Synthesis and anti-HIV-1 activity of 2'-"up"-fluoro analogs of active anti-AIDS nucleosides 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (DDC)

• Published in: Journal of medicinal chemistry Vol. 33; no. 8; pp. 2145 - 2150
• Main Authors: Watanabe, Kyoichi A, Harada, Kazuho, Zeidler, Joanna, Matulic-Adamic, Jasenka, Takahashi, Kiyobumi, Ren, Wu Yun, Cheng, Ling Chin, Fox, Jack J, Chou, Ting Chao
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.08.1990
• Subjects: AIDS/HIV; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Cell Line; Cell Survival - drug effects; Chemical Phenomena; Chemistry; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; HIV Antigens - analysis; HIV-1 - drug effects; HIV-1 - immunology; Humans; Molecular Structure; