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David W. Boykin Professor, Emeritus, Organic Chemistry Ph.D., University of Virginia, (1965) Dr. David Boykin Department of Chemistry Georgia State University P.O. Box 4098 Atlanta, Georgia 30302-4098
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Currently, research in our group focuses on drug design and synthesis. Our synthesis work centers on development of molecules that selectively interact with nucleic acids, which is hypothesized to lead to the observed biological activity. Synthetic work underway is directed toward discovery of new therapeutic agents for treatment of a variety of infectious diseases. These projects involve important collaborations with other scientists at Georgia State University, at other universities and institutes, and in industry.
Our approach to development of new antimicrobial agents is based upon the ability of certain diaryldiamidines (dications) to bind selectively to the minor groove of AT regions of DNA and thereby inhibits one or more DNA dependant enzymes such as the topoisomerases. Molecules selected for synthesis include the following features: (a) dicationic; (b) a shape that complements the minor groove of B-DNA; (c) recognition units (H-bond donors and acceptors) on the edge of the molecule facing the floor of the groove; and (d) variable bulk on the outer edge of the molecule. Since these dicationic molecules do not have good oral bioavailability an important part of our research program is directed toward developing orally effective prodrugs for the diamidines. Our current emphasis is on protozoan diseases and AIDS related opportunistic diseases. Currently, one of our prodrugs is in three Phase II clinical trials; one for human African trypanosomiasis , one for malaria and the other for Pneumocystis carinii pneumonia.
The human genome project as well as the sequencing of the genomes of various organisms offers a wealth of DNA targets for both therapeutic and diagnostic applications. In collaboration with Professor W. David Wilson at Georgia State University, we have recently shown that an unfused aromatic dication (aromatic diamidine) can recognize specific sequences of DNA by binding in the minor groove as a stacked-dimer. The dimer binding is strong, highly cooperative and, in contrast to related minor groove binding dications, recognizes both GC and AT base pairs in the binding site. A number of compounds in the unfused aromatic dication series have shown excellent ability to enter cells, exert useful biological activity and show relatively low nonspecific toxicity. We are pursuing compound synthesis and DNA interaction studies to increase our understanding of the structural features that influence dimer formation as well as interaction specificity and affinity. The goal of these studies is to probe the importance of structural features f or formation of the stacked dimer species. We are particularly interested in developing new classes of compounds that can interact with DNA as stacked-dimers. Such compounds have the ability to simultaneously recognize both strands of DNA with significantly enhanced binding strength and specificity. We are continuing to develop new types of compounds that can recognize a number of DNA sequences with high specificity.
Representative Publications
H. Göker, D.W. Boykin , S. Yild, Synthesis and Potent Antimicrobial activity of Some Novel 2-Phenyl or Methyl-4H-1-Benzopyran-4-ones carrying amidinobenzimidazoles, Bioorg. Med. Chem., 13, 1707-1714 (2005).
L. Stefanovic, C. E. Stephens, D. W. Boykin, B. Stefanovic, Inhibitory effect of dicationic diphenylfurans on production of type I collagen by human fibroblasts and activated hepatic stellate cells, Life Sciences, 76, 2011-2026 (2005).
C. Bailly, R. K. Arafa, F. Tanious, W. Laine, C. Tardy, A. Lansiaux, P. Colson, D. W. Boykin,W D.Wilson, Molecular determinants for DNA minor groove recognition: Design of bis-guanidinium derivative of ethidium highly selective for AT-rich DNA sequences, Biochemistry, 44, 1941-1952 (2005).
J H. Ansede, R D. Voyksner, M. A. Ismail, D. W. Boykin, R R. Tidwell and J E Hall, In Vitro Metabolism of an Orally Active O-Methyl Amidoxime Prodrug for the Treatment of CNS Trypanosomiasis, Xenobiotica, 35, 211-225 (2005).
W.D Wilson, B. Nguyen, F. A. Tanious, A. Mathis, J. E. Hall, C. E. Stephens, D. W. Boykin, Dications That Target the DNA Minor Groove: Compound Design and Preparation, DNA Interactions, Cellular Distribution and Biological Activity, Current Medicinal Chemistry-Anti-Cancer Agents, 5, 389-408 (2005).
M. L. Stewart, S. Krishna, R. J.S. Burchmore, R. Brun, H. P. De Koning, D. W. Boykin, Ri. R. Tidwell, J. Ed. Hall, M. P. Barrett, Detection of arsenical drug resistance in Trypanosoma brucei using a simple fluorescence test, Lancet, 366, 486-487 (2005).
H. Göker , S. Ö;zden , S. Yildiz , D. W. Boykin, Synthesis and Potent Antibacterial Activity against MRSA of Some Novel 1,2-Disubstituted-1H-Benzimidazole-N-alkylated-5-carboxamidines, E. J. Med. Chem, 40, 1062- 1067 (2005).
R. K. Arafa, R. Brun, T. Wenzler, F. A.Tanious, W. D. Wilson, C. E. Stephens and D. W. Boykin, Synthesis, DNA Affinity, and Antiprotozoal Activity of Fused Ring Dicationic Compounds and their Prodrugs, J Med Chem, 48, 5480-5488 (2005).
