERED CROSS-PREDICTIONS

Balázs Szappanos1, László Nyitray2, András Perczel1,3, Zoltán Gáspári1

1Eötvös Loránd University, Institute of Chemistry, Structural Chemistry and Biology Laboratory

2Eötvös Loránd University, Department of Biochemistry 3ELTE-MHAS Protein Modeling Research Group

Prediction of protein structural features from sequence data is a key point in biomolecular modelling and functional assessment. Whereas prediction of secondary structure is reaching an accuracy comparable to that of recognizing it from 3D coordinates, analysis of so-called low-complexity regions – including repeated motifs or segments with biased amino acid composition – often requires expert use of specialist bioinformatic tools. In this paper we focus on two major manifestations of such regions, namely, coiled-coil and disordered segments, both considered as highly abundant motifs in eukaryotic proteomes. Coiled-coils are superhelices formed by typically two or more rarely more α-helices while disordered parts of proteins lack well-defined three dimensional structure due to their dynamic behaviour typically attributed to shorter peptides. Although these two structures are clearly distinguishable in a given protein structure and have different sequence-specific signatures in principle, due to the many conceptually different algorithms used for their detection, they might be erroneously recognized from sequences in practice. Moreover, classifying a coiled-coil protein segment as disordered might not even be considered as erroneous as one might argue that the segment is not folded without its partner(s). To characterize such discrepancies in detail, we tested several widely-used coiled-coil and disorder prediction programs on different databases to determine the rate of correct and false predictions. Our results show misprediction of coiled-coil segments as disordered ones or the reverse can not be neglected in sequence analysis. We show that certain algorithms are more sensitive than others and suggest combinations to maximize the rate of correct predictions.



P20 Posters

P20 COMPLIANCE OF PROTEIN STRUCTURAL ENSEMBLES WITH EXPERIMENTAL NMR DATA

Annamária F. Ángyán1, Balázs Szappanos1 , András Perczel1,2, Sándor Pongor3 and Zoltán Gáspári1

1Eötvös Loránd University, Institute of Chemistry,

Structural Chemistry and Biology Laboratory; 2ELTE-MHAS Protein Modeling Research Group;

3International Centre for genetic Engineering and Biotechnology, Trieste, Italy

NMR spectroscopy can provide a wealth of information on protein structures in solution in the form of various structural and dynamical parameters. Traditional structure calculation techniques use only NOE (and RDC) data and the resulting ensemble is usually not in compliance with dynamical parameters such as backbone S2 values. Recent developments in molecular simulations of biomolecules allow the incorporation of multiple experiment-derived restraints yielding a conformational ensemble revealing the internal dynamics of the system (the DER and MUMO protocols). We have developed a tool named CoNSEnsX (Consistency of NMR-derived Structural Ensembles with experimental restraints) to assess of the accuracy of protein structural ensembles determined by NMR spectroscopy. The server takes three files as input, a PDB file, an X-plor format distance restraint file and an NMR-star file containing the available NMR parameters (chemical shifts, S2 order parameters, residual dipolar couplings and J-couplings). The program outputs measures of correspondence (e.g. correlation and ensemble-averaged Q-factor) between the available measured parameters and their back-calculated counterparts based on the structures submitted. Examples of protein ensembles will be presented along with their results achieved with the CoNSEnsX program. We hope that this approach will contribute to promoting the ensemble view of protein structures.



Posters P21

P21 STRUCTURAL EVALUATION OF POTENTIAL LIGANDS TARGETING GLP-1 RECEPTOR

Petra Rovó1, Pál Stráner1, Viktor Farkas1, András Perczel1,2

1Eötvös Loránd University, Institute of Chemistry, Structural Chemistry and Biology

Laboratory; 2ELTE-MHAS Protein Modeling Research Group

Type 2 diabetes is a metabolic disorder characterised by high blood glucose due to insulin resistance. Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone involved in glucose homeostasis and stimulation of insulin release from pancreatic -cells through specific interaction with the G protein coupled GLP-1 receptor (GLP-1R). The major drawback to use GLP-1 in clinic is its rapid degradation by the enzyme dipeptidyle peptidase IV (DPP IV). Exendine-4 (EX-4) is a naturally occurring GLP-1R agonist sharing 53% homology with the human GLP-1, lacking DPP IV recognition site and showing higher binding affinity to GLP-1R1. Crystal structure of the EX-4 bound GLP-1R revealed that the superior affinity of EX-4 is due to its higher -helical propensity in solution and due to its C-terminal extension – also known as Trp-cage – which forms additional stabilizing contact with the receptor2.

