Mark S. Cushman, Ph.D. Professor of Medicinal Chemistry Phone: (765) 494-1465 Fax: (765) 494-6790 E-mail: cushman@purdue.edu Full directory listing

Specialization: Medicinal Chemistry

Education

Research: Medicinal Chemistry

Our research group is engaged in the design and synthesis of a variety of molecules that interact with specific enzymes and membrane-bound receptors. This effort involves the integration of basic concepts in organic reaction mechanisms, synthetic organic chemistry and biochemistry. At the present time, potential anti-AIDS agents, anticancer agents, and antibiotics are being designed, synthesized, and tested. In the anti-AIDS drug design and synthesis area, we are presently focusing on the synthesis of new non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs). We have recently reported a novel series of alkenyldiarylmethane (ADAM) NNRTIs that are potent inhibitors of the cytopathic effect of HIV-1. These compounds are being structurally modified in order to obtain novel ADAMs that: 1) have lower toxicities, 2) remain active against mutant reverse transcriptases that are resistant to the existing NNRTIs, 3) have the ability to suppress the emergence of resistant viral strains, 4) have synergistic anti-HIV activity in combination with other anti-HIV agents, 5) are metabolically stable, 6) have a wide range of activity vs. various HIV-1 strains, and 7) have high affinities for RT. The design of new ADAMs is being facilitated through computer graphics molecular modeling approaches. We are also working on the design and synthesis of anti-viral agents against viruses that can be weaponized. A specific goal of this project is to design and synthesize ligands that are targeted to the hydrophobic binding pocket of the Sindbis virus capsid protein. These molecules are fashioned to block the interaction of the viral capsid protein with the N-terminal arm of an adjacent capsid protein molecule, which should inhibit capsid assembly. In addition, the occupation of the hydrophobic binding pocket of the viral capsid protein by the inhibitor is also expected to block the binding of the cell membrane-bound E2 glycoprotein spikes, thus inhibiting viral budding. In the anti-cancer drug development area, we are focusing on novel indenoisoquinoline inhibitors of topoisomerase I. One of the main goals of this project is to synthesize topoisomerase I inhibitors that will facilitate crystallization and X-ray structure determination of ternary complexes containing the enzyme, a DNA fragment, and the inhibitor. This will provide insight into the mechanism of action of the indenoisoquinolines as topoisomerase I inhibitors and it will shed light on how other topoisomerase I inhibitors work as well. Work in this area has led to the synthesis of indenoisoquinolines containing polyamine side chains that confer exceptional potency as topoisomerase I inhibitors and as cytotoxic agents in human cancer cell cultures. A second project in the anticancer drug design area involves the design and synthesis of brefeldin A prodrugs that induce apoptosis in cancer cell cultures. We are also preparing affinity columns for use in the identification of brefeldin A receptors. A final research interest in our group is the design and synthesis of inhibitors of enzymes involved in the biosynthesis of riboflavin. In addition to the synthesis of therapeutically useful antibiotics, a main goal of this project is to create new methodology that will provide high resolution structures of complexes formed between the enzymes and metabolically stable analogs of hypothetical reaction intermediates.

Representative Publications

Cinelli, M. A.; Cordero, B.; Dexheimer, T. S.; Pommier, Y.; and Cushman, M. "Synthesis and Biological Evaluation of 14-(Aminoalkyl-aminomethyl)aromathecins as Topoisomerase I Inhibitors: Investigating the Hypothesis of Shared Structure-Activity Relationships," Bioorg. Med. Chem. 17, 7145-7155 (2009).

Talukdar, A.; Breen, M.; Bacher, A.; Illarionov, B.; Fischer, M.; Georg, G.; Ye, Q.-Z.; Cushman, M. "Discovery and Development of a Small Molecule Library with Lumazine Synthase Inhibitory Activity," J. Org. Chem. 74, 5123-5134 (2009).

Zhao, Y.; Bacher, A.; Illarionov, B. Fischer, M. Georg, G.; Ye, Q.-Z., Fanwick, P. E.; Franzblau, S. G; Wan, B.; Cushman, M. "Discovery and Development of the Covalent Hydrates of Trifluoromethylated Pyrazoles as Riboflavin Synthase Inhibitors with Antibiotic Activity Against Mycobacterium tuberculosis," J. Org. Chem. 74, 5297-5303 (2009).

Maiti, A.; Sturdy, M.; Marler, L.; Pegan, S. D; Mesecar, A. D; Pezzuto, J. M.; Cushman, M. "Synthesis of Casimiroin and Optimization of Its Quinone Reductase 2 and Aromatase Inhibitory Activity," J. Med. Chem. 52, 1873-1884 (2009).

Deng, B.-L.; Zhao, Y.; Hartman, T. L.; Watson, K.; Buckheit, R. W. Jr.; Pannecouque, C.; De Clercq, E.; Cushman, M., "Synthesis of Alkenyldiarylmethanes (ADAMs) Containing Benzo[d]isoxazole and Oxazolidin-2-one Rings, a New Series of Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors," Eur. J. Med. Chem. 44, 1210-1214 (2009).

Y. Pommier and M. Cushman, "The Indenoisoquinoline Non-Camptothecin Topoisomerase I Inhibitors: Update and Perspectives." Mol. Cancer Ther. 8, 1008-1014 (2009).

R. P. Bakshi, D. Sang, A. Morrell, M. Cushman, and T. A. Shapiro, "Activity of Indenoisoquinolines against African Trypanosomes," Antimicrob. Agents Chemother. 53, 123-128 (2009).

Yu, T.-Y.; O'Connor, R. D.; Sivertsen, A. C.; Chiauzzi, C.; Poliks, B.; Fischer, M; Bacher, A.; Haase, I.; Cushman, M.; Schaefer, J. "¹⁵N{³¹P} REDOR NMR Studies of the Binding of Phosphonate Reaction Intermediate Analogues to Saccharomyces cerevisiae Lumazine Synthase," Biochemistry 47, 13942-13951 (2008).

M. Cuendet, C. P. Oteham, A. Maiti, B. A. Craig, M. Cushman, R. C. Moon and J. M. Pezzuto, "Zapotin Prevents Mouse Skin Tumorigenesis During the Stages of Initiation and Promotion," Anticancer Res. 28, 3705-3709 (2008).

Y. L. Song and M. Cushman, "The Binding Orientation of a Norindenoisoquinoline in the Topoisomerase I-DNA Cleavage Complex Is Primarily Governed by π-π Stacking Interactions," J. Phys. Chem. B 112, 9484-9489 (2008).

Curriculum Vitae

Click here for a full CV for Mark S. Cushman. (an Adobe Acrobat file)