Research Interests: Anti-Cancer Drug Development; Metabolism-based Drug Design of Antifolates; Biochemical Pharmacology of Natural Products; Synthetic Organic Chemistry; Metabolism of Antifolate Drugs. The primary focus of research in this laboratory is to develop antifolate drugs for the treatment of neoplastic, microbial, autoimmune and inflammatory diseases. New drugs are designed, synthesized and evaluated using the appropriate biochemical and pharmacological test systems for their potential therapeutic use. Metabolism-based drug design involves the modulation or elimination of biotransformations of drugs that contribute to toxicity and undesirable side effects without compromising their therapeutic effectiveness. Molecules are chemically engineered to preserve target specificity, pharmacological control and to improve therapeutic index. We have used metabolism-based drug design for the clinical development of the experimental anti-cancer drug MDAM (4'-methylene-10-deazaaminopterin) for the treatment of human solid tumors and the pre-clinical development of Mobiletrex (M-trex). Tumor selective anti-cancer drugs are being developed by targeting therapeutic agents to cancer cells via carriers and receptors that are over-expressed in these tissues. Typical strategies include molecular engineering of potential entities to optimize their interaction with the over-expressed carriers or receptors or tagging a powerful therapeutic agent to synthetic binders of the carriers or receptors that are subsequently internalized and released in a biologically active form. Either approach, if successful, results in tumor selective cell kill, thereby achieving selective toxicity in the chemotherapy of cancer. Known differences in the structures of mammalian versus microbial folate dependent enzymes are being exploited for the design and development of novel anti-microbial agents. Existing collaborations will permit us to biologically evaluate all potential drugs to their fullest extent in all areas of therapeutic interests. Collectively, research in our laboratory should provide expertise in drug design, experimental therapeutics, enzyme inhibitors, drug synthesis and development. Representative Publications: Nair MG. Metabolically Inert Anti-inflammatory and Anti-tumor Antifolates. U.S. Patent 5,912,251 (1999). Nair MG, and Liu L. New and Novel Nonclassical Folate Analog Inhibitors of Glycinamide Ribonucleotide Formyltransferase. U.S. Patent 5,593,999 (1997). Nair MG, Nair IG, and Pati R. Enantiomers of Non-polyglutamylatable deazaaminopterin. U.S. Patent, 5,550,128 (1996). Nair MG, Fayard ML, Lariccia JM, Amato AE, McGuire JJ, Galivan JH, and Kisliuk RL. Metabolism-blocked folate analog inhibitors of dihydrofolate reductase. Synthesis and biological evaluation of Mobiletrex. Med. Chem. Research 1999; 9:176-185. Lobo AP, Nair MG, Changchain LM, Weichsel A, Montfort WR, and Maley F. Mode of action of site-directed irreversible folate analog inhibitors of thymidylate synthase. Biochemistry 1998; 37,4535-4542. Faessel HM, Slocum HK, Jackson RC, Boritzki TJ, Rustum YM, Nair MG, Greco WR. Super in vitro synergy between inhibitors of dihydrofolate reductase and inhibitors of other folate-requiring enzymes: the critical role of polyglutamylation. Cancer Res 1998; 15;58(14):3036-50. Turrens JF, Lariccia J, Nair MG. Resveratrol has no effect on lipoprotein profile and does not prevent peroxidation of serum lipids in normal rats. Free Radic Res 1997; 27(6):557-62.
 
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