J. Y. Saulter, J. R. Kurian, L. A. Trepanier, R. R. Tidwell, A. S. Bridges, D.W. Boykin, C. E. Stephens, M. Anbazhagan and J. E. Hall, Reductive Metabolism of Antimicrobial Amidoxime Prodrugs by Cytochrome b5 and NADH Cytochrome b5 Reductase, Drug Metabolism and Disposition, 33, 1889-1893 (2005).
M.N.C. Soeiro; E.M. de Souza; C. E. Stephens and D.W. Boykin, Aromatic Diamidines as Antiparasitic Agents, Expert Opin. Invest. Drugs, 14, 957-972 (2005).
M. A. Ismail, A. Batista-Parra, Y. Miao, W. D. Wilson, T. Wenzler, R. Brun, D. W. Boykin, Dicationic Near-Linear Biphenyl Benzimidazole Derivatives as DNA-Targeted Antiprotozoal Agents, Bioorg. Med. Chem., 13, 6718-6726 (2005).
Y. Miao, M. Lee, A. Batista-Parra, M. A. Ismail, S. Neidle, D. W. Boykin, W. D. Wilson, Out of Shape DNA Minor Groove Binders:Induced Fit Interactions of Heterocyclic Dications with the DNA Minor Groove, Biochemistry, 44, 14701-14708 (2005).
Mohamed A. Ismail, David W. Boykin and Chad E. Stephens, An Efficient Synthesis of 2,5'-Diarylbichalcophenes, Tetrahedron Letters, 47, 795-797 (2006).
P. Athri, T. Wenzler, P. Ruiz, R. Brun, D. W. Boykin, R. Tidwell and W. D. Wilson, 3D QSAR on a library of heterocyclic diamidine derivatives with antiparasitic activity, Bioorganic and Medicinal Chemistry, 14, 3144-3152 (2006).
M. Mathis, J. L. Holman, L. M. Sturk, M. A. Ismail, D. W. Boykin, R. R. Tidwell, and J. E. Hall, Accumulation and Intracellular Distribution of Antitrypanosomal Diamidine Compounds DB75 and DB820 in African Trypanosomes, A.ntimicrob Agents and Chemother., 50, 2185 –2192 (2006).
E. M. de Souza, R. Menna-Barreto, T. C. Araujo-Jorge, A. Kumar, Q. Hu, D. W. Boykin, M. N. C. Soeiro, Antiparasitic activity of aromatic diamidines is related to apoptosis-like death in Trypanosoma cruzi, Parasitology, 133, 75-79 (2006).
E. M. de Souza , G. Melo, D. W. Boykin, A. Kumar, Q. Hu and M. de Nazaré C. Soeiro,, Trypanocidal activity of the phenyl-substituted analogue of furamidine DB569 against Trypanosoma cruzi infection in vivo, J of Antimicrobial Chemotherapy, 58, 610-614. (2006).
E. M. White, F. Tanious, M. A. Ismail, A. P. Reszka, S. Neidle, D. W. Boykin, W. D. Wilson, Structure-Specific recognition of quadruplex DNA by organic cations: Influence of shape, substituents and charge, Biophysical Journal, in press (2006).
M. A. Ismail, R. K. Arafa, R. Brun, T. Wenzler, Yi Miao, W. Dl Wilson , Cl Generaux, Al Bridges, J. E. Hall and D.W. Boykin, Synthesis, DNA Affinity, and Antiprotozoal Activity of Linear Dications: Terphenyl Diamidines and Analogues., J Med Chem, 49, 5324-5332 (2006).
M. A. Ismail and D.W. Boykin, Synthesis of Deuterium and 15N-Labelled 2,5-Bis[5-amidino-2-pyridyl]furan and 2,5-Bis[5-(methoxyamidino)-2-pyridyl]furan, J Labelled Cpd Radiopharm, 49, 985-996 (2006).
L.Hu, Z. Li, Y. Li, J. Qu, Y.-H. Ling, J.-D Jiang, D. W. Boykin, Synthesis and Structure-Activity Relationships of Carbazole Sulfonamides as a Novel Class of Potent Antimitotic Agents Against Solid Tumors, Med Chem, 49, 6273-6282 (2006).
S. Chackal-Catoen, Y.Mao, W. D. Wilson, T. Wenzler, R. Brun and D. W. Boykin, Dicationic DNA-Targeted Antiprotozoal Agents: Naphthalene Replacement of Benzimidazole, Bioorganic and Medicinal Chemistry, 14, 7434-7445 (2006).
M. Z. Wang, J. Y. Saulter, E. Usuki, Cheung, M. Hall, A. Bridges, G. Loewen, O. T. Parkinson, C. E. Stephens. J. L. Allen, D. C. Zeldin, D. W. Boykin, R. R. Tidwell, A. Parkinson, M. F. Paine and J. E. Hall, CYP4F Enzymes are the Major Enzymes in Human Liver Microsomes that catalyze the O-Demethylation of the Antiparasitic Prodrug DB289, Drug Metab Dispos, 34, 1985-1994 (2006).