The truncated derivative of EX-4 (EX-4 (9-39)) acts as antagonist at the GLP-1R and thus can be used for mechanistic studies3. In this study we designed, synthesised and evaluated the structural features of several EX-4 derivatives using ECD and NMR techniques. The staring model was the de novo designed Trp-cage miniprotein (TC6b) which is structurally related to the C-terminal fragment of EX-44. The gradual N-terminal elongation of TC6b with the corresponding residues of EX-4 revealed a periodic change in the helical content of the peptides.

1 Perry T., Nigel HG., Trends Pharmacol. Sci., 2003, 24, 377-383.

2 Runge S., Thorgersen H., Madsen K., Lau J., Rudolph R., J. Biol. Chem., 2008, 283, 11340-11347. 3 Goke R., Fehmann H. C., Linn T., Schmidt H., Krause M., Eng J., Goke, B., J. Biol. Chem., 1993, 268, 19650–19655.

4 Hudáky P., Stráner P., Farkas V., Váradi G., Tóth G., Perczel A., Biochemistry, 2008, 47, 1007-1016.


Appendix 24 – 26th September 2009

Author index

AUTHOR INDEX

A

Aitken, David J................................II, I, II, 2, 4, 12 Ángyán, Annamária F......................................... 48

B

Barra, M. ............................................................ 41 Benedek, Gabriella ......................................27, 33 Bordess, Andrea................................................. 10 Branchadell, Vicenç.......................................17, 35 Bull, Steven............................................2, 4, 6, 46 Burnley, B. Tom.................................................. 29

C

Campbell, Fred................................................... 29 Caumes, C. ...................................................41, 44 Clayden, Jonathan ......................................13, 16

D

D’hooghe, Matthias .............................................. 9 Da Silva, Eric..........................................13, 17, 35 De Kimpe, Norbert................................I, II, 2, 4, 9 De Santis, E. .................................................41, 44 Declerck, Valérie........................................... 5, 12 Delatouche, Regis .............................................. 10 Denonne, Frédéric.............................................. 21 DePol, Silvia ....................................................... 10

E

Edwards, Alison A...........................23, 28, 41, 44 Edwards, Thomas A. .......................................... 29 Evans, Caroline ...........................................28, 46

F

Farkas, Viktor ................................................19, 49 Ferrand, Yann ..............................................20, 25 Formicola, Lucia ................................................. 10 Forró, Enikő ................. IV, 4, 8, 31, 32, 33, 39, 43 Fülöp, Ferenc.... I, II, III, IV, 1, 2, 9, 30, 31, 32, 33,

38, 39, 40, 42, 43 Fülöp, Lívia ....................................................... 40 Fustero, Santos .......................................... 2, 4, 7

G

Gáspári, Zoltán ......................................28, 47, 48 Gorrea, Esther .......................................17, 27, 35 Guarna, Antonio ......................................5, 11, 34 Guichard, Gilles.........................................2, 13, 18 Guitot, Karin ....................................................... 10

Gutiérrez-Abad, Raquel................................ 27, 36

H

Heckel, Alexander............................................. 26 Hegedüs, Zsófia ................................................. 30 Hetényi, Anasztázia .................................... 28, 42 Hjelmgaard, T. .............................................. 41, 44

J

Jänis, Janne ....................................... 3, 28, 45, 53 Jensen, Knud J. ............................................ II, 15

K

Kazi, Brigitta................................................ 28, 43 Kiss, Loránd....................................... IV, 31, 32, 43 Kümin, Michael ................................................... 14

L

Laitaoja, Mikko.................................................... 45 Láng, András ...................................................... 19 Leemans, Erika..................................................... 9 Lohi, Olli ............................................................. 45

M

Malkova, Bara..................................................... 29 Mándity, István M........................................ 28, 40 Mangelinckx, Sven ............................................... 9 Martinek, Tamás A. ................... II, IV, 2, 30, 33, 40 Meiresonne, Tamara ............................................ 9

N

Nagel, Yvonne A. ........................................ 28, 37 Nonn, Melinda ............................................. 27, 31 Nyitray, László .................................................... 47

O

Ortuño, Rosa M.................... I, II, 2, 13, 17, 35, 36

P

Palkó, Márta ....................................................... 33 Peeters, Sietske ................................................... 9 Perczel, András................. II, 3, 13, 19, 47, 48, 49 Permi, Perttu....................................................... 45 Pihjalamaa, Tero ................................................ 45 Plante, Jeff P. ..................................................... 29 Pongor, Sándor .................................................. 48


24 – 26th September 2009 Appendix

Author index

R

Reiser, Oliver .............................................3, 4, 10 Rovó, Petra ............................................19, 28, 49 Roy, O. ............................................................... 41 Roy-Faure, Sophie.................................28, 41, 44

S

Sahr, Florian....................................................... 10 Schönstein, László ......................................27, 32 Sillanpää, Reijo .................................................. 38 Smith, Martin D. ................................................ 24 Somlai, Csaba.................................................... 42 Stráner, Pál ........................................................ 49 Szakonyi, Zsolt ................................ IV, 28, 30, 38 Szappanos, Balázs........................................47, 48 Szolnoki, Éva ...............................................27, 30

T

Taillefumier, C. ..............................................41, 44 Tasnádi, Gábor ............................................28, 39 Tomasini, Claudia................................II, 3, 20, 22 Torres, E. ........................................................... 17

Tóth, Gábor K. ........................................ 19, 40, 42 Trabocchi, Andrea ...................................... 27, 34

U

Upert, Grégory ............................................ 13, 14

V

Vainiotalo, Pirjo......................................... 3, 45, 55 Valjakka, Jarkko ................................................. 45 Van Hende, Eva ................................................... 9 Vass, Elemér ................................................ 40, 42 Verniest, Guido..................................................... 9 Viiri, Keijo ........................................................... 45

W

Warriner, Stuart L. .............................................. 29 Wéber, Edit......................................................... 33 Wennemers, Helma...................................... 14, 37 Wilson, Andrew J.......................... II, 2, 20, 27, 29

Z

Zorn, Chiara........................................................ 10



Participants in alphabetical order

PARTICIPANTS IN ALPHABETICAL ORDER

Prof. Aitken, David Université Paris-Sud, France ICMMO, Bat.420, Université Paris-Sud, 15 rue Georges Clemenceau, 91405 Orsay cedex, France; tel: +33613205838; e-mail: [email protected]

Ángyán, Annamária Eötvös Loránd University 1117 Budapest Pázmány Péter sétány 1/A; tel: +36-1-372-2500/1408; e-mail: [email protected]

Dr. Arzel, Erwan COST; 149 avenue Louise; 1050 Brussels; Belgium; tel: 003225333817; e-mail: [email protected]

Balázs, Árpád University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: (36)-62-545-562; e-mail: [email protected]

Dr. Bátori, Sándor Medicinal Chemistry, Sanofi Aventis (Chinoin) Zrt., Tó u. 1-5, H-1045, Budapest, Hungary; tel: +36 1 5052254; e-mail: [email protected]

Benedek, Gabriella University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: (36)-62-545-562; e-mail: [email protected]

Dr. Bull, Steven University of Bath University of Bath; tel: 01225 862655; e-mail: [email protected]

Prof. Clayden, Jonathan University of Manchester Oxford Road, Manchester M13 9PL, UK; tel: 0161 275 4612; e-mail: [email protected]

Dr. Da Silva, Eric Universidad Autonoma de Barcelona Dept Quimica Organica, C7-426, Campus Bellaterra, 08193, Barcelona; tel: 0034 93 581 2925; e-mail: [email protected]

Prof. De Kimpe, Norbert Ghent University Coupure links 653, B-9000 Ghent, Belgium; tel: 32-9-264.59.51; e-mail: [email protected]

Dr. Declerck, Valérie Université Paris-Sud 11, Orsay, France 15 Rue Georges Clemenceau; tel: +33169153235; e-mail: [email protected]

Dr. Denonne, Frederic UCB Pharma Chemin du Foriest - 1420 Braine-lAlleud - Belgium; tel: +3223863272; e-mail: [email protected]

Dr. Edwards, Alison Medway School of Pharmacy Anson Building, Central Avenue, Chatham Maritime ME4 4TB; tel: +44 (0) 1634 883846; e-mail: [email protected]

Evans, Caroline University of Bath University of Bath; tel: 01225 862655; e-mail: [email protected]

