 |
| Born
Moscow, Russia, 1971. |
| Moscow
State University, Diploma, 1993. |
| University
of Chicago, Ph.D., 1998. |
| University
of Pennsylvania, Postdoctoral Associate, 1998-2000. |
| University
of Chicago, Assistant Professor, 2000-2006. |
| University
of Chicago, Associate Professor, 2006-present. |
CTCMLD, Director,
2008-Present |
| |
| Accolades |
| 2008
Magomedov-Scherbinina Memorial Prize, University of
Rochester. |
| 2007
Novartis Chemistry Lectureship. |
| 2006 SSOCJ
Lectureship Award, Japan. |
| 2005
National Science Foundation CAREER Award. |
| 2005
GlaxoSmithKline Chemistry Scholar Award. |
| 2004
Camille Dreyfus Teacher-Scholar Award. |
| 2004
Amgen Young Investigator's Award. |
| 2004
American Cancer Society Research Scholar. |
| 2003
Alfred P. Sloan Fellow. |
| 1997
Elizabeth R. Norton Prize for Excellence in Graduate. |
| 1993
Diploma with Honors, Moscow State University. |
|
|
| Sergey
A. Kozmin |
| Associate
Professor |
|
|
| |
| Research
Interests: |
| Our
research program brings together the complimentary knowledge of organic
synthesis, medicinal chemistry, biochemistry, cellular biology and
animal pharmacology in order to identify an arsenal of small-molecule
agents that target new molecular mechanisms of combating cancer cell
growth in vitro and in vivo. |
| |
|
Small-Molecule Modulation of Cytokinesis.
The final stage of cell division involves the assembly of the
contractile ring attached to the plasma membrane to create a cleavage
furrow that partitions the cell into two lobes. Since the contractile
ring is composed of actin filaments, compounds that depolymerize actin
are capable of inhibiting cell division. We developed the practical
synthesis of bistramide A, identified actin as the primary cellular
receptor of this natural product, crystallized the bistramide A-actin
complex and discovered that bistramide A covalently cross-linked its
protein target in the cell. Our current studies are aimed at evaluation
of in vivo efficacy of rationally designed, fully synthetic
compounds that mimic the function of the parent natural product but
minimize its general toxicity. |
 |
| |
| Small-Molecule Modulation of Eukaryotic Protein Synthesis. While inhibition of protein synthesis has been exploited as a highly effective antibiotic strategy, this approach has not been employed by any of the existing FDA approved anticancer agents. We developed a fully stereocontrolled synthesis of spirofungin A and demonstrated that this natural product selectively blocked activity of isoleucyl tRNA synthetase. To understand the remarkable specificity of this inhibitor, we are cloning, expressing, purifying human isoleucyl tRNA synthetase for the subsequent crystallization of the protein/small-molecule complex. In addition, we are assembling a series of simplified analogs of spirofungin A for evaluating the ability of such compounds to inhibit tumor growth in vivo. |
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| |
| Small-Molecule Regulation of Eukaryotic Energy Metabolism. The energy production in eukaryotic cells utilizes two ATP-generating pathways, including glycolysis and oxidative phosphorylation. We established that leucascandrolide A and neopeltolide, two structurally homologous marine natural products, inhibited oxidative phosphorylation in both yeast and mammalian cells. This finding was enabled by the development of a unified synthetic strategy to this class of complex polyketide-based macrolides. Subsequent cell-based, genetics and biochemical studies established cytochrome bc1 complex as the cellular target of leucascandrolide A and neopeltolide. Our work provided the molecular basis of a highly potent antiproliferative activity of this class of marine natural products, identifying them as useful biochemical tools for investigation of the eukaryotic energy metabolism. |
 |
| High-Throughput Synthesis and New Reaction Discovery. Efficient introduction of scaffold diversity into small molecule libraries is one of the most challenging conceptual problems of modern high-throughput organic synthesis. The resulting libraries are expected to probe a large segment of chemical diversity space increasing the probability of identifying new bioactive compounds. We are developing new methods and strategies for the parallel introduction of a variety of diverse polycyclic scaffolds into new small-molecule libraries. A particular emphasis is placed on exploring the fundamental reactivity of electron rich alkynes to enable rapid assembly of a range of cyclic structures. This work is carried out as a part of a newly established Chicago Tri-Institutional Center for Chemical Methods and Library Development, which bridges seven research groups at three leading universities in the Chicago area.
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| Selected
References |
| Ulanovskaya, O.; Janjic, J.; Matsumoto, K.; Schumacker, P. T.; Kron, S. J.; Kozmin, S. A. Chemical Synthesis Enables Identification of Cytochrome bc1 Complex as the Cellular Target of Leucascandroide A and Neopeltolide. Nature Chem. Biol.,
2008, 4,
418-424. |
| Rizvi, S.; Rock, R.; Kozmin, S. A. The Dual Mode of Action of Bistramide A Entails Severing of Actin Filaments and Covalent Protein Modification. Proc. Natl. Acad. Sci. USA. 2008, 105, 4088-4092.
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| Marjanovic, J.; Kozmin, S. A. Spirofungin A: Stereoselective Synthesis and Inhibition of Isoleucyl-tRNA Synthetase. Angew. Chem. Int. Ed. 2007, 46, 9010-9013.
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| Rizvi, S.; Tereshko, V.; Kossiakoff, A. A.; Kozmin, S. A. Structure of Actin-Bistramide A Complex at 1.35 Å Resolution. J. Am. Chem. Soc. 2006, 128, 3882-3883.
|
| Sun, J.; Conley, M.; Zhang, L.; Kozmin, S. A. Gold and Platinum-Catalyzed Cycloisomerizations of 1,5-Enynes to Cyclohexadienes with a Broad Alkyne Scope. J. Am. Chem. Soc. 2006, 128, 4991-4993.
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| Sun, J.; Kozmin, S. A. Silver-Catalyzed Hydroamination of Siloxy Alkynes. Angew. Chem. Int. Ed. 2006, 45, 4991-4993.
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| Statsuk, A. V.; Bai, R.; Baryza, J. L.; Verma, V. A.; Hamel, E.; Wender, P. A.; Kozmin, S. A. Actin is the Primary Cellular Receptor of Bistramide A. Nature Chem. Biol. 2005, 1, 383-388.
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| Zhang, L.; Kozmin, S. A. Gold-Catalyzed Assembly of Heterobicyclic Systems. J. Am. Chem. Soc. 2005, 127, 6962-6963.
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| Zhang. L.; Kozmin, S. A. Gold-Catalyzed Cycloisomerizations of Siloxy Enynes to Cyclohexadienes. J. Am. Chem. Soc. 2004, 126, 11806-11807.
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| Statsuk, A. V.; Liu, D.; Kozmin, S. A. Synthesis of Bistramide A. J. Am. Chem. Soc. 2004, 126, 9546-9547.
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| Kozmin, S. A.; Wang, Y. A Three-Dimensional Array for Multiparallel Synthesis. Angew. Chem. Int. Ed. Engl. 2003, 42, 903-905.
|
| Wang, Y.; Janjic, J.; Kozmin, S. A. Synthesis of Leucascandrolide A via a Spontaneous Macrolactolization. J. Am. Chem. Soc. 2002, 124, 13670-13671.
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Organic Chemistry 