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Department of Chemistry & Centre for Biotechnology Brock University St. Catharines, Ontario h6p://www.brocku.ca/chemistry/
Transcript of Department of Chemistry & Centre for Biotechnology › mathematics-science › chemistry ›...
Department of Chemistry & Centre for Biotechnology
Brock University St. Catharines, Ontario
h6p://www.brocku.ca/chemistry/
Brock University
• Located in St. Catharines, ON – Short drive from Buffalo, Niagara
Falls, Hamilton, and Toronto – In the heart of the Niagara wine
region
• ~18,000 undergraduate students and ~1500 graduate students – A medium-‐sized university with a
smaller-‐school feel
Finding Solutions Today, for the Challenges of Tomorrow
Brock signs agreement with Lorus TherapeuOcs Inc. to develop anOcancer drugs
Brock prof’s venture wins business of the year
Behie, SW; Zelisko, PM; Bidochka, MJ. Science, 2012, 1576-‐77
Research generates > $1 million from licensing revenues
Advanced
Biomanufacturing
Centre
The Department of Chemistry
• Graduate programs offered: – MSc in Chemistry – PhD in Chemistry – MSc in Biotechnology – PhD in Biotechnology
• Research areas: – AnalyOcal chemistry – Inorganic chemistry – Organic chemistry – Physical & computaOonal
chemistry
Programme and Admission Requirements
• Offer graduate programmes leading to a Master of Science (MSc) and/or Doctor of Philosophy (PhD) degree
• Require an Hons. BSc degree (≥75% average)
– May be admitted to the programme with a qualifying year if not all of the requirements are met
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Programme and Admission Requirements
• Applications can be made at any time – Formal admission is generally September
1, January 1, or May 1 • Applications require a recent
transcript, an Application Form, a Statement of Interest form, and letters from three references
– Forms can be downloaded from the School of Graduate Studies website (www.brocku.ca/gradstudies/forms/)
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Financial Support • Graduate students receive a research
assistantship and the opportunity to teach in the undergraduate laboratory programme – Research assistantship is supplemented by
supervisor’s grants – Applicants are encouraged to contact the potential
supervisor prior to submitting a formal application • Brock graduate students are eligible for a
host of internal and external grants to supplement their stipends
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The Brock Advantage
Major instrumentation, just as in much larger universities…
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NMR Spectroscopy (300 MHz and 600 MHz magnets)
The Brock Advantage
Major instrumentation…
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Mass spectrometry (MALDI-‐TOF, EI, CI, ESI, FAB, GC-‐MS)
The Brock Advantage
Major instrumentation…
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Gas Chromatography
EPR Spectroscopy
HPLC
The Brock Advantage
… with a small school feel
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The Brock Advantage
• Proximity to major Canadian and US cities: – Hamilton: ~45 min. by car – Toronto: ~1.3 hours by car – Buffalo, NY: ~35 min. by car
• All the advantages of a big city without having to live in one!
• Major sporting, cultural, and entertainment events are only a short car/bus trip away
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The Brock Advantage
• Just a few minutes hike from the Chemistry Department
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Cairns Family Health and Biosciences Research Complex
It’s Not All Work
• A very social department – BBQs, Christmas parOes, etc.
– Even a Chemistry band!
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Research Interests
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Chemistry and Biochemistry of Vitamin-E (Tocopherol), Mechanism of Lipid Transfer Proteins
Jeffrey Atkinson, Brock University, Chemistry & Biotechnology [email protected]
Background: �� Synthesis and biological evaluaOon of different
forms of vitamin E Results: �� Synthesis of deuterated forms of Vitamin E for
biokineOc studies �� Synthesis of fluorescent tocopherols for in vitro
and in vivo lipid transfer studies �� Synthesis of tocopherol-‐based P450 inhibitors �� Expression of naOve and mutant human
tocopherol transfer proteins �� Protein structure and funcOon (see Dr. Heather
Gordon) ScienDfic Uniqueness: �� CombinaOon of organic synthesis, protein
chemistry, and molecular biology �� First creaOon of molecular tools for analysis of
tocopherol transfer and membrane biochemistry by fluorescence
Impact and Advantages: �� RaOonal molecular approach to vitamin E
biochemisty �� Strong collaboraOons with nutriOonal biochemists
and health science researchers around the world
O
HO
Fluorophore
Human αα-Tocopherol Transfer Protein
Protein mediated tocopherol transfer to and from biological and model membranes can be followed by FRET & stopped flow fluorescence
O(D3C)
(CD3)
HO
D
D
(CD3)
O
HO
α-Tocopherol,phenolic lipophilic antioxidant & membrane enzyme modulator
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Environmental Analytical Chemistry; Trace Element Analysis
Ian D. Brindle, Brock University, Chemistry & Biotechnology Dean, Faculty of Mathematics and Science
Development of analyOcal methods for environmental and other samples. Gas chromatography/mass spectrometry and nuclear magneOc resonance applied to organometallic species and to environmental problems. Trace and ultra-‐trace determinaOon of elements in complex matrices. ApplicaOons of mass spectrometry in analyOcal chemistry.
Reductant
Sample
Argon
Sample
MSIS™ (Dual Mode Operation)
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Research Goals: Research in the Dudding group focuses on the use of computaOonal theory to gain insight into the mechanisOc origins of stereoselecOvity in catalyOc asymmetric reacOons. The models derived from these studies are uOlized to guide the development of new stereoselecOve catalysts and asymmetric reacOon methodologies. Specific reacOons of interest are asymmetric Steler and aza-‐Steler reacOons, Brønsted acid catalyzed asymmetric procedures and chiral nucleophilic catalyzed annulaOons. Significance: The advent of modern computaOonal chemistry has had a profound effect on chemists’ understanding of organic reacOon mechanisms. Through computaOon, chemists are now frequently able to raOonalize or predict the outcome of experiment with a high level of certainty. In this respect a parOcularly useful applicaOon of computaOon relates to the modeling of catalyOc asymmetric methods with the obvious end goal being the use of theory to design an opOmal catalyst for a desired chiral chemical transformaOon. The emerging potenOal of in silico based design approaches in asymmetric catalysis offers great promise as an environmentally friendly alternaOve for streamlining the discovery process and lessening the demand placed upon chemical resources. In this respect the work being conducted in the Dudding group is making possible innovaOve methods grounded both in experiment and computaOon which allow for the rapid cost-‐efficient producOon of chiral pharmaceuOcals and highly prized chemicals.
Computationally Directed Asymmetric Catalysis
Travis Dudding, Brock University, Chemistry & Biotechnology [email protected]
OO
OO
HH
O
OH
H
Sterically Defined Reaction Pocket
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Model system: Abstracted loops From crystal structure.
Loop conformational distribution is restricted when in presence of other loops.
Isolated loop Loop in assembly
Research Goals: To understand relaOonship between anObody selecOvity and specificity and the inherently flexible anOgen binding site. Methodology: Use Monte Carlo simulaOons to sample the complete conformaOonal distribuOon of a model anObody binding site. ObjecDve: To characterize the conformaOonal change in the anObody binding site in the presence and absence of a model anOgen. Results: Intraloop interacOons are more influenOal than interloop interacOons in determining pepOde loop shape. Significance: Most consistent with view that anObody binding site displays conformaDonal isomerism: AnOgen binds selecOvely to a pre-‐exisOng conformaOon that may not be at the global minimum in potenOal energy.
Monte Carlo Simulations of Model Antibody Binding Sites
Heather L. Gordon, Brock University, Chemistry & Biotechnology [email protected]
AnDbody binding site: 6 loops on β-‐barrel framework
95-97% conformations identical between isolated and assembled loops.
Monte Carlo simulations employ random numbers.
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Clean Manufacturing of Pharmaceuticals via Enzymatic and Electrochemical Methods
Tomas Hudlicky, Brock University, Chemistry and Biotechnology [email protected]
Background: �� Converson of toxic aromaOc compounds to chiral
building blocks for use in manufacturing Results: �� ”Green” synthesis of funcOonalized catechols �� Short synthesis of anOtumor agents �� Synthesis of carbohydates and oligoinositols �� Electrochemical oxidaOons and reducOons �� Short approach to morphine ScienDfic Uniqueness: �� BiooxidaOon of aromaOcs has no chemical
equivalent �� Tandem electrochemistry–enzyme methods are
most efficient �� Removal of potenOal waste products by strategic
conversion to value-‐added compounds Impact: �� Concept of EffecOve Mass Yield �� One-‐step synthesis of funcOonalized
catechols �� ”No reagent” synthesis
R R
OH
OH
toluene dioxygenase
alkaloidssugarscyclitolsprostaglandinsterpenespolymersoligomers
organicchemistry
R = alkyl, aryl, halogen
R R
OH
OH
Br OH
OH
OH
OH
1. toluene dioxygenase
2. electro-chemistry3. H2O
O
O NH
OH
OHOH
OH
OOH
O
OH
NCH3
OH
OH
OH
OMe
OMe
MeO
MeOpancratistatin morphine
combretastatin A-1
L-chiro-4HO OH
OH
OH
OH
HO
HO
OH
O
OHO
OH
OH
OH
O
OH
HO
HO
HO
HO
OH
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Development of Rigid Chiral N-Heterocyclic Carbenes Derived from Phenanthrolines
Costa Metallinos, Brock University, Chemistry [email protected]
Background: N-‐Heterocyclic carbenes (NHCs) with an imidazolidine framework can be classified as one of three general structural types: (a) Imidazolinylidenes (1) which have a saturated backbone; (b) unsaturated imidazolylidenes (2), and (c) benzimidazolylidenes (3). There are comparaOvely few reports of chiral benzimidazolylidenes. This can be alributed in part to limitaOons imposed by tradiOonal syntheOc routes, which have restricted their structural diversificaOon.
ScienDfic Uniqueness: Previously we have described a
route to a rigid tetracyclic benzimidazolylidene (7) derived from phenanthroline (4) (Metallinos et al. Org. Le6. 2004, 6, 3641). The key step in the preparaOon of this ligand involved a convenient reducOon of the pyridyl rings to make octahydrophenanthroline (5). We have expanded this methodology to prepare enanOomerically pure rigid chiral benzimidazolium salt precursors of benzimidazolylidenes (e.g. 8 and 9). Our approach to the structural diversificaOon of this sub-‐class of NHCs holds promise for their future applicaOons in asymmetric synthesis.
NNPh PhN N
PhPh
i-Pr
i-Pr
31
NNAr Ar
2
N NHNNH
5
HC(OEt)3
1 equiv HCl80 °C
0.5 equiv Pd(OAc)2THF, reflux
6Cl
N N
1,10-phenanthroline 4
N
NN
NPdCl
Cl
NaBH3CN
7
N N
8BF4
N N
9BF4
H
H
H
H
Background • TransiOon metal (TM) complexes subsOtuted by main group element (MGE) ligands, i.e.
LnM-‐ERk, oten exhibit unusual metal-‐ligand and ligand-‐ligand bonding; • There is a conOnuing interest in complexes with mulOple metal-‐ligand bonds (silylenes,
phosphinidenes, borylenes etc) and in coordinaOon of mulOple E=E bonds to metals (complexes of disilenes, silenes, silaimines, diphosphenes etc);
• Much of current research is focused on studying nonclassical interligand interacOons. Research Goals • To develop the chemistry of transiOon metal hydrides in new ligand environments; • Synthesis, structure and reacOvity of TM hydrides and MGE complexes; • Study of nonclassical interligand interacOons. Methodology • New syntheOc strategies to MGE and hydride complexes:
– reacOons of MGE halides with hydrides; – selecOve funcOonalizaOon of E-‐H bonds in complexes; – E-‐E coupling reacOons on TM complexes;
• X-‐ray and neutron diffracOon, NMR, IR, EPR, DFT calculaOons. Results • Pioneering research on Interligand Hypervalent InteracOons • New types of Si-‐H... M agosOc complexes • New approaches to diphosphene complexes • One of the first σ-‐complexes of the Si-‐Si bond Significance/Impact • New syntheOc methodologies • New insight into the nature of M-‐L
and L-‐L bonding
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Organometallic and Coordination Chemistry
Georgii Nikonov, Brock University, Chemistry [email protected]
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Developing Analytical Methods for Analyzing Environmental, Food, and Biological Samples
Vadoud Niri, Brock University, Chemistry [email protected]
Background: �� Our research interests are mostly in method development for analyzing different kinds of samples including environmental samples
(water, air, soil, plants, etc), food samples (wine, coffee, rice, etc.) and biological samples (urine, blood, etc.) using different sampling and analyOcal techniques such as chromatographic and electranalyOcal methods
Environmental Analysis: �� Obviously, it is not only important to protect our environment from contaminaOon, but also to monitor the levels of contaminants to
ensure that their concentraOon level is lower than maximum allowed level. Since the maximum concentraOon levels for many contaminants are low, sensiOve analyOcal methods are required. The cerOfied laboratories which deal with environmental samples are sOll relying on tradiOonal solvent extracOon techniques which are both hazardous and Ome and labor consuming. Therefore, our research focus in this area is developing fast, sensiOve and solvent-‐free techniques for both sampling and analyzing contaminants in environmental samples including water, air and soil.
Food Analysis: �� CombinaOon of organic synthesis, protein chemistry, and molecular biology �� First creaOon of molecular tools for analysis of tocopherol transfer and membrane
biochemistry by fluorescence Bioanalysis: �� Developing highly sensiOve and precise methods for determinaOon of newly introduced drugs in pharmaceuOcal products and
biological media is one of the challenges in all pharmaceuOcal companies and clinical laboratories. The analyOcal method is chosen based on the chemical properOes of the drug compounds. While high performance liquid chromatography (HPLC) with UV, florescence or mass spectrometry is the common analyOcal technique for this purpose, electroanalyOcal techniques can also be used for the determinaOon of the compounds with electrochemical acOvity properOes.
Biofuels: �� Biofuels offer an alracOve alternaOve to petroleum-‐based fuels. These fuels can be created from different sources including crop oils
and biomasses. One of the challenges in biofuel studies is to customize analyOcal techniques for analyzing the products during the process. These techniques will allow us to idenOfy and quanOfy reacOon products during the process, construct a detailed mechanism and improve the quality of the fuel.
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Novel Hybrid Organic/Inorganic Molecular Materials
!
Melanie Pilkington, Brock University, Chemistry [email protected]
Background: �� Inorganic crystal engineering. �� The preparaOon of magneOc, electronic and opOcal
materials from molecular building blocks. Results: �� Synthesis and characterisaOon of new
tetrathiafulvalene (TTF) building blocks. �� SyntheOc strategies for the preparaOon of
funcOonalised phthalocyanines (Pcs). �� Synthesis, characterisaOon and study of molecule-‐
based magneOc materials e.g. high spin clusters, 3-‐D networks, 1-‐D coordinaOon polymers and spin-‐crossover compounds.
ScienDfic Uniqueness: �� ExploiOng the use of metal binding sites as the key
element for the construcOon of dual property hybrid materials.
�� Target the synergy between the properOes of the inorganic and organic components in each system to assemble new materials.
Impact and Advantages: �� Dual property materials with
synergisOc properOes. �� Development of new electronic,
opOcal and/or magneOc devices that will be the cornerstones of new technology.
A New TTF DerivaOve with Four Pyridine Binding Sites
A Novel Fully Conjugated Phenanthroline Appended Phthalocyanine.
A High Spin (S = 51/2) [MnII9MoV6] Molecular Cluster
A Three-‐Dimensional Bimetallic Network [NbIV{µµCN)4MnII(H2O)2}2]·∙2H2O 1-‐D MagneOc CoordinaOon Polymer
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Novel Approaches to Fundamental Problems in Computational Chemistry and Physics
Stuart M. Rothstein, Brock University, Chemistry & Physics [email protected]
Background: • Chemistry: the factors involved in the
interacOon of biomolecules with themselves, with DNA, and with solvent are not well understood.
• Physics: one can derive accurate results from quantum theory by taking expectaOon values of operators over the truly exact electron distribuOon, not just an approximate one, contaminated by a trial funcOon
Results: �� Chemistry: Using sophisicated staOsOcal
methods we developed computer codes to cluster quantum and classical molecular dynamics trajectories, and to visualize the resulOng clusters. In applicaOons
done in collaboraOon with groups in Germany, Japan, and Brock, this approach provided a local descripOon of protein folding, of non-‐bonded interacOons in biological systems
(figure), and of high-‐frequency moOons in proteins, associated with their biological funcOoning.
Human ααrol Transfer Protein
Results: • Physics: quantum Monte Carlo methods can sample the unknown exact wavefuncOon. We recently discovered how to sample the unknown exact probability density as well. We are applying this methodology to calculate very accurate esOmates of polarizabiliOes of chemical systems. ScienDfic Uniqueness: Our research has a strong interdiscipinary flair, drawing on computaOonal and theoreOcal chemistry and physics, high-‐performance compuOng and mathemaOcs to tackle fundamental problems. Impact and Advantages: • Chemistry: we extract the signal from the noise in biomolecular simulaOon data beler than standard approaches, and our visualizaOons provide a novel,
CRP-‐cAMP-‐DNA complex.
much-‐needed local view of bio-‐molecular interacOons. Impact and Advantages: • Physics: quantum Monte Carlo
is the most promising approach to ab iniDo electronic structure of large molecules.
Group website: hlp://www.brocku.ca/chemistry
/faculty/Rothstein
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Molecular Nanomagnets and Structural Models of the Oxygen-Evolving Center of Photosystem II Based on
Multinuclear/Multifunctional 3d- and 4f-Metal Complexes Theocharis C. Stamatatos, Brock University, Chemistry
Background: �� Synthesis, spectroscopic, magnetochemical and photoluminescence
characterizaOon, and biological evaluaOon of mulOnuclear 3d-‐, 4f-‐, and 3d/4f-‐metal complexes
Results: �� A molecular, ’bolom-‐up’ approach to the nanoscale through the synthesis
of polynuclear homo-‐ and hetero-‐metallic 3d-‐ and 4f-‐metal complexes �� Synthesis of mulOfuncOonal molecular magneOc materials displaying dual
physical properOes �� Synthesis of new high-‐spin molecules, single-‐molecule magnets and single-‐
chain magnets �� Synthesis and detailed study of analogues (molecular models) of the
acOves sites of several redox enzymes �� Biological implicaOons and studies for mononuclear, ‘low-‐weight’
complexes ScienDfic Uniqueness: �� CombinaOon of inorganic and organic synthesis, coordinaOon chemistry,
magnetochemistry, photoluminescence, catalysis, biology, materials science and engineering
Impact and Advantages: �� A challenging prospect in mulOnuclear metal cluster chemistry is to
operate spins within magneOc coordinaOon complexes to accomplish quantum logic processes (quantum compuOng informaOon processing)
�� Strong collaboraOons with a wide range of chemists, physisists, biologists and chemical engineerings around the world
Synthetic Inorganic Chemistry
Molecular Magnetism PhotoluminescenceLight
Quantum Computing
Mn O
Mn Mn
Ca
O
O
O
MnO
Bioinorganic Chemistry
Synthetic Inorganic Chemistry
Molecular Magnetism PhotoluminescenceLight
Quantum Computing
Mn O
Mn Mn
Ca
O
O
O
MnO
Bioinorganic Chemistry
-1
-0.5
0
0.5
1
-0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8
0.008 T/s0.004 T/s0.002 T/s0.001 T/s
MM//MM
ss
µµ00HH ((TT))
0.04 K
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Structure and Function of Photosynthetic Proteins Electron Spin Resonance Spectroscopy
Art van der Est, Brock University, Chemistry & Biotechnology [email protected]
O(D3C)(CD3)
HOD
D
Plight
P+A1-‐ P+FX-‐
Photosynthesis
Photosystem I Electron spin resonance signals
from photosystem I
Goals: �� Beler understanding of solar energy
conversion in photosyntheOc organisms
Results: �� DeterminaOon of electron transfer rates
in Photosystem I using electron spin resonance
�� Studies of site directed mutants to determined the pathway of electron transfer.
