During the past five years, we have synthesized over 200 new nucleosides analogues. Biological evaluation by Dr. Raymond Schinazi of Emory University/VA Medical Center suggested that several targeted compounds had potent and selective anti-HIV-1 activities in human lymphocytes. From these efforts we have identified at least six promising compounds. These include 3'-azido-2',3'-dideoxyuridine (AzddU, AZDU or CS-87), 3'-azido- 2',3'-dideoxy-5-methylcytosine (AZMdC), N6-Me-ddA, N6-methyl-2'-F-ddA, 3'- deoxy-3'fluoro-5-methylcytosine, and 9-beta-(2,3-dideoxyribofuranosyl)-6- chloropurine (6-CI-P). Among these nucleosides, AZdU has been undergoing clinical trials in patients with AIDS and AIDS-related complex. In order to determine the usefulness of the other nucleosides, biochemical, pharmacological, and toxicological studies are in progress. We plan to continue exploring the structure-activity relationships of 3'- azido-2',3'-dideoxy-,2',3'-dideoxy-and 2',3'-didehydro-2',3'-dideoxy- nucleosides. Stereoselective synthetic methods developed in our laboratory will be used to facilitate the synthesis. Additionally, new classes of anti-HIV nucleosides, BCH-189 and dioxolane-T analogues and their C- nucleosides will be synthesized and evaluated as potential anti-HIV agents. Asymmetric synthesis of 1,3-dioxolane and 1,3-oxothiolane moieties have recently been accomplished by our group from a chiral template, D-mannose, which can be used for condensation with various heterocyclic moieties, resulting in enantiomerically pure nucleosides. Additionally, we also plan to synthesize oxetanocin analogs and three-membered carbocyclic ring nucleosides. If time permits, nucleosides with various substituted heteroatoms (sulfur, oxygen, nitrogen, and selenium) in the ribose ring will be synthesized to study the exhaustive structure-activity relationships of the carbohydrates and heterocyclic moieties. The long term goal of this application is to discover improved and new anti-HIV nucleosides that do not show cross-resistance with the existing anti-HIV nucleosides. Additionally, the proposed compounds will also be evaluated in other anti-viral screening systems including HCMV, herpes, RSV, human hepatitis B virus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032351-03
Application #
2067215
Study Section
AIDS and Related Research Study Section 2 (ARRB)
Project Start
1992-01-01
Project End
1995-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Georgia
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Athens
State
GA
Country
United States
Zip Code
30602
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Asif, Ghazia; Hurwitz, Selwyn J; Obikhod, Aleksandr et al. (2007) Pharmacokinetics of the anti-human immunodeficiency virus agent 1-(beta-D-dioxolane)thymine in rhesus monkeys. Antimicrob Agents Chemother 51:2424-9
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Wang, Jianing; Jin, Yunho; Rapp, Kimberly L et al. (2005) Synthesis, antiviral activity, and mechanism of drug resistance of D- and L-2',3'-didehydro-2',3'-dideoxy-2'-fluorocarbocyclic nucleosides. J Med Chem 48:3736-48
Gadthula, Srinivas; Chu, Chung K; Schinazi, Raymond F (2005) Synthesis and anti-HIV activity of beta-D-3'-azido-2',3'-unsaturated nucleosides and beta-D-3'-azido-3'-deoxyribofuranosylnucleosides. Nucleosides Nucleotides Nucleic Acids 24:1707-27
Rais, Reem H; Al Safarjalani, Omar N; Yadav, Vikas et al. (2005) 6-Benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: activities and selective toxicities. Biochem Pharmacol 69:1409-19

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