Venkatram Mereddy, PhD

Research Summary

• New generation anti-cancer agents
• Discovery of new synthetic methods and reagents

Discovery of new synthetic methods and reagents:
The formation of carbon-carbon and carbon-heteroatom bonds is of fundamental importance in organic chemistry. Research in this area in our lab addresses problems in synthetic methodology with focus on the design of highly functionalized synthons to incorporate several synthetic operations in one unit. A significant emphasis will also be placed on the discovery and development of new stereoselective synthetic methods and reagents as means for achieving synthetic goals with the aim of finding simple solutions to complex synthetic problems.

Stereoselective total syntheses of new generation anticancer molecules and the mechanism based design of analogs:
A major objective of this research program is the total synthesis of natural products displaying interesting biological properties, containing challenging structural features, and/or occurring in low natural abundance. In this area, we work on molecules that show promise of being developed into clinically useful new generation anti-cancer agents. Synthesis and examination of key partial structures and the corresponding unnatural enantiomers of the natural products will also be taken up. We also address the structural basis of the natural products interactions with biological targets and define fundamental relationships between structure, functional reactivity, and properties. These multi-disciplinary projects involve complex molecule synthesis, molecular biology and computational chemistry.

Rational design, syntheses and biological evaluation of novel antifolates as antibacterial and antineoplastic agents:
Folates play an essential role in the metabolism of the biosynthesis of purines and pyrimidines for all living organisms. They are involved in the processes of cell reproduction, in which numerous enzymes that use folates either as cofactor or as substrate are involved. Antifolate drugs are molecules that interfere with the microbial and human folate metabolic pathway at some level. Work in this area involves the mechanism based rational design, synthesis and biological evaluation of novel exploratory antifolates as inhibitors several enzymes such as Thymidylate synthase (TS), Dihydrofolate reductase, (DHFR) Serine hydroxymethyltransferase (SHMT), Folylpolyglutamyl synthetase (FPGS), g-Glutamylhydrolase (g-GH), Glycinamide-ribonucleotide transformylase (GARTfase), and Amino-imidazole-carboxamideribonucleotide transformylase (AICARTfase). The molecules synthesized in this project will be evaluated for potential applications as antibacterial and antitumoral agents.

Development of methodologies for targeted drug delivery:
A recent trend in cancer chemotherapy involves administration of high-dose multiple drug treatment regimens at the earliest points of diagnosis. However, high toxicity of chemotherapeutic agents towards normal tissues leads to severe physiological effects leading to patient fatalities. Targeted drug delivery systems promise to expand the therapeutic windows of drugs by increasing the selective delivery to the target tissues. This procedure in turn will lead to a reduction in minimum effective dose of the drug, the accompanying drug toxicity, and an overall improvement in therapeutic efficacy. The goal of this interdisciplinary research project is to design and develop novel drug delivery systems that target cancer cells selectively.