Exploratory research project funded by CNCSIS, By PN II ‘Ideas’ program

DNA INTERACTION AND CARDIOTOXICITY OF SOME ANTITUMOR DRUGS: PHYSICO-CHEMICAL AND BIOCHEMICAL

STUDIES

Project no. 486/2009

Project manager: Dr. Mirela Enache

Project duration: 01.05.2009 - 30.04.2012

Abstract

Molecular recognition of nucleic acids and proteins by different ligands ia an area of fundamental and practice

interest. It is a subject that exists at the interface of chemistry and biology since interactions involving biological molecules are best

understood if they are described in physico-chemical terms. In this general context, drug-DNA interactions are of particular

importance not least because the intracellular target for a wide range of anticancer drugs is DNA, but also because the current

treatment for many types of cancer is unsatisfactory, both in terms of controlling the disease and in terms of adverse side effects.

Therefore, a central goal in many chemical and biological laboratories, both in academia research and industry, is to rationally

design novel drugs capable of sequence- and structure-specific recognition of DNA in vivo, acting as specific modulators of gene

activity. The question is: What are the rules that govern the molecular recognition of DNA by drugs? In order to address this

question it is necessary to obtain information on structure of drug-DNA complex, the dynamics of complex formation, and the

energetics that drive the process. Also, in the rationally design of new antitumor drugs beside the increase of specificity and

therapeutic efficacy of these drugs, another aim is to obtain new compounds without cardiac toxicity, which currently limits the

clinical use of antitumor antibiotics. In this context, studies proposed in the present project will lead to the determination of

complete thermodynamic profile for the interaction of some antitumor antibiotics with DNA and quantitative understanding of the

factors which govern this interaction, and also the evidence of redox properties of these drugs and the understanding at molecular

level of the electronic structural features implied in chemical reactivity in oxido-reduction processes. This study will be developed in

two directions:

- the study of the interaction of some antitumor drugs with nucleic acids, it is one of the mechanisms responsible for antitumor activity

- the study of the redox activation of losoxantrone and mitoxantrone, possible responsible for cardiac toxicity.

Crt. No.

Name of the budget

category

2009 2010 2011 Total, lei

1. Staff expenses 41.987 239.453 129.600 411.040

2. Indirect expenses (overheads)

13.684,52 99.040,48 34.235 146.960

3. Mobilities 2.450,81 31.849 17.000 51.299,81

4. Logistic costs 23.021,19 222.679 25.000 270.700,19

5. Total 81.143,52 593.021,48 205.835 880.000

Project budget

No. crt.Surname and first

name Year of birthDidactic

/scientific title Doctorate

1 PREDA LOREDANA 1975Researcher yes

2 POPA VLAD TUDOR 1952 SRI yes

3 TOADER ANA MARIA 1978 Researcher PhD student

4 LATUS ALINA 1982 Researcher PhD student

5 ENACHE MADALIN IANCU

1973 SRII yes

List of the research team members

CV Mirela EnacheThe scientific competence domains:- the physico-chemical characterization of molecular interactions (drugs – biopolymers interactions)- the study of redox activation of some antitumor drugs- radical processes in biological compounds -the evaluation of some index of oxidative stress in normal and pathological conditions (aging, diabetes, diseases associated with diabetes)Publised papers in the domain of the proposed topic: M. Enache, C. Bendic, E. Volanschi, Spectroelectrochemistry of the redox activation of anti-cancer drug mitoxantrone, Bioelectrochemistry, 72, 10-20, 2008M. Enache, D. Bulcu, I. Serbanescu, E. Volanschi, Interaction of actinomycin D with anionic surfactant, sodium dodecyl sulphate: spectral and electrochemical investigations, Revue Roumaine de Chimie, 52, 725-731, 2007C. Bendic, M. Enache, E. Volanschi, Analysis of actinomycin D - DNA model complexes using a quantum chemical criterion: Mulliken overlap populations, Journal Molecular Graphics and Modelling, 24, 10-16, 2005M. Enache, E. Volanschi, Electrochemical and spectral study of the interaction of antitumoral drug mitoxantrone with DNA, Revue Roumaine de Chimie, 50, 131-140, 2005C. Bendic, M. Enache, E. Volanschi, A possible model for the actinomycin D - DNA complexes at high drug to polymer ratios:molecular modeling and overlap population analysis, Revue Roumaine de Chimie, 50, 677-681, 2005 E. Volanschi, M. Enache, Spectroelectrochemical study and MO-modeling of the reductive activation of antitumoral drug actinomycin D, Revue Roumaine de Chimie, 47: 741-750, 2002M. Enache, M. Hillebrand, E. Volanschi, Spectral study of the interaction of actinomycin D with calf thymus DNA, Romanian Journal of Biophysics, 11: 93-105, 2001

