Synthesis and antiviral activity of several 2,5'-anhydro analogs of 3'-azido-3'-deoxythymidine (AZT), 3'-azido-2',3'-dideoxyuridine (AZU), 3'-azido-2',3'-dideoxy-5-halouridines, and 3'-deoxythymidine against human immunodeficiency virus (HIV-1) and Rauscher-Murine leukemia virus (R-MuLV)

• Published in: Journal of medicinal chemistry 1989-08, Vol.32 (8), p.1891-1895
• Main Authors: Lin, Tai Shun, Shen, Zhi Yi, August, E. Michael, Brankovan, Vera, Yang, Hyekyung, Ghazzouli, Ismail, Prusoff, William H
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemical synthesis; Carbohydrates. Nucleosides and nucleotides; Chemical Phenomena; Chemistry; Deoxyuridine - analogs & derivatives; Deoxyuridine - chemical synthesis; Deoxyuridine - pharmacology; Exact sciences and technology; HIV-1 - drug effects; human immunodeficiency virus; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Rauscher Virus - drug effects; Thymidine - analogs & derivatives; Thymidine - chemical synthesis; Thymidine - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00128a034

Several 2,5'-anhydro analogues of 3'-azido-3'-deoxythymidine (AZT), 3'-azido-2'3'-dideoxyuridine (AZU), 3'-azido-2'3'-dideoxy-5-bromouridine, 3'-azido-2',3'-dideoxy-5-iodouridine, and 3'-deoxythymidine and the 3'-azido derivative of 5-methyl-2'-deoxyisocytidine have been synthesized for evaluation as potential anti-HIV (human immunodeficiency virus) agents. These 2,5'-anhydro derivatives, compounds 13-17, demonstrated significant anti-HIV-1 activity with IC50 values of 0.56, 4.95, 26.5, 27.1, and 48 microM, respectively. Compared to that of the parent compounds AZT and AZU, the respective 2,5'-anhydro analogues, compounds 13 and 14, were somewhat less active. Whereas AZT was cytotoxic with a TCID50 of 29 microM, the toxicity of the 2,5'-anhydro derivative of AZT, compound 13, was reduced considerably to a TCID50 value of greater than 100 microM. The 2,5'-anhydro analogue of 5-methyl-2'-deoxyisocytidine also demonstrated anti-HIV-1 activity with an IC50 value of 12 microM. These compounds were also evaluated against Rauscher-Murine leukemia virus (R-MuLV) in cell culture. Among them, AZT, 3'-azido-2',3'-dideoxy-5-iodouridine, 3'-azido-2',3'-dideoxy-5-bromouridine, and 2,5'-anhydro-3'-azido-3'-deoxythymidine (13) were found to be most active, with IC50 values of 0.023, 0.21, 0.23, and 0.27 microM, respectively.