Dr. Faure, Sophie UMR 6504 - SEESIB, Clermont Université, Auvergne, France 24 avenue des Landais, 63177 Auvergne cedex, France; tel: 04 73 40 52 25; e-mail: [email protected]

Dr. Ferrand, Yann Bordeaux 2, rue Robert Escarpit; tel: 05 40 00 30 11; e-mail: [email protected]




Dr. Forró, Enikő University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: 003662544964; e-mail: [email protected]

Prof. Fustero, Santos Universidad de Valencia. Facultad de Farmacia. Dpto. Química Orgáncia Avda Vicente Andrés Estellés s/n 46100-BURJASST (Valencia) Spain; tel: +34 963544279; e-mail: [email protected]

Prof. Fülöp, Ferenc University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: 36 62 545564; e-mail: [email protected]

Dr. Gáspári, Zoltán Eötvös Loránd University 1117 Budapest, Pázmány Péter s. 1/A; tel: +36-1-3722500 ext. 1408; e-mail: [email protected]

Gorrea Morral, Esther Universitat Autonoma de Barcelona Campus Bellaterra, Edifici C, Departament Quimica, C7/426, 08193, Bellaterra, Barcelona, Spain; tel: 0034935812925; e-mail: [email protected]

Prof. Guarna, Antonio University of Florence Via della Lastruccia 13, 50019 Sesto Fiorentino, ITALY; tel: +39 055 4573538; e-mail: [email protected]

Dr. Guichard, Gilles Institut Européen de Chimie et de Biologie 2 rue Escarpit - 33170 Pessac, France; tel: 06 63 75 78 34; e-mail: [email protected]

Gutiérrez Abad, Raquel Universitat Autonoma de Barcelona Campus Bellaterra, Edifici C, Departament Quimica, C7/426, 08193, Bellaterra, Barcelona, Spain; tel: 0034935812925; e-mail: [email protected]

Prof. Heckel, Alexander University of Frankfurt Max-von-Laue-Str. 9; tel: +49 (69) 798-29821; e-mail: [email protected]

Dr. Hetényi, Anasztázia University of Szeged, Faculty of General Medicine, Department of Medical Chemistry 6720 Szeged, Tisza L. krt. 107.; tel: +3662546833; e-mail: [email protected]

Dr. Jänis, Janne University of Joensuu, Department of Chemistry P.O. Box 111, FI-80101 Joensuu, FINLAND; tel: +358-13-2513356; e-mail: [email protected]

Prof. Jensen, Knud J. University of Copenhagen IGM, KU-LIFE, Thorvaldsensvej 40, DK-1871 Frederiksberg, Denmark; tel: +45 3533 2430; e-mail: [email protected]

Kazi, Brigitta University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: (36)-62-545-562; e-mail: [email protected]

Dr. Kiss, Lorand University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: +36-62-546809; e-mail: [email protected]

Mándity, István University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: 0662545768; e-mail: [email protected]

Dr. Martinek, Tamás A. University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: +3662545768; e-mail: [email protected]




Dr. Miklós, Ferenc University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: (62) 544 000/1963; e-mail: [email protected]

Nagel, Yvonne University of Basel, Department of Chemistry St. Johanns-Ring 19, 4056 Basel, Switzerland; tel: +41 61 267 1130; e-mail: [email protected]

Nonn, Melinda University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: (36)-62-545-562; e-mail: [email protected]

Prof. Ortuno, Rosa M Universitat Autonoma de Barcelona Universitat Autonoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; tel: 34 93 408 2699; e-mail: [email protected]

Ötvös, Sandor Balazs Institute of Pharmaceutical Chemistry, University of Szeged Szeged Alkony str. 4.; tel: +3620/252-0693; e-mail: [email protected]

Prof. Parola, Abraham H. Ben-Gurion University of the Negev; Department of Chemistry; The Faculty of Natural Sciences, Ben-Gurion University, P.O. Box; 653, Beer Sheva, Israel, 84105; tel: 97286472454, +972528795945; fax: +97286472943; e-mail: [email protected]

Prof. Perczel, András Eötvös Loránd University 1117 Budapest, Pázmány Péter s. 1/A; tel: +36-1-3722500 ext. 1653; e-mail: [email protected]

Prof. Reiser, Oliver University of Regensburg Universitätsstr. 31; tel: +499419434631; e-mail: [email protected]

