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PULSe Home > Faculty Members A-C > Mark Cushman
Mark Cushman
Current Research Interests:
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.
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.
Selected Publications:
189. M. Cushman, T. Sambaiah, G. Jin, B. Illarionov, M. Fischer, and A. Bacher, "Design, Synthesis, and Evaluation of 9-D-Ribitylamino-1,3,7,9-tetrahydro-2,6,8-purinetriones Bearing Alkyl Phosphate and a,s-Difluorophosphonate Substituents as Inhibitors of Riboflavin Synthase and Lumazine Synthase, J. Org. Chem. 69, 601-612 (2004).
190. B. D. Gehm, A. S. Levenson, H. Liu, E.-J. Lee, B. M. Amundsen, M. Cushman, V. C. Jordan, J. L. Jameson, "Estrogenic Effects of Resveratrol in Breast Cancer Cells Expressing Mutant and Wild-type Estrogen Receptors: Role of AF-1 and AF-2," J. Steroid Biochem. Mol. Biol. 88, 223-234 (2004).
191. M. A. Silvestri, M. Nagarajan, E. De Clercq, C. Pannecouque, and M. Cushman, "Design, Synthesis, Anti-HIV Activities, and Metabolic Stabilities of Alkenyldiarylmethane (ADAM) Non-nucleoside Reverse Transcriptase Inhibitors," J. Med. Chem. 47, 3149-3162 (2004).
192. A. Morrell, S. Antony, G. Kohlhagen, Y. Pommier, and M. Cushman, "Synthesis of Nitrated Indenoisoquinolines as Topoisomerase I Inhibitors," Bioorg. Med. Chem. Lett. 14, 3659-3663 (2004).
193. M. Koch, C. Breithaupt, S. Gerhardt, I. Haase, S. Weber, M. Cushman, R. Huber, A. Bacher, and M. Fischer, "Structural Basis of Charge Transfer Complex Formation by Riboflavin Bound to 6,7-Dimethyl-8-ribityllumazine Synthase," Eur. J. Biochem. 271, 3208-3214 (2004).
194. X. Xiao, S. Antony, G. Kohlhagen, Y. Pommier, and M. Cushman, "Design, Synthesis, and Biological Evaluation of Cytotoxic 11-Aminoalkenylindenoisoquinoline and 11-Diaminoalkenylindenoisoquinoline Topoisomerase I Inhibitors," Bioorg. Med. Chem. 12, 5147-5160 (2004).
195. X. Xiao, P. E. Fanwick, and M. Cushman, "Synthesis, Crystal Structure and Conversion of the Polycyclic Tris-anhydrotetramer of o-Aminobenzaldehyde to Cu(TAAB)2+, Synthetic Communications 34, 3901-3907 (2004).
196. X. Xiao, S,. Antony, G. Kohlhagen, Y. Pommier, and M. Cushman, "A Novel Autoxidative Cleavage Reaction of 9-Fluoredenes Discovered During the Synthesis of a Potential DNA-Threading Agent," J. Org. Chem. 69, 7495-7501 (2004).
197. J. Chen, T. Sambaiah, B. Illarionov, M. Fischer, A. Bacher, and M. Cushman, "Design, Synthesis, and Evaluation of Acyclic C-Nucleoside and N-Methylated Derivatives of the Ribitylaminopyrimidine Substrate of Lumazine Synthase as Potential Enzyme Inhibitors and Mechanistic Probes," J. Org. Chem. 69, 6996-7003 (2004).
198. A. B. Edsall, A. K. Mohanakrishnan, D. Yang, P. E. Fanwick, E. Hamel, A. D. Hanson, G. Agoston, and M. Cushman, "Effect of Altering the Electronics of 2-Methoxyestradiol on Cell Proliferation, on Cytotoxicity in Human Cancer Cell Cultures, and on Tubulin Polymerization," J. Med. Chem. 47, 5126-5139 (2004).
199. M. Nagarajan, A. Morrell, B. C. Fort, M. R. Meckley, S. Antony, G. Kohlhagen, Y. Pommier, and M. Cushman, "Synthesis and Anticancer Activity of Simplified Indenoisoquinoline Topoisomerase I Inhibitors Lacking Substitutions on the Aromatic Rings, J. Med. Chem. 47, 5651-5661 (2004).
