Richard F. Borch, Ph.D., M.D. Head, Department of Medicinal Chemistry and Molecular Pharmacology Professor of Medicinal Chemistry and Molecular Pharmacology Phone: (765) 494-1403 Fax: (765) 494-1414 E-mail: borch@purdue.edu Full directory listing

Specialization: Anticancer Drugs: Design, Synthesis, and Mechanisms of Action

Education

Research: Anticancer Drugs: Design, Synthesis, and Mechanisms of Action

Our laboratory has a long-standing interest in the development of new drugs for the treatment of cancer. Current efforts are focused on the design, synthesis and activation mechanisms of novel prodrugs that undergo enzyme-catalyzed activation in the tumor cell to liberate a toxic phosphoramidate, phosphate or phosphonate. Several different targets are under investigation to exploit this approach. First, we have applied this novel prodrug chemistry to deliver and release therapeutic concentrations of cytotoxic nucleotides intracellularly in tumors that are resistant to the corresponding nucleosides because of transport or kinase deficiency. Second, this chemistry has been incorporated into the design and synthesis of novel phosphotyrosine peptidomimetic prodrugs (1) that interfere with cell signaling pathways regulating cell proliferation. Cell-based assays have confirmed that the phosphotyrosine peptidomimetic prodrugs deliver the bioactive phosphate and inhibit tumor cell proliferation. We have also extended this chemistry to the synthesis of phosphatase-resistant phosphopeptidomimetics by incorporating a difluoromethylphosphonate group as a phosphate surrogate. This provides technology for the design, synthesis and intracellular delivery of long-lived phosphate-based antagonists and phosphatase inhibitors.

Finally, in collaboration with the Gibbs lab we have developed a novel series of prodrugs (2) designed to inhibit farnesyl transferase, an important enzymatic target in tumor cells. Although these prodrugs have minimal activity as single agents, in combination with one of the widely used statin drugs they are nanomolar inhibitors of tumor cell proliferation and induce a potent G1 cell cycle arrest. Current efforts are focused on the synthesis of analogs possessing improved pharmaceutical properties that will lead to the development of an effective therapeutic agent.

Representative Publications

Choi, J. Y. and Borch, R.F.. Highly efficient synthesis of enantiomerically enriched 2-hydroxymethylaziridines by enzymatic desymmetrization. Org. Lett. 9:215-218 (2007).

Boutselis, I.G., Yu, Z., Zhang, Z.-Y. and Borch, R.F. Synthesis and cell-based activity of a potent and selective PTP1B inhibitor prodrug. J. Med. Chem. 50, 856-864 (2007).

Wu, W. and Borch, R.F. Synthesis and biological activity of N-2,3-dihydroxypropyl-N-4-chlorobutyl nucleoside phosphoramidate prodrugs. Mol. Pharmaceutics 3: 451-456. (2006)

Garrido-Hernandez, H., Moon, K.D., Geahlen, R.L., and Borch, R.F. Design and synthesis of phosphotyrosine peptidomimetic prodrugs. J. Med. Chem. 49: 3368-336. (2006)

Wu, W., Freel Meyers, C.L., and Borch, R.F. A novel method for the preparation of nucleoside triphosphates from activated nucleoside phosphoramidates. Org. Lett. 6: 2257-2260. (2004)

Tobias, S.C. and Borch, R.F. Synthesis and biological evaluation of a cytarabine phosphoramidate prodrug. Mol. Pharmaceutics 1: 112-116. (2004)

Meyers, C. L. F. and Borch, R. F. A novel method for the immobilization of nucleotides. Org. Lett. 5: 341-344 (2003).

Hernick, M. and Borch, R. F. Studies on the mechanisms of activation of indolequinone phosphoramide prodrugs. J. Med. Chem. 46: 148-154 (2003).

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).

Tobias, S. C. and Borch, R. F. Synthesis and biological studies of novel nucleoside phosphoramidate prodrugs. J. Med. Chem. 44, 4475, 2001.