Rovó, Petra Eötvös Loránd University 1117 Budapest Pázmány Péter sétány 1/A; tel: +36 1 209 0555; e-mail: [email protected]

Sántáné Dr. Csutor, Andrea Preclinical Process Research Laboratory, Sanofi Aventis (Chinoin) Zrt., Tó u. 1-5, H-1045, Budapest, Hungary; tel: +36 1 5052051; e-mail: [email protected]

Schindler, József BioBlocks Kft. 1095 Budapest, Mester u. 5.; tel: +36-20-33-44-940; e-mail: [email protected]

Schönstein, László University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: (36)-62-545-562; e-mail: [email protected]

Dr. Smith, Martin University of Oxford Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA; tel: 44 1865 285103; e-mail: [email protected]

Dr. Szakonyi, Zsolt University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: 36-62546809; e-mail: [email protected]

Szolnoki, Éva University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: 36-62-545-562; e-mail: [email protected]

Szomor Tiborné, Mária Preclinical Process Research Laboratory, Sanofi Aventis (Chinoin) Zrt., Tó u. 1-5, H-1045, Budapest, Hungary; tel: +36 1 5051719; e-mail: [email protected]




Tasnádi, Gábor University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: +36203198194; e-mail: [email protected]

Prof. Tomasini, Claudia Università di Bologna Dipartimento di Chimica Ciamician - Università di Bologna - Via Selmi 2 - 40126 bologna - Italy; tel: +39-0512099596; e-mail: [email protected]

Prof. Tóth, Gábor K. University of Szeged Dóm tér 8; tel: 545139; e-mail: [email protected]

Dr. Trabocchi, Andrea University of Florence Via Palazzo dei Diavoli 124/B, 50142 Firenze, ITALY; tel: +39 055 4573507; e-mail: [email protected]

Dr. Upert, Grégory University of Basel, Department of Chemistry Department of Chemistry, St Johanns Ring 19; tel: +41612671130; e-mail: [email protected]

Dr. Ürögdi, László BioBlocks Kft. 1095 Budapest, Mester u. 5.; tel: +36-30-44-77-049; e-mail: [email protected]

Prof. Vainiotalo, Pirjo University of Joensuu Univ. Joensuu, Department of Chemistry, PO Box 111, 80101 Joensuu, Finland; tel: +358505224345; e-mail: [email protected]

Weber, Edit University of Szeged, Institute of Pharmaceutical Chemistry H 6720 Szeged, Eötvös u. 6., Hungary; tel: +36 62 545768; e-mail: [email protected]

Prof. Wilson, Andrew J. University of Leeds School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK; tel: +44 (0)1133431409; e-mail: [email protected]



Szeged

SZEGED

BRIEF HISTORY OF THE CITY OF SUNSHINE1 River Tisza has lured human inhabitants to the Szeged region since the beginning of time. According to written sources, Agathursos and Signunna tribes settled in the region during the iron-age (700-600 BC). Most experts assume that the word Tisza is derived from their language (tijah means river in their language).

Nomad Hungarian tribes conquered the area in 896 and established a state three times as large as it is today. Some remnants of the early settlements established around this time remained. The first mention of Szeged in public documents was in 1138. By that time, a castle was raised on the settlement, and Szeged was given the rank of free royal town (1246). By 1522 Szeged was one of the largest cities in Hungary, with a population of 7000 (same as Buda's and Pest's).

The Turkish army of Ibrahim captured and plundered the castle of Szeged on 28-29th of September in 1526, thus the region came under Turkish rule. On the 23rd of October in 1686, the city was reoccupied with the help of the Austrian forces. After the liberation of Szeged, the city became the starting point of further attacks directed to the south. The country's situation actually did not improve, since one occupant (the Turks) was replaced by another (Austrians). The Hungarian people wanted to be free of foreign rule. These patriotic feelings led to the outbreak of the Rákóczi War of Independence. Hungarian troops attempted to capture Szeged's castle from the Austrian troops in 1704, but the defending forces managed to impede the attack.

