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PULSe Home > Faculty Members A-C > Richard Borch
Richard F. Borch
Current Research Interests:
Our laboratory has a long-standing interest in the development of new drugs for the treatment of cancer. Current efforts are focused on the development of cytotoxic agents that exhibit increased selectivity for tumor vs. normal cells. The approach addresses the design, synthesis and activation mechanisms of novel prodrugs containing a non-cytotoxic phosphoramidate ester that undergo enzyme-catalyzed activation in the tumor cell to liberate a toxic phosphoramidate ion. Several different strategies are under investigation to exploit this approach. First, a series of bioreductive alkylating agents has been developed that undergoes selective activation under hypoxic conditions. The lead compounds are highly toxic to human tumor cell lines in vitro and exhibit potent activity against human tumor xenografts in vivo. They also exhibit minimal toxicity at therapeutic doses, suggesting that they are excellent candidates for clinical development. Second, DT-diaphorase (DTD) is an enzyme that is overexpressed in a number of human solid tumors and thus can be exploited as a target for the development of a novel series of prodrugs. We have synthesized a number of quinone prodrugs and demonstrated that they are excellent substrates for the purified human enzyme (kcat/KM > 107 M-1s-1). The lead compounds are exceptionally toxic to human tumor cell lines in vitro and show antitumor activity against human tumor xenografts in vivo.
Finally, we have developed novel prodrug chemistry to deliver and release nucleotides and tyrosine phosphates intracellularly. This chemistry has been incorporated into the design of novel phosphotyrosine peptidomimetic and nucleotide prodrugs that interfere with pathways regulating cell proliferation. We have confirmed that the prodrugs deliver nucleotide and inhibit intracellular enzymatic activity. Cell-based assays have also demonstrated that the phosphotyrosine peptidomimetic prodrugs deliver the active inhibitor and block intracellular signaling pathways
Selected Publications:
Tobias, S.C. and Borch, R. F. Synthesis and biological studies of novel nucleoside phosphoramidate prodrugs. J. Med. Chem. 44: 4475-4480 (2001).
Meyers, C. L. F. and Borch, R. F. A novel method for the preparation of nucleoside diphosphates. Org. Lett. 3: 3765-3768 (2001).
Hernick, M., Flader, C. and Borch, R. F. Design, synthesis and biological evaluation of indolequinone phosphoramidate prodrugs targeted to DT-diaphorase. J. Med. Chem. 45: 3540-3548 (2002).
Hernick, M. and Borch, R.F. Studies on the mechanisms of activation of indolequinone phosphoramide prodrugs. J. Med. Chem. 46: 148-154 (2003).
Meyers, C. L. F. and Borch, R. F. A novel method for the immobilization of nucleotides. Org. Lett. 5: 341-344 (2003).
Tobias, S.C. and Borch, R. F. Synthesis and biological evaluation of a cytarabine ?phosphoramidate prodrug. Mol. Pharmaceutics 1, in press ( March 2004).
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