Abstract

This investigation has as its goal the design and synthesis of a series of 3'-deoxy pyrimidine and purine nucleoside analogs, and some of their nucleotide addition, the 2', 3'-unsaturated, 2', 3'-dideoxy-ara-C derivatives of 3-deazacytidine will be synthesized and evaluated as potential anti-HIV and anti-CMV agents. The approaches to be employed include the development of methodology mass spectrum, and other spectroscopic techniques, and the determination of their biological and biochemical effects. Recently, a lead compound, 1-(3-deoxy-B-D-threopentofuranosyl) cytosine (3'-deoxy-ara-C), has been synthesized and evaluated for its antiviral activity in this laboratory. Our preliminary studies have shown that 3'- deoxy-ara-C not only has potent anti-HCMV activity (ED50 = 0.31 ug/mL vs ED50 = 0.92 ug/mL for DHPG), but also is structurally different from DHPG. Based on these findings, the 5'-mono- and triphosphates of 3'-deoxy-ara-C will be prepared for biochemical studies. The understanding of the mechanism of action of 3'-deoxy-ara-C may lead to the design and synthesis of new antiviral agents with a better therapeutic index.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI029430-03
Application #
3144252
Study Section
Special Emphasis Panel (ARR (V1))
Project Start
1990-03-01
Project End
1993-02-28
Budget Start
1992-03-01
Budget End
1993-02-28
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

Zoulim, F; Dannaoui, E; Borel, C et al. (1996) 2',3'-dideoxy-beta-L-5-fluorocytidine inhibits duck hepatitis B virus reverse transcription and suppresses viral DNA synthesis in hepatocytes, both in vitro and in vivo. Antimicrob Agents Chemother 40:448-53
Lin, T S; Luo, M Z; Liu, M C et al. (1996) Design and synthesis of 2',3'-dideoxy-2',3'-didehydro-beta-L-cytidine (beta-L-d4C) and 2',3'-dideoxy 2',3'-didehydro-beta-L-5-fluorocytidine (beta-L-Fd4C), two exceptionally potent inhibitors of human hepatitis B virus (HBV) and potent inhibitors of human J Med Chem 39:1757-9
Lin, T S; Luo, M Z; Liu, M C et al. (1994) Synthesis and biological evaluation of 2',3'-dideoxy-L-pyrimidine nucleosides as potential antiviral agents against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). J Med Chem 37:798-803
Lin, T S; Luo, M Z; Liu, M C et al. (1994) Antiviral activity of 2',3'-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC) and 2',3'-dideoxy-beta-L-cytidine (beta-L-ddC) against hepatitis B virus and human immunodeficiency virus type 1 in vitro. Biochem Pharmacol 47:171-4
Lin, T S; Zhu, J L; Dutschman, G E et al. (1993) Syntheses and biological evaluations of 3'-deoxy-3'-C-branched-chain-substituted nucleosides. J Med Chem 36:353-62
Prusoff, W; Lin, T S; Pivazyan, A et al. (1993) Empirical and rational approaches for development of inhibitors of the human immunodeficiency virus--HIV-1. Pharmacol Ther 60:315-29
Pivazyan, A D; Birks, E M; Wood, T G et al. (1992) Inhibition of poly(ADP-ribose)polymerase activity by nucleoside analogs of thymidine. Biochem Pharmacol 44:947-53
Lin, T S; Yang, J H; Liu, M C et al. (1991) Synthesis and anticancer activity of various 3'-deoxy pyrimidine nucleoside analogues and crystal structure of 1-(3-deoxy-beta-D-threo-pentofuranosyl)cytosine. J Med Chem 34:693-701
Lin, T S; Luo, M Z; Liu, M C et al. (1991) Synthesis and anticancer and antiviral activities of various 2'- and 3'-methylidene-substituted nucleoside analogues and crystal structure of 2'-deoxy-2'-methylidenecytidine hydrochloride. J Med Chem 34:2607-15