1 History of Szeged, http://www.szegedportal.hu/index.php?pg=140



Szeged

For a long time Szeged served as a military outpost. Due to the hardness of everyday life and the 1712 flood, the population of Szeged decreased significantly. To improve the city's population many nationalities were invited to settle. In 1719, the city regained its free royal rights and in 1721 a famous grammar school was established here. The first witch hunt suits were started in 1728 and the first 15 people sentenced were executed by burning on a piece of land which has nowadays the name of Island of the Witches. Szeged had 21,519 inhabitants by 1787. At the turn of the century, the foundation of the first Szeged press (Orbán Grünn) was a huge achievement.

In the Reform Period which began in 1825 and is associated with Earl István Széchenyi and Lajos Kossuth, the development of the town speeded up. Industrial works and banks appeared in the city. At the same time, the ever improving highway and railway systems of the country reached Szeged. During the War of Independence (1848-49), when the country was fighting the ruling Habsburgs again, Szeged played a prominent part. The famous recruiting speech of Lajos Kossuth was delivered on the Klauzál square on the fall of 1848. Szeged was the home of the last revolutionary government in July 1849. The Hungarian revolutionary troops fought a battle not too far from the city, but were defeated by the opposing forces that surpassed their numbers.

The 12th of March in 1879 brought Szeged's darkest hour- the Great Flood. Like most big cities, Szeged was plagued by disease and fire but no one knew there was worse to come. It can be said that the coming catastrophe was also due to bad timing. Both the river Tisza and the river Maros were filled with tremendous water caused by the melting of snow in the Carpathian Mountains. Shortly after midnight (surprising everybody completely) the dyke near the outskirts of Szeged was torn and literally washed the whole city away. Of the 70,000 people living in the city, 151 died that day. Only 265 houses remained standing, and 5458 were destroyed.

The news of the disaster spread throughout Europe. Concerts and fundraisings where held all over the continent to help to rebuild Szeged. With the financial help of Vienna, London, Brussels, Paris, Rome and Berlin a new modern city was built with an exemplary layout of avenues and boulevards, with a strikingly homogenous architecture that preserves the Eclecticism and Art Nouveau of the turn of the century. Thus its present layout of wide streets, incorporating a network of three rings with avenues crossing them, gives the city its fairly modern and organized appearance. The major avenues were named after the contributing cities, and later a monument was built in memory of the Great Flood.

During World War I (when 18,000 men went to the battle from Szeged) the city was first captured by the French and then the Serbian forces. After Hungary lost WWI, two-third of the country's land was lost.

During World War Two (under German occupancy) a ghetto was established for the Jewish community. Later many of them were transported to concentration camps. Szeged's war casualties numbered six thousand men, women and children.

After World War II, the Central and Eastern European countries came under the control of the USSR. These countries were plundered for valuables and everything movable was shipped to the Russian motherland to ease the incurred war losses. Communism was forced on the people, and collectivization was started...

In 1970 and 2006 Szeged was close to another catastrophe. River Tisza came one inch close to the top of the city's dykes. Due to the tremendous effort of the citizens of Szeged the repeat of the Great Flood of 1879 was prevented. After Hungary broke free of the Soviet block in 89-90, a slow recovery has started.

Great Flood at Dugonics square (Picture courtesy of the Szeged Somogyi Library)



Szeged

After the fall of soviet reign, most of the large factories (like the rubber factory, the clothing factory and the match factory) slowly started to go bankrupt. Today the most important elements of the industry are oil refining and natural gas production, together with the Pick and Medikemia factories. Szeged has many prominent High Schools and a well-know University. More than 10,000 students study at the University of Szeged. The University has the following faculties and colleges: College of Agriculture, Faculty of Food Engineering, Juhász Gyula Teacher Training College, Faculty of Music, Faculty of Arts, Faculty of Economics and Business Administration, Faculty of Health Sciences, Faculty of Law, Faculty of Medicine, Faculty of Pharmacy, Faculty of Science.

Szeged, the seat of Csongrád County and the Dél-Alföld region, and is one of Hungary’s economic, educational and cultural centers.

According to the Shanghai list, University of Szeged is one of the best universities in Central Europe.



Szeged

SOME SIGHTS AND ATTRACTIONS IN SZEGED1

Ferenc Móra Museum, 6720 Szeged Roosevelt square 1-3 Tel: +36 62 549-040, http://www.mfm.u-szeged.hu/angol/index.html

Móra Ferenc Museum is housed in the Palace of Education on Roosevelt square, where outstanding archeological, ethnographical, fine arts, environmental protection and pharmacy history exhibitions can be seen. The museum features permanent exhibitions on archaeology, fine arts, ethnography, natural history and pharmacy history and periodic shows on varying subjects.

