Thomas I. Kalman
Office: 678 Natural Sciences Complex
Phone: (716) 645-4253
B.S./M.S. Technical University of Budapest
Ph.D., University at Buffalo (1968)
NIH Pre- and Postdoctoral Fellow (1967-70)
Awards and Honors:
Research Career Development Awardee, NIGMS, NIH (1971-76)
Fellow, American Institute of Chemists
American Cancer Society Scholar Award (1996)
Design, Synthesis and Study of Enzyme Inhibitors, Nucleoside & Nucleotide Analogues and Prodrugs; Design of Molecular Probes; Design of Organic Semiconductors; Study of Anticancer and Antiviral Drug Action and Resistance.
Our laboratory has been engaged in a multidisciplinary anticancer and antiviral drug discovery research endeavor that utilizes a combination of mechanism-based and structure-based design strategies. Our drug discovery effort focused on the design of mechanism-based inhibitors of key enzymes in nucleotide metabolism, which are responsible for the biosynthesis of the building blocks of DNA and RNA. These design strategies require a considerable insight into the molecular mechanisms of catalysis performed by the target enzymes, which are probed by kinetic and equilibrium isotope effect studies, and molecular modeling. Enzyme inhibitory activities of the compounds synthesized are determined using purified enzymes, as well as cellular enzyme systems.
The following enzyme targets have been studied recently:
- thymidylate synthase that is essential for de novo biosynthesis of DNA-thymine;
- thymidine phosphorylase, also known as platelet derived endothelial cell growth factor, involved in tumor angiogenesis, a process required for the growth of solid tumors.
- I. Kalman and L. Lai, “6-Substituted 5-Fluorouracil Derivatives as Transition State Analogue Inhibitors of Thymidine Phosphorylase,” Nucleosides Nucleotides & Nucleic Acids 2005, 24, 367-374.
- Jackson, S. Chopra, R. D. Smiley, P. O’Neal Maynard, A. Rosowsky, E. R. London, L. Levy, T. I. Kalman and E. E. Howell, “Calorimetric Studies of Ligand Binding in R67 Dihydrofolate Reductase,” Biochemistry 2005, 44, 12420-12433.
- I. Kalman, “Rational Design of Nucleotide Analogs as Mechanism-Based Inhibitors of Thymidylate Synthase”, in Frontiers in Nucleosides and Nucleic Acids, R. F. Schinazi and D. C. Liotta, Eds., 2004, pp. 401-429.
- -J. Jiang and T.I. Kalman, “Synthesis of 4-Formyl-4-imidazolin-2-one Nucleosides, Isomers of Uridine and 2′-Deoxyuridine,” Nucleosides Nucleotides & Nucleic Acids 2004, 23, 307-316.
- L. Saxl, J. Reston, Z. Nie, T.I. Kalman and F. Maley, “Modification of Escherichia coli Thymidylate Synthase at Tyrosine-94 by 5-Imidazolylpropynyl-2′-deoxyuridine 5′-Monophosphate,” Biochemistry 2003, 42, 4544-4551.
- I. Kalman, Z. Nie and A. Kamat, “5-Propynylpyrimidine Nucleoside Derivatives: Rationally Designed Mechanism-Based Inactivators of Thymidylate Synthase,” Nucleosides Nucleotides & Nucleic Acids 2001, 20, 869-871.
- I. Kalman and Z. Nie, “Rational Design of Selective Antimetabolites of DNA-Thymine Biosynthesis: 5-Propynylpyrimidine Nucleoside Derivatives,” Nucleosides Nucleotides 2000, 19, 357-369.
- S. Maurer, J. Pan, B.P. Booth, T.I. Kalman and H.-L. Fung, “Examination of N-Hydroxylation as a Prerequisite Mechanism of Nitric Oxide Synthase Inactivation,” Bioorg. Med. Chem. Lett. 2000, 10, 1077-1080.
- I. Kalman, Z. Nie and A. Kamat, “Mechanism-Based Inactivation of Thymidylate Synthase by 5-(3-Fluoropropyn-1-yl)-2’-deoxyuridine 5’-Phosphate,” Bioorg. Med. Chem. Lett. 2000, 10, 391-394.
- T.I. Kalman, K. Sen and X.-J. Jiang, “Mechanism of Inhibition of HIV Reverse Transcriptase by 1-(2’-Deoxy-b-D-ribofuranosyl)-4-acetylimidazolin-2-one (Imidine),” Nucleosides Nucleotides 1999, 18, 847-848.