200. J. Chen, B. Illarionov, A. Bacher, M. Fischer, I. Haase, G. Georg, Q. Ye, Z. Ma, and M. Cushman, "A High-Throughput Screen Utilizing the Fluorescence of Riboflavin for Identification of Lumazine Synthase Inhibitors," Anal. Biochem. 338, 124-130 (2005).
201. S. Antony, G. Kohlhagen, M. Jayaraman, S. Cao, F. Durrani, Y. M. Rustum, M. Cushman, and Y, Pommier, "Cellular Topoisomerase I Inhibition and Antiproliferative Activity by MJ-III-65 (NSC 706744), an Indenoisoquinoline Topoisomerase I Poison," Mol. Pharmacol. 67, 523-530 (2005).
202. B. L. Staker, M. D. Feese, M. Cushman, Y. Pommier, D. Zembower, L. Stewart, and A. B. Burgin, "Structures of Three Classes of Anticancer Agents Bound to the Human Topoisomerase I-DNA Covalent Complex, " J. Med. Chem. 48, 2336-2345 (2005).
203. E. Morgunova, W. Meining, B. Illarionov, I. Haase, G. Jin, A. Bacher, M. Cushman, "Crystal Structure of Lumazine Synthase from Mycobacterium tuberculosis as a Target for Rational Drug Design," Biochemistry 44, 2746-2758 (2005).
204. X. Xiao, Z.-H Miao, S. Antony, Y. Pommier, and M. Cushman, "Dihydroindenoisoquinolines Function as Prodrugs of Indenoisoquinolines," Bioorg. Med. Chem. Lett 15, 2795-2798 (2005).
205. X. Xiao, S. Antony, Y. Pommier, and M. Cushman, "On the Binding of Indeno[1,2-c]isoquinolines in the DNA-Topoisomerase I Cleavage Complex," J. Med. Chem. 48, 3231-3238 (2005).
206. A. Ioanoviciu, S. Antony, Y. Pommier, B. L. Staker, L. Stewart, and M. Cushman, "Synthesis and Mechanism of a Series of Norindenoisoquinoline Topoisomerase I Poisons Reveal an Inhibitor with a Flipped Orientation in the Ternary DNA-Enzyme-Inhibitor Complex As Determined by X-Ray Crystallographic Analysis," J. Med. Chem. 48, 4803-4814 (2005).
207. H. Y. Kim, C. Patkar, R. Warrier, R. Kuhn, and M. Cushman, "Design, Synthesis, and Evaluation of Dioxane-Based Antiviral Agents Targeted Against the Sindbis Virus Capsid Protein," Bioorg. Med. Chem. Lett. 15, 3207-3211 (2005).
208. X. Xiao and M. Cushman, "An Ab Initio Quantum Mechanics Calculation that Correlates with Ligand Orientation and DNA Cleavage Site Selectivity in Camptothecin-DNA-Topoisomerase I Ternary Cleavage Complexes," J. Amer. Chem. Soc. 127, 9960-9961 (2005).
209. X. Xiao and M. Cushman, "A Facile Method to Transform trans-4-Carboxy-3,4-dihydro-3-phenyl-1(2H)-isoquinolines to Indeno[1,2-c]isoquinolines," J. Org. Chem. 70, 6496-6498 (2005).
210. X. Xiao and M. Cushman, "The Effect of E-ring Modifications in Camptothecin on Topoisomerase I Inhibition: A Quantum Mechanics Treatment," J. Org. Chem. 70, 9584-9587 (2005).
211. B.-L. Deng, T. L. Hartman, R. W. Buckheit, Jr., C. Pannecouque, E. De Clercq, P. E. Fanwick, and M. Cushman, "Synthesis, Anti-HIV Activity, and Metabolic Stability of New Alkenyldiarylmethane HIV-1 Non-Nucleoside Reverse transcriptase Inhibitors, J. Med. Chem. 48, 6140-6155 (2005).
212. A. Ramsperger, M. Augustin, A.-K. Schott, S. Gerhardt, T. Krojer, W. Eisenreich, B. Illarionov, M. Cushman, A Bacher, R Huber, and M Fischer, "Crystal Structure of an Archaeal Pentameric Riboflavin Synthase Complex with a Substrate Analog Inhibitor: Stereochemical Implications," J. Biol. Chem. (in press).
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