The Somogyi Library (http://www.sk-szeged.hu), Dóm square.

After the great flood (1879), Szeged was rebuilt as a modern city with international cooperation. Its cultural rebirth was started by a generous offer from Károly Somogyi (1811-1888), prebend of Esztergom, who donated the city his library of 43,701 volumes, a collection of major scientific value at the time, thus became the founder of the present library. The collection represented a wide variety of disciplines, and it was intended to form the basis of a university to be established in the city. The Somogyi Library opened on 16th October in 1883.

The new library building, taking 6 500 sq. meters of ground space, was opened on 6th June in 1984, and it is open to readers on workdays from 10 am to 7 pm., on Saturdays from 10 am to 4 pm. Currently, the stock includes over 880 000 books and 600 newspapers and periodicals. In addition, there are 13 smaller libraries throughout the city. The new library building consists of a ground floor, and four upper levels.

Votive Church, Dóm square. The twin-towered Votive Church is a spectacular brown brick giant that was vowed after the Great Flood in 1879 but not completed until 1930. Inside, the huge nave and gigantic organ (11,500 pipes in all) dominate the entire scene. Beneath is the Dóm Museum where a small collection of monstrance, crosses and goblets can be found from across the Great Hungarian

Saint

ws the various moments in life through Christian symbols.

Plain.

Dömötör Tower, Dóm square.The Early Gothic styled Dömötör Tower discovered during the demolishment of Saint Dömötör Church - previously situated here - is the oldest monument of the city (13th century). In its gate, the relief of Agnus Dei (12th century) of the Romanesque style former church is exposed. In its interior, there are frescos painted by Vilmos Aba-Novák. Its top level and the roof are from 1930. Carved stones from the roman-era and saved from the demolished castle are included in the orders of arches of the doorway and its spandrel holds the oldest sculptural monument of the city, the copy of the 12th century Stone Lamb. The wrought iron door, the artwork of smith master János Bille, the “Door of Life”, sho

1 Explore Szeged, http://www.szegedindex.hu/explore/

http://www.mfm.u-szeged.hu/angol/index.html

http://www.sk-szeged.hu/component/content/article/344.html



Szeged

Szeged Open-Air Festival (www.szegediszabadteri.hu) Dóm square. The series of celebration programmes connected to the consecration of the Votive Church provided an opportunity to conduct a "public rehearsal" in the autumn of 1930. The superb acoustic properties of the square surrounded by the arcade appeared to be an excellent location to stage open air theatrical performances. Over 40 years of its „new era", more than 3 million spectators have watched 142 plays performed on a total of 657 occasions. On the 25th anniversary of resuming the Szeged Open-Air Festival, the event was awarded the „largest open-air theatre of the country" title, and still possesses in these days.

National Pantheon, Dóm square contains Szeged's most important monuments and is the centre of events during the annual summer festival. The National Pantheon - statues and reliefs of 80 prominent persons running along an arcade - is a short trip in Hungarian art, literature, culture and history. Even the Scotsman Adam Clark, who supervised the building of Budapest's Chain Bridge, wins accolades.

New Synagogue (www.zsinagoga.szeged.hu) Jósika street 10. One of the most beautiful synagogues in Europe with Eclectic, Moorish and Art Nouveau elements built in 1900-1903, the masterpiece of Lipót Baumhorn - the most important synagogue architect in the country. The idea came from the chief rabbi Immánuel Löw, and its glass windows of a unique colour harmony was painted by Miksa Róth.

Reök Palace (Regional All Arts Centre), Tisza Lajos boulevard 56. This typical Spanish Antoni Gaudi type house is among the most attractive buildings of this style in Europe. The citizens of Szeged call the place simply “The Horse’s Rump” because it stands behind an equestrian hussar statue raised in honour of the heroes of the First World War. The establishment operating in Reök Palace offers both temporary and periodic programs for visitors. It also hosts several events in the frame of cultural festivals in Szeged.

