David W. Boykin

David W. Boykin David W. Boykin
Regents' Professor of Chemistry, Emeritus
Organic Chemistry

B.S. (1961):  University of Alabama
M.S. (1963) :  University of Virginia
Ph.D. (1965) :  University of Virginia
Postdoctoral Fellowship (1966) :  University of Virginia

Dr. David W. Boykin
Department of Chemistry
Georgia State University
P.O. Box 3965
Atlanta, Georgia 30302-3965

Department Office Phone: 404-413-5500

Phone: 404-413-5498
Lab Phone: 404-413-5496
Fax: 404-413-5505
Office: 686 Kell Hall
Email:  dboykin@gsu.EDU

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 inhibit 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. Recently, we have shown that certain linear diamidines also can bind in the minor groove with high affinity thus broadening the conventional design strategy. 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.  One of our prodrugs was in two Phase III clinical trials; one for human African trypanosomiasis and the other for Pneumocystis carinii pneumonia, however it has recently been withdrawn due to toxicity.

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 for 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).

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 Chemitry, 126, 140-153 (2007).

J. L. Gonzalez, C. E. Stephens, T. Wenzler, R. Brun, F. A. Tanious, W. D. Wilson, T. Barszcz, K. A. Werbovetz, D. W. Boykin, Synthesis and Antiparasitic Evaluation of Bis-2,5-[4-guanidinophenyl]thiophenes, Eur. J. Med. Chem. 42, 552-557(2007).

L. Hu, Z-r. Li, Y-m. Wang, J-d. Jiang D. W. Boykin Structure-activity relationships of novel pyridinyl and pyrimidinylcarbazole sulfonamides as antiproliferative agents Bioorganic and Medicinal Chemistry Letters , 17, 1193-1196 (2007).

M. Munde, M. Lee, S. Neidle, R. Arafa, D. W. Boykin, Y. Liu, C. Bailly, W. D. Wilson Induced Fit Conformational Changes of a "Reversed Amidine" Heterocycle: Optimized Interactions in a DNA Minor Groove Complex, J Am Chem Soc, 129, 5688-5698 (2007).

A.C. Rospal, J. E. Hall, S. Bakunova, D.A. Patrick, S. Bakunov, C. E. Stephens, D.W. Boykin, R.R. Tidwell. In vitro activity of dicationic compounds against a North American foxhound isolate of Leishmania infantum, Vet. Parasitol., 145, 207-216 (2007).

I Midgley, K. Fritzpatrick, L. M. Taylor, T. L. Houchen, S. J. Henderson, S. J. Wright, Z. R. Cybulski, B. A. John, A. McBurney, D. W. Boykin, K. L. Trendler. Pharmacokinetics and Metabolism of the prodrug DB289 in rat and monkey and its conversion to the antiprotozoal/antifungal drug DB75 Drug Metabolism and Disposition 35, 955-967 (2007).

L. Hu, J.-d. Jiang, J. Qu, Y. Li, J. Jin, Z-r. Li, D. W. Boykin. Novel potent antimitotic heterocyclic ketones: synthesis, antiproliferative activity and structure-activity relationships, Bioorganic and Medicinal Chemistry Letters , 17, 3613-3617 (2007).

MP Barrett, DW Boykin, R Brun and RR Tidwell Human African trypanosomiasis: Pharmacological Re-engagement with a Neglected Disease. Brit. J. Pharmacol., 152, 1155- 1171 (2007).

C. F. Silva, M. M. Batista, R. A. Mota, E. M. deSouza, C. E. Stephens, P. Som, D W. Boykin and M.N.C. Soeiro, Activity of reversed diamidines against Trypanosoma cruzi in vitro, Biochem Pharmacol, 73, 1936-1946 (2007).