CV Preda Loredana The scientific competence domains: -molecular electrochemistry field - the role of the electronic structure of substrate on the reactivity of intermediates in electrochemical processes (coupled spectral, electrochemical and theoretical studies on different sulfone compounds) and the effects of solvent (electrochemical studies on ionic liquids) on the rate and the mechanism of electrochemical reactions.

Publised papers:Reactivity of substituted seven-membered heterocyclic sulfones: Spectroelectrochemical study and theoretical modeling, L. Preda, V.Lazarescu, M.Hillebrand, E.Volanschi, Electrochimica Acta 2006, 51, 5587-5595; Heterogeneous electron-transfer kinetics of nitro compounds in room-temperature ionic liquids, C.Lagrost, L. Preda, E. Volanschi, P. Hapiot, J. Electroanal. Chem, 2005, 585, 1-7;The cathodic behaviour of poly(alkyl) and (aryl) sulfones revised. Mechanistic and theoretical approaches, J.F.Bergamini, P.Hapiot, C.Lagrost, L. Preda, J.Simonet, E.Volanschi, Phys.Chem.Chem.Phys., 2003, 5, 4846-4850; Reducerea electrochimica a benzaldehidei si acetofenonei pe electrod de platina modificat chimic cu tetrafenil porfirine,C. Lete, N.D.Totir, C.Giorza, L. Preda, Rev. Roumaine Chim., 2003, 54, 411-413; Electrochemical study and MO-Modelisation of some substituted benzo-thiophenes, L. Preda, C.Topala, I.Baciu, E.Volanschi, UPB Sci.Bull., Series B, , 2001, 63, 421-428

CV Popa Vlad TudorThe scientific competence domains: -Thermal analysis: differential scanning calorimetry (DSC), differential thermal analysis (DTA), termogravimetric analysis (TGA); termodinamica chimica, chemical kinetic general, catalysis omogena and heterogena; complex reactions theory; neuniformity models in heterogen catalysis.

Publised papers:V. T. Popa and J. A. Schwarz, Two-Step Sequences with Extended Temkin Nonuniform Reactivity. Rate-Determining Step Revisited, Chem. Engn. Sci., 51 (1996) 3657; V. T. Popa, C. Contescu and J. A. Schwarz, Nonuniformity Windows at the Oxide/Aqueous Interface. Apparent Proton Transfer Rates in pH-jump Relaxation Kinetics, Polish J. Chem., 71 (1997) 583; V. T. Popa and E. Segal, Shape Analysis of DSC Ice Melting Endotherms: Towards an Estimation of the Instrumental Profile, J. Thermal Anal., 69 (2002) 149; M. O. Vlad, V. T. Popa, E. Segal and J. Ross, Multiple Rate-Determining Steps for Non-Ideal and Fractal Systems, J. Phys. Chem. B, 109 (2005) 2455; M. O. Vlad, F. Moran, V. T. Popa, S. Szedlascek, J. Ross, Functional. Fractal nonlinear response with application to rate processes with memory, allometry, and population genetics, PNAS, 104, 4798-4803, 2007; M. O. Vlad, A. D. Corlan, V. T. Popa, J. Ross, On anti-portfolio effects in science and technology with application to reaction kinetics, chemical synthesis, and molecular biology, PNAS, 104, 18398-18403, 2007

CV Enache Madalin IancuThe scientific competence domains: -general microbiology, biochemistry, nanobiotechnology. Isolation and charcterization of a new halophilic archaeon Haloferax prahovense; phylogeny of haloalkaliphilic archaea inferred from rpoB’ and RpoB’ sequences (complementary to SSU rRNA Halobacteriaceae taxonomy).

