Our research interests are aimed toward investigating and manipulating the noncovalent interactions that govern molecular recognition in biological systems. We are studying interactions between proteins and their ligands, between proteins and DNA, and the noncovalent interactions that dictate protein secondary and tertiary structure. These projects utilize traditional tools of organic chemistry such as synthesis and spectroscopic evaluation of molecular structure and conformation, and also employ a variety of more biological techniques such as electrophoresis, enzymology, and protein isolation and purification.

The diversity of our publications this year demonstrates that all aspects of my research program are moving ahead. One of our papers describes our development of inhibitors for protein tyrosine phosphatases. These enzymes play an important role in controlling all intracellular signal transduction pathways, and inhibitors of phosphatases are useful for treating a variety of diseases including type II diabetes and infection by Yersinia pestis, the causative agent of bubonic plague. We have examined how the linker structure in a series of divalent inhibitors influences their potency, and discovered inhibitors with nanomolar activity against the Yersinia phosphatase. Three papers describe our continuing work to develop potent and selective inhibitors for a variety of proteases. Inhibitors of the serine protease plasmin have potential as cancer chemotherapeutic agents that are targeted toward the processes of metastasis and angiogenesis. We have also discovered that squaric/hydroxamic acid hybrids are a completely new motif for the design of matrix metalloprotease inhibitors. This study represents a new research direction for my group.

Our other three papers are in the general area of asymmetric catalysis. This is an area that is a major focus of current research in organic chemistry, and it is critical for the production of pharmaceutical agents and fine chemicals. Two of the manuscripts describe our discovery of modular amino acid-based catalysts for the enantioselective addition of vinylzinc reagents to aldehydes to yield chiral allylic alcohols. Using an iterative optimization strategy we have found catalysts for this reaction that give up to 95% enantiomeric excess and excellent yields. The final manuscript describes our use of an enzyme as high throughput tool to measure the enantiomeric excess of large numbers of samples. This work broadens our previously described EMDee procedure (enzymatic method to determine ee) by requiring the enzyme to simply bind to the analyte, rather than process it as a substrate. In this manuscript, we describe the application of this strategy to the analysis of chiral sulfoxides.

National Institutes of Health - General Medicine: "A New Class of Serine and Cysteine Protease Inhibitors"; $850,931; 5/1/03 - 4/30/06

"Investigations of Linker Structure on the Potency of a Series of Bidentate Protein Tyrosine Phosphatase Inhibitors" Xie, J.; Seto, C. T. Bioorg. Med. Chem. 2005, 13, 2981.

"A Positional Scanning Approach to the Discovery of Dipeptide-Based Catalysts for the Enantioselective Addition of Vinylzinc Reagents to Aldehydes" Sprout, C. M.; Richmond, M. L.; Seto, C. T. J. Org. Chem. 2005, 70, 7408.

"A Comparison of Cyclohexanone and Tetrahydro-4H-thiopyran-4-one 1,1-dioxide as Pharmacophores for the Design of Peptide-Based Inhibitors of the Serine Protease Plasmin" Xue, F.; Seto, C. T. J. Org. Chem. 2005, 70, 8309.

"Enantioselective Addition of Vinylzinc Reagents to Aldehydes Catalyzed by Modular Ligands Derived from Amino Acids" Richmond, M. L.; Sprout, C. M.; Seto, C. T. J. Org. Chem. 2005, 70, 8835.

"Using Enzyme Inhibition as a High Throughput Method to Measure the Enantiomeric Excess of a Chiral Sulfoxide" Sprout, C. M.; Seto, C. T. Org. Lett. 2005, 7, 5099.

"Selective Inhibitors of the Serine Protease Plasmin: Probing the S3 and S3' Subsites Using a Combinatorial Library" Xue, F.; Seto, C. T. J. Med. Chem. 2005, 48, 6908.

"Squaric Acid-Based Peptidic Inhibitors of Matrix Metalloprotease-1 (MMP-1)" Onaran, M. B.; Comeau, A. B.; Seto, C. T. J. Org. Chem. 2005, 70, 10792.

"Squaric Acids: A New Motif for Designing Inhibitors of Protein Tyrosine Phosphatases" Xie, J.; Comeau, A. B.; Seto, C. T. Org. Lett. 2004, 6, 83.

"Parallel Synthesis of a Library of Bidentate Protein Tyrosine Phosphatase Inhibitors that are Based on the ?-Ketoacid Motif" Chen, Y. T.; Seto, C. T. Bioorg. Med. Chem. 2004, 12, 3289.

"Solid-Phase Synthesis of Chiral N-Acylethylenediamines and Their Use as Ligands for the Asymmetric Addition of Alkylzinc and Alkenylzinc Reagents to Aldehydes" Sprout, C. M.; Richmond, M. L.; Seto, C. T. J. Org. Chem. 2004, 69, 6666.