A. M. Mathis, A. S. Bridges, M. A. Ismail, A. Kumar, I. Francesconi, M. Anbazhaan, Q. Hu. F. A. Tanious, T. Wenzler, J. Saulter, W. D. Wilson, R. Brun, D. W. Boykin, R. R. Tidwell, J E. Hall, Diphenylfurans and Aza Analogs: Effects of structural modification on in vitro activity, DNA binding and accumulation and distribution in trypanosomes, Antimicrob. Agents and Chemother., 51, 2801-2810 (2007).

M. N. C. Soeiro, E. M. de Souza and D. W. Boykin, Anti-parasitic activity of aromatic diamidines and their patented literature, Expert Opinion Therapeutic Patents, 17, 927-939 (2007).

C. F. Silva; M. M.Batista; E. M.Souza; M. N. L. Meirelles; C. E. Stephens; P. Som; D. W. Boykin; M. N. Soeiro. Cellular effects of reversed amidines on Trypanosoma cruzi. Antimicrob. Agents and Chemother., 51, 3803- 3809 (2007).

M. Munde, Cordonnier, A. Lansiaux, C. Bailly, D. W. Boykin, W. D. Wilson, Design of DNA Minor Groove Binding Diamidines that Recognize GC basepair sequences: A Novel Dimeric-Hinge Motif, J Am Chem Soc, 129, 13732-13743 (2007).

Y. Liu, A. Kumar, D. W. Boykin, W. D. Wilson, Sequence and Length Dependent Thermodynamic Differences in Heterocyclic Diamidine Interactions at AT Base Pairs in the DNA Minor Groove. Biophysical Chemistry 131, 1-14 (2007).

L. Hu, Z-r. Li, J-N. Li, J. Qu, J.-D. Jiang D. W. Boykin 3-(2’Bromopropionylamino) benzamides as novel S-phase arrest agents. Bioorganic and Medicinal Chemistry Letters, 17, 6847-6852 (2007).

M. A. Ismail, R. K. Arafa, T. Wenzler, R. Brun, F A. Tanious, W. D. Wilson, D. W. Boykin, Sy nthesis and Antiprotozoal Activity of Novel Bis-Benzamidino Imidazo[1,2-a]pyridines and 5,6,7,8-Tetrahydro-imidazo[1,2-a]pyridines, Bioorganic and Medicinal Chemistry, 16, 683-691 (2008).

L. Hu, R. K. Arafa, M. A. Ismail, T. Wenzler, R. Brun , M. Munde , W. D. Wilson, S. Nzimiro, S. Samyesudhas, K. A. Werbovetz, D. W. Boykin Azaterphenyl Diamidines as Antileishmanial Agents. Bioorganic and Medicinal Chemistry Letters , 18, 247-251 (2008)

S. M. Rahmathullah, S. K. Jones, J. E. Hall, R. R. Tidwell, D. W. Boykin Carbamate Prodrugs of N-Alkylfuramidines, Eur. J. Med Chem. 43, 174-177 (2008).

S. Badr, M. M. El-Kerdawy, F. A. Tanious, W. D. Wilson, D. W. Boykin, Synthesis of 4,8-Substitiutednaphtho[2,1-b]thiophene Threading Intercalators, J. Hetero. Chem. 45,123-128 (2008).

A. Kumar, M. Say, D. W. Boykin, Synthesis of New Substituted Trimethylstannyl Indoles, Synthesis, 707-710(2008).

A. Leepin, A. Studli, R. Brun , C. E. Stephens, D. W.Boykin , Andrew Hemphill Host cells participate in the in vitro effects of new-generation diamidine-analogues against tachyzoites of the intracellular apicomplexan parasites Neospora caninum and Toxoplasma gondii, Antimicrob. Agents and Chemother. 52 , 1999-2008 (2008).

P. Peixoto, Y. Liu, S. Depauw, M-P. Hildebrand, D. W. Boykin, C. Bailly, W. D. Wilson and M-H. David-Cordonnier. Direct inhibition of the DNA binding activity of POU transcription factors Pit-1 and Brn-3 by selective binding of a phenyl-furan-benzimidazole dication. Nucleic Acids Res. 36, 3341-3353 (2008).