Publised papers:Madalin Enache, T. Itoh, T. Fukushima, R. Usami, L. Dumitru, M. Kamekura, 2007, Phylogenetic relationships within the family Halobacteriaceae inferred from rpoB’ gene and protein sequences - Int J Syst Evol Microbiol, 57, 10, 2289 - 2295. (IF 2.744); Madalin Enache, T. Itoh, M. Kamekura, G. Teodosiu, L. Dumitru, 2007, Haloferax prahovense sp.nov., an extremely halophilic archaeons isolated from a Romanian salt lakes, Int J Syst Evol Microbiol, 57, 2, 393 – 397. (IF 2.744); M. Gartner, C. Trapalis, M. Anastasescu, P. Osiceanu, A. Ghita, Madalin Enache, L. Dumitru, T. Stoica, M. Zaharescu, S.–H. Suh, 2007, Doped sol-gel tio2 films for biological applications, Bulletin of Korean Chemical Society - in press (IF 0.933); T. Oncescu, P. Oancea, Madalin Enache, G. Popescu, L. Dumitru, M. Kamekura, 2007, Halophilic bacteria are able to decontaminate dichlorvos, a pesticide, from saline environments, Central European Journal of Biology, 2, (4), 563 – 573. (IF – în curs de evaluare ISI Thompson); - capitole in carti: (1) L. Dumitru, G. Teodosiu Popescu, Madalin Enache, R. Cojoc, I. Kleps, T. Ignat, 2007, S-layer of Haloferax sp. GR 2 (JCM 13922): isolation, characterization and binding to silicon nanostructurated substrates, Vol. 10, Seria Micro and nanoengineering , Ed. Academiei Romane, 146 – 152; (2) Madalin Enache, 2007, Tehnici moleculare utilizate pentru studiul diversitatii microbiene in mediile extreme, Vol. Biodiversitatea de la concepte fundamentale la aplicatii biotehnologice, Ed. M. Enache & L. Dumitru, Editura Academiei Romane, 75 – 86.

CV Toader Ana Maria

– scientific researcher in Instituite of Physical Chemistry and PhD student (2005) at Faculty of Chemistry, scientific supervizor - Prof. Elena Volanschi.

Title of doctoral thesis: Study of electrode processes involving biological active compounds by physico-chemical methods.

Published papers: (1) A. M. Toader, D. Bulcu si E. Volanschi, Spectroelectrochemical study of the redox

behaviour of questiomycin drugs in aprotic media, Revue Roumaine de Chimie 51 (4) 307-315, 2006;

(2) A. M. Toader, C. Diaconu, E. Volanschi, Spectroelectrochemical Study of the Hemin - Glutathione Interaction in the Absence and Presence of Surfactants – ECS Transactions, vol. 3, 155-166, 2007;

(3) A. M. Toader, C. Diaconu, E. Volanschi, Electrochemical and spectral study of the hemin-surfactant interaction in solution, Revue Roumaine de Chimie 52 (1-2), 159-167, 2007

CV Latus Alina

- scientific researcher in Instituite of Physical Chemistry and PhD student (2007) at Faculty of Chemistry, scientific supervizor - Prof. Elena Volanschi.

Title of doctoral thesis: Study of redox processes and drug-biopolymer interactions by electrochemical and spectral methods.

Published papers: Alina Latus, Elena Volanschi, Electrochemical and spectral study of the redox behaviorand cardiotoxicity of anticancer drugs with antraquinone structure: quinizarin, Rev.Roum. Chim., 2008, 53(12), 1131-1140.

Results dissemination 2009 (1.05.2009-1.12.2009)

Published papers

M. Enache, E. Volanschi, Spectral characterization of dimerization equilibrium of antitumor drugmitoxantrone, Revue Roumaine de Chimie – in press

Book chapter

M. Enache, E. Volanschi, Cardiotoxicitatea antibioticelor antitumorale din perspectiva transferului deelectron si stresului oxidativ, in Adaptarea la stres: conditie de supravietuire si/sau factor de biodiversitate, Editura Academiei Romane, 2009, pag. 104-120, ISBN 979-973-27-1540-0

Presentations at international meetings:

M. Enache, I. Anghelache, E. Volanschi, Spectral and electrochemical investigation of the interactionof some antitumor drugs with DNA in the absence and presence of surfactants, XXth InternationalSymposium on Bioelectrochemistry and Bioenergetics, May 10-14, 2009, Sibiu, Romania

A. Latus, M. Enache, E. Volanschi, Etude electrochimique et spectrale de l’activation redox desmedicaments anticancereux derives de l’anthracycline, Journees d’Electrochimie, Juillet 6-10, 2009,Sinaia, Romania

I. Anghelache, A. M.Toader, A. Latus, M. Enache, E. Volanschi, Spectroelectrochimie des interactionsmedicaments-biopolymers, Journees d’Electrochimie, Juillet 6-10, 2009, Sinaia, Romania