Heroes' Gate (Aradi vértanúk square), was built in 1936 in honour of heroes of the World War I. Its arches are decorated with the frescos representing the terrors of the World War I painted by Vilmos Aba-Novák. Of the two stone soldiers guarding the Gate, the one on the left is the statue raised for the fallen, the other on the right is the statue for the surviving heroes.

http://www.szegediszabadteri.hu/

http://www.zsinagoga.szeged.hu/



Szeged

Anna Medical, Thermal and Experience Bath, in Tisza Lajos boulevard 24 - built in 1896 and recently renewed - offers modern, up-to-date services based on the beneficial properties of its thermal water for its guests. A bath course of Anna thermal water is recommended primarily as a complement to locomotors disorder treatment, and a drinking course for hyperacidity.

The City Hall of Szeged (Szeged, Széchenyi square 10-11). is the most beautiful building of the Széchenyi square. Its slender spire with a round oriel, is one of the symbols of Szeged. The Parliament held sessions in its assembly hall twice in July 1849, registering one of the most progressive laws at that time on national minorities. The City Hall is connected with the “Bridge of Sighs”, to the neighboring council house, that was constructed for the King’s days in 1883, when Franz Joseph took a visit to the city during the reconstruction after the great flood of 1879. The lodgings of the King and his retinue were divided between the two buildings, thus a closed bridge was constructed to create an easy access between them. Coloured window glasses ornament the staircase, on one of which the famous quote by Franz Joseph; can be read: “Szeged will be more splendid than it has ever been before!” Oil paintings decorate the council hall and the ceiling fresco was painted by Zsigmond Vajda. In summertime, the charming courtyard of the Town Hall is the venue of chamber music concerts held within the “Musical Court” events and prose performances are also held in the frame of the “City Hall Evenings.”

The Szeged National Theatre (H-6720 Szeged, Vaszy Viktor square 1). Like the Víg Theatre in Budapest, it was constructed by the famous theatre builder and designer company Hellmer and Fellner of Vienna, in eclectic neo- Baroque style. It opened in 1883, but burnt down in 1885, though a year later in 1886 it could reopen once again. The facade of the theatre is ornamented by the statues of Ferenc Erkel and József Katona made by Antal Tápai. The ceiling frescoes inside were painted by Zsigmond Vajda. The theatre now provides performances in the genres of drama, opera and ballet. (http://www.szinhaz.szeged.hu/sznsz/ and http://www.szegedikortarsbalett.hu/en)

The Water Tower. The main monument in the Szent István square is the water tower, designed by Szilárd Zielinski. The monument is made of reinforced concrete to store 1004.8 cubic meters of water and was constructed in late 1904. The renewed square serves as a memorial park and a public park for relaxation. Keeping its original function, the water tower is a tourist sight as well. The Foucault pendulum set up inside demonstrates the rotation of the Earth on its axis. Having climbed up its many stairs, one can admire the view of Szeged, the River Tisza and the immense Great Hungarian Plain from the top.

http://www.szinhaz.szeged.hu/sznsz/

http://www.szegedikortarsbalett.hu/en



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COST

COST is an intergovernmental framework for European Coopera-tion in Science and Technology, allowing the coordination of natio-nally-funded research on a Euro-pean level. COST contributes to reducing the fragmentation in Euro-pean research investments and opening the European Research Area to cooperation worldwide.

The goal of COST is to ensure that Europe holds a strong position in the field of scientific and technical research for peaceful purposes, by increasing European cooperation and interaction in this field. This research initiative makes it possible for the various national facilities, institutes, universities and private industry to work jointly on a wide range of Research and Development (R&D) activities.

COST – together with EUREKA and the EU framework programmes – is one of the three pillars of joint European research initiatives. These three complementary structures have differing areas of research.

COST has clearly shown its strength in non-competitive research, pre-normative cooperation, and solving environmental, cross-border and public utility problems. It has been successfully used to maximise European synergy and added value in research cooperation and is a useful tool to further European integration. Ease of access for institutions from non-member countries also makes COST a very interesting and successful tool for tackling topics of a truly global nature.

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As a precursor of advanced multidisciplinary research, COST plays a very important role in building a European Research Area (ERA). It anticipates and complements the activities of the EU Framework Programmes, constituting a “bridge” towards the scientific communities of emerging countries. It also increases the mobility of researchers across Europe and fosters the establishment of scientific excellence in the nine key domains:

1. Biomedicine and Molecular Biosciences

2. Food and Agriculture

3. Forests, their Products and Services

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6. Earth System Science and Environmental Management

7. Information and Communication Technologies

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In addition, Trans-Domain Proposals allow for broad, multidisciplinary proposals to strike across the nine scientific domains.



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