Stephen HanessianProfessor, Chemistry Professor, Pharmaceutical Sciences Director, Medicinal Chemistry and Pharmacology Graduate Program (MCP) Joint appointment, Pharmacology |
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Research Interests |
Organic Synthesis, Medicinal Chemistry, Natural Products | |
| URLs | osiris.corg.umontreal.ca/ | |
| Chemistry Home Page | ||
| Pharmaceutical Sciences Home Page | ||
| Pharmacology Home Page | ||
| See below for selected publications or click here for additional publication listing available via PubMed | ||
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Academic Distinctions |
Doctorate Honoris Causa, University of Urbino, Italy (2006) Achaogen Research Chair (2006) Isis Pharmaceuticals Research Chair (2003) Queen Elisabeth Golden Jubilee Medal (2002) Doctorate Honoris Causa, University of Moncton, NB, Canada (2001) Bernard Belleau Award in Medicinal Chemistry (CSC) (2001) Doctorate Honoris Causa, University of Siena, Italy (2001) Officer of the Order of Canada (1998) Compagnon Lavoisier - Quebec Order of Chemists (1997) Killam Memorial Prize Natural Sciences (1997) Science Personality of the Year La Presse (1996) Prix Marie-Victorin Quebec Science Prize (1996) Canada Gold Medal for Science and Engineering (1996) A.C. Cope Scholar Award American Chemical Society (1996) M. L. Wolfrom Award American Chemical Society (1993) E. Smissman Medal University of Kansas (1992) Bell Canada Forum Award (1991) NSERCC Chair in Medicinal Chemistry (1990) Fellow, Killam Foundation (1989-90) Fellow, Royal Society of Canada (1988) Alfred Bader Award in Organic Chemistry CSC (1988) CIC Palladium Medal (1988) Urgel-Archambault Award Quebec Association for the Advancement of Science (1987) Hudson Award American Chemical Society (1982) Merck Sharpe & Dohme Award Chemical Institute of Canada (1974) |
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| Appointments |
Parke Davis & Co., Ann Arbor Michigan 1961-1968 McConnell Professor, University of Montreal, 1970-1979 NSERCC - Chair in Medicinal Chemistry, University of Montreal, 1990-1995 Professor, UCI, since 2000 Isis Pharmaceuticals Research Chair, University of Montreal, 2003-2006 Achaogen Research Chair, University of Montreal, 2006-Present |
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Research Abstract |
Professor Hanessian's research interests span a wide cross-section of activities that include natural products synthesis, aspects of medicinal chemistry and prototypical drug discovery, synthetic methodology, catalysis and asymmetric processes, molecular recognition, carbohydrates and peptides, and computer-assisted synthesis. 1. Strategies in the Total Synthesis of Natural Products We've had a long-standing interest in the design and synthesis of natural products using available optically-active compounds as starting materials and methods relying on asymmetric synthesis. Our strategies are based on the recognition of symmetry elements and functional group overlaps with the target and appropriate precursors. This type of approach has been very successful because it combines the aesthetic value of stereochemical decoding with the intellectual stimulation of asymmetric synthesis. Our current efforts are focused on developing strategies that combine the merits of generality, practicality and overall appeal. The approach has been computerized (see topic No. 8). 2. Molecular Aspects of Medicinal Chemistry and Drug Design Over the years, we've had an active program in the total and semi-synthesis of antibiotics as well as in their chemical modification based on biological rationales. Quantamycin, a computer-simulated inhibitor of ribosomal binding is an example of a successful, biologically inspired synthetic program. Avermectin, a potent anthelmintic agent has been the target of total synthesis and chemical modification. Other total syntheses of clinically important molecules include thienamycin, dihydromevinolin, ajmalicine, tetrahydrolipstatin, reserpine, among others. A number of current research programs deal with the validation of biochemical hypotheses (mode of action, etc.) through rational design of models and novel drugs. An active area of research involves the design of peptidomimetics, enzyme inhibitors, antagonists, novel β-lactams and -lactamase inhibitors relying on structure-based design and available X-ray data. Another area of current interest is the design and synthesis of RNA-binding molecules, including aminoglycoside antibiotics. (See topic No.9) 3. Immunochemistry and Drug Targeting The design of artificial antigens and related entities, capable of eliciting an immune response and the production of specific antibodies is a challenging task. We are involved in the assembly of strategically situated bioactive subunits and their clustered variants for better antigen presentation. These projects have enormous relevance in the area of cancer immunotherapy and organ transplantation. In magnetotherapy, we are involved in collaborative work dealing with the attachment of drug substances to a polymeric matrix with immobilized iron oxide nanoparticles. The drug is delivered to a tumor site and accumulates by magnetic activation. 