"Peptidic a-Ketocarboxylic Acids and Sulfonamides as Inhibitors of Protein Tyrosine Phosphatases" Chen, Y. T.; Xie, J.; Seto, C. T. J. Org. Chem. 2003, 68, 4123.

"Chiral N-Acyl-ethylenediamines as New Modular Ligands for the Catalytic Asymmetric Addition of Alkylzinc Reagents to Aldehydes" Sprout, C. M.; Seto, C. T. J. Org. Chem. 2003, 68, 7788.

"Using a Lipase as a High Throughput Screening Method for Measuring the Enantiomeric Excess of Allylic Acetates" Onaran, M. B.; Seto, C. T. J. Org. Chem. 2003, 68, 8136.

"Modular Ligands Derived from Amino Acids for the Enantioselective Addition of Organozinc Reagents to Aldehydes" Richmond, M. L.; Seto, C. T. J. Org. Chem. 2003, 68, 7505.

"Inhibitors of Plasmin that Extend into Both the S and S' Binding Sites: Cooperative Interactions Between S1 and S2" Abato, P.; Yuen, C. M.; Cubanski, J. Y.; Seto, C. T. J. Org. Chem. 2002, 67, 1184.

"Divalent and Trivalent a-Ketocarboxylic Acids as Inhibitors of Protein Tyrosine Phosphatases" Chen, Y. T.; Seto, C. T. J. Med. Chem. 2002, 45, 3946.

"a-Ketocarboxylic Acid-Based Inhibitors of Protein Tyrosine Phosphatases" Chen, Y. T.; Onaran, M. B.; Doss, C. J.; Seto, C. T. Bioorg. Med. Chem. Lett. 2001, 11, 1935.

"EMDee: An Enzymatic Method for Determining Enantiomeric Excess" Abato, P.; Seto, C. T. J. Am. Chem. Soc. 2001, 123, 9206.

"The Effects of Buffers on the Thermodynamics and Kinetics of Binding Between Positively-Charged Cyclodextrins and Phosphate Ester Guests" Ghosh, M.; Zhang, R.; Lawler, R. G.; Seto, C. T. J. Org. Chem. 2000, 65, 735.

"Biotinylation of Substituted Cysteines in the Nicotinic Acetylcholine Receptor Reveals Distinct Binding Modes for a-Bungarotoxin and Erabutoxin a" Spura, A.; Riel, R. U.; Freedman, N. D.; Agrawal, S.; Seto, C. T.; Hawrot, E. J. Biol. Chem. 2000, 275, 22452.

"Hydrolysis of Amides Catalyzed by 4-Heterocyclohexanones: Small Molecule Mimics of Serine Proteases" Ghosh, M.; Conroy, J. L.; Seto, C. T. Angew. Chemie. Int. Ed. Engl. 1999, 38, 514 - 516.

"4-Heterocyclohexanone-Based Inhibitors of the Serine Protease Plasmin" Sanders, T. C.; Seto, C. T. J. Med. Chem. 1999, 42, 2969.

"A Combinatorial Library of Serine and Cysteine Protease Inhibitors that Interact with Both the S and S' Binding Sites" Abato, P.; Conroy, J. L.; Seto, C. T. J. Med. Chem. 1999, 42, 4001.

"Inhibition of Phosphatase Activity by Positively-Charged Cyclodextrins" Ghosh, M.; Sanders, C. T.; Zhang, R.; Seto, C. T. Org. Lett. 1999, 1, 1945.

"13C NMR Studies Demonstrate that Tetrahydropyranone-Based Inhibitors Bind to Cysteine Proteases by Reversible Formation of a Hemithioketal Adduct" Conroy, J. L.; Seto, C. T., J. Org. Chem. 1998, 63, 2367.

"Synthesis of Cyclohexanone-Based Cathepsin B Inhibitors that Interact with Both the S and S' Binding Sites" Conroy, J. L.; Abato, P.; Ghosh, M.; Austermuhle, M. I.; Kiefer, M. R.; Seto, C. T. Tetrahedron Lett. 1998, 39, 8253 - 8256.

"Using the Electrostatic Field Effect to Design a New Class of Inhibitors for Cysteine Proteases" Conroy, J. L.; Sanders, T. C.; Seto, C. T. J. Am. Chem. Soc. 1997, 119, 4285.

• Eli Lilly Predoctoral Fellow - Harvard University: 1991 - 1992
• United States Army Medical Research and Materiel Command: Breast Cancer Research Initiative - Career Development Award - Brown University: 1996 - 2000
• Salomon Faculty Research Award - Brown University: 1996 - 1998
• Award for Outstanding Academic Advising - Brown University: 2000

American Chemical Society
American Association for the Advancement of Science