�� Computer modelling dynamics (see Dr. Gordon)
ScienDfic Advances: �� Development of spin polarizaOon as
effecOve tool for studying electron transfer.
Impact: �� Beginning to unravel the basic
principles of efficient solar energy conversion
�� Strong internaOonal collaboraOons with sciencOsts working in this field
Background • Oligonucleotide synthesis, siRNA synthesis • Glycoconjugates and glycobiology • Drug delivery Research Goals • Understanding the chemistry, biochemistry,
and biology of nucleic acids, carbohydrates, and bioconjugates
Research Projects • Synthesis of oligonucleotide phosphate–phosphorothioate random chimeras • Solid phase synthesis of oligoribonucleotides/siRNAs using the Cpep chemistry • Novel siRNA analogues • Chemical mimicry of bacterium Pseudomonas aeruginosa surface
carbohydrate-binding proteins – carbohydrate interactions Significance • Methodology for the synthesis of oligoribonucleotides on multi-gram scales • Understanding lectin–carbohydrate interactions • Development of bioconjugates pertinent to human health
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Carbohydrates, Nucleic Acids, and Bioconjugates Hongbin (Tony) Yan, Brock University, Chemistry and Biotechnology
O
O
R1O
PO
NR2
O
N
OEt
Cl
NC
2'-Cpep ribonucleoside phosphoramidite
O
B'O
PO
X
O BO
O
O
oligonucleotide phosphate-phosphorothioate chimeras
Applied Biosystem 3400 DNA Synthesizer
carbohydrate
Cationic lipid
Neutral lipid
Glycoliposome
• The goals of this research are: (1) to invesOgate the interacOon(s) of silicon-‐based molecules with biological systems; (2) to develop systems where enzymes can be used to perform chemistry at, or near, silicon in place of the more tradiOonal, and somewhat more toxic/expensive, metal-‐based catalyst systems; and to (3) explore applicaOons such as biomaterials, drug delivery devices, sealants, coaOngs, and agriculture products to name but a few.
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Organosilicon Chemistry and the Chemistry of Silicone and Silicone-Modified Materials
Paul Zelisko, Brock University, Chemistry and Biotechnology [email protected]
Si 1
Si2
OSi
3
OSi
2
Si1
OO
O
O
O
O
n
TES-PDMS
1
3
2 Spinning
side band
Cross-linking
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 2 4 6 8 10
RelaDve prop
orDo
n of 29Si integral of
phenyltrimetho
xysilane
Time (hr)
enzyme
Dn
For more information visit us at:
www.brocku.ca/chemistry www.brocku.ca/gradstudies
www.brocku.ca/biotechnology
Application forms for graduate studies: www.brocku.ca/gradstudies/forms/
Or contact Prof. Tony Yan at:
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