4. Glycosidic Linkage in Life Processes Because of the importance of the glycosidic linkage in nature, we've had an on-going program concerned with the development of novel syntheses of O-, S-, N- and C-glycosides. Many of these procedures have been used in the synthesis of biologically important glycosides. The synthesis and attachment of selected drugs to different biological carriers constitutes another exciting research program involving "targeted drug therapy". Our work has resulted in the development of iterative glycoside synthesis in solution and on solid phase. The design of anomeric leaving groups, especially with unprotected glycosyl donors is an active area of research. 5. New Synthetic Methods, Chemical Diversity, Amino Acids and Peptides Stereo and regiocontrol are critical factors in the design of new reactions. We have been interested in the development of new protecting groups as well as activating groups in displacement reactions and in the exploration of stereocontrolled C-C bond formation by free radical and ionic reactions involving acyclic and cyclic substrates. Iterative approaches to the construction of polypropionate subunits using organometallic reagents and other conceptually novel aspects of introduction of carbon substituents in acyclic and cyclic molecules are on-going activities. These projects constitute alternatives to nature's biochemical pathways through synthesis. Application to solid phase chemistry is possible. 6. Asymmetric Synthesis and catalysis As in any modern organic chemistry laboratory, we are interested in combining innovation with practicality. Conceptually novel approaches to asymmetric synthesis in olefination, Michael addition and related bond-forming reactions are active research programs. We have developed highly stereocontrolled syntheses of substituted cyclopropanes and of acyclic chains containing contiguous carbon substituents. Aspects of catalytic reactions with novel ligands with appropriate metals and in metal-free systems are on-going research activities. 7. Molecular Recognition, Self-Assembly, Peptide Secondary Structure and RNA Binding An area of current interest is concerned with molecular environment, intrinsic electronic properties and chemical logic in the design of architecturally interesting molecules. With the proper combination of properties, conditions and energy requirements, recognition between molecules can take place based on what can be loosely termed "chemical complementarity". In this regard we have shown that the combination of C2 symmetrical diamines and diols lead to self-assembled supramolecular structures (Supraminols) with intriguing topologies. H-bonding plays an important role in such molecular recognition and a variety of supramolecular structures can be designed. An active area of research in my group involves the chemical modification of cyclodextrins with the objective of preparing polyfunctional derivatives as well as the design of artificial catalytic cavities. The synthesis of helical and topologically interesting unnatural peptides is an on-going activity. The design and synthesis of RNA-binding molecules based on X-ray crystallographic data is being actively pursued in the group. 8. Computer Aided Chemistry and Molecular Modeling We have developed unique computer programs that offer a powerful tool for synthetic chemists interested in natural products and in drug design. The "Chiron Program" is an interactive computer program for the analysis and perception of stereochemical features in molecules and for the selection of chiral precursors in organic synthesis. It features two parts: CASA (Computer Assisted Stereochemical Analysis) is concerned with the recognition of stereochemical and symmetry elements in a molecule. For example it will assign R/S, E/Z stereochemistry. It will also perform a variety of other operations (Fischer and extended projections, chiral substructure searching) CAPS (Computer Assisted Precursor Selection) will probe the structure in question and suggest appropriate chiral and achiral precursors. The input and output are graphical and highly interactive. A 3-D drawing and simulation process is also available. Over one-hundred laboratories world-wide are users of the Chiron program. (For examples see our website http://osiris.corg.umontreal.ca under The Chiron Program). 9. Special Projects As part of several medicinally-related projects in collaboration with pharmaceutical research laboratories worldwide we are involved in the design and synthesis of prototypical molecules based on biochemical rationales or X-ray crystallographic data of enzymes. Current research projects involve the structure-based design and synthesis of inhibitors of thrombin, BACE (-secretase), renin, endothelin converting enzyme (ECE), and penicillin binding proteins. |
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| Publications |
K. Ersmark, J. R. Del Valle, S. Hanessian, Chemistry and Biology of the Aeruginosin Family of Serine Protease Inhibitors, Angew Chem. 47, 1202 (2008). S. Hanessian, S. Guesn, L. Riber, J. Marin, A. Benoist, P. Mennecier, A. Rupin, T. J. Verbeuren, G. De Nanteuil, "Targeting ACE and ECE with Dual Acting Inhibitors", Bioorg. Med. Chem. Lett.18, 1058 (2008). S. Hanessian, D. Simard, M. Bayrakdarian, E. Therrien, I. Nilsson, O. Fjellstrm, "Design, Synthesis, and Thrombin Inhibitory Activity of Pyridin-2-ones as P2/P3 Core Motifs", Bioorg. Med. Chem. Lett. 18, 1972 (2008). S. Hanessian, J. A. Grzyb, F. Cengelli, L. Juillerat-Jeanneret, "Synthesis of chemically funcitonalized superparamagnetic nanoparticles as delivery vectors for chemotherapeutic drugs", Biorg. Med. Chem. 16, 2921 (2008). S. Hanessian, V. Vinci, K. Fettis, T. Maris, M.T. P. Viet, "Self-Assembly of Non-cyclic Bis-D- and L-tripeptides into Higher Order Tubular Constructs Design, Synthesis And X-ray Crystal Superstructure", J. Org. Chem. 75, 1181 (2008). (Feature article).) S. Hanessian, L. Auzzas, "Alternative and Expedient Asymmetric Syntheses of L-(+)Noviose", Org. Lett. 10, 261 (2008). S. Hanessian, B. Deschenes-Simard, "Exploring the Remarkable Reactivities of Heterobicyclic Tetrazoles Access to Functionally Diverse and Versatile Heterocyclic Scaffolds", Organic Letters 10, 1381 (2008). S. Hanessian, C. Hocquelet, C. K. Jankowski, "Synthesis of aminocyclodextrin carboxylic acids.", Synlett 5, 715 (2008). S. Hanessian, G. Charron, A. Billich, D. Guerini, Constrained azacyclic cyclic analogues of the immunomodulatory agent FTY720 as molecular probes for sphingosine 1-phosphate receptors, Bioorg. Med. Chem. Lett. 17, 491 (2007). S. Hanessian, J. Szychowski, P. Kandasamy, N. B. Campos-Reales Pineda, A. Furtos, J. W. Keillor, Ring-to-Ring Macrocyclic Aminoglycosides as Probe for APH(3)IIIa Kinase, Bioorg. Med. Chem. Lett., 17, 3221 (2007). S. Hanessian, K. Ersmark, X. Wang, J. R. Del Valle, N. Blomberg, Y. Xue, O. Fjellstrm, Structure-based Organic Synthesis of Unnatural Aeruginosin Hybrids as Potent Inhibitors of Thrmobin, Bioorg. Med. Chem. Lett., 17, 3480 (2007). S. Hanessian, L. Auzzas, G. Giannini, M. Marzi, W. Cabri, M. Barbarino, L. Vesci, C. Pisano, "?-Alkoxy Analogues of SAHA (Vorinostat) as Inhibitors of HDAC. A Study of Chain-Length and Stereochemical Dependence, Bioorg. Med. Chem. Lett. 17, 6261 (2007). J. Kondo, K. Pachamuthu, B. Franois, J. Szychowski, S. Hanessian, E. "Westhof, Crystal Structure of the Bacterial Ribosomal Decoding Site Complexed with a Synthetic Doubly Functionalized Paromomycin Derivative: a New Specific Binding Mode to an A-Minor Motif enhances in vitro Antibacterial Activity." ChemMedChem 2 ,1631 (2007). S. Hanessian, S. Guillemette, Karolina Ersmark, P1, P3 Truncated Analogs of Oscillarin and their Inhibitory Activity against Blood Coagulation Factors, Chimia, 61, 361 (2007). O. Loiseleur, D. Ritson, M. Nina, P. Crowley, T. Wagner, and S. Hanessian, Ring-Modified Analogues and Molecular Dynamics Studies to Probe the Requirements for Fungicidal Activities of Malayamycin A and its N-Nucleoside Variants, J. Org. Chem. 72, 6353 (2007). S. Hanessian, J. Szychowski, S. S. Adhikari, G. Vasquez, P. Kandasamy, E. E. Swayze, M. T. Migawa, B. Franois, J. Wirmer-Bartoschek, E. Westhof, Structure-based Design, Synthesis and A-site rRNA Co-crystal Complexes of Functionally Novel Aminoglycoside Antibiotics I: C-2 Ether Analogues of Paromomycin, J. Med. Chem. 50, 2352 (2007). S. Hanessian and G. J. Reddy, Total Synthesis and Stereochemical Confirmation of 2,5-Diaryl-3,4-dimethyl-tetrahydrofuran Lignans: (+)-Fragransin A2 (+)-Talaumidin, (-)-Saucernetin and (-)-Verrucosin, Synlett 3, 475 (2007). S. Hanessian, S. Adhikari, J. Szychowski, P. Kandasamy, X. Wang, M. T. Migawa, R. H. Griffey, E. E. Swayze, Probing the Ribosomal RNA A-site with Functionally Diverse Analogues of Paromomycin Synthesis of Ring I Mimetics, Tetrahedron, 63, 874 (2007). |
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| Other Experience |
Consultant; Pharmaceutical, Biotech, and Agrochemical Industries |
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| Link to this profile | http://www.faculty.uci.edu/profile.cfm?faculty_id=5470 | |
| Last updated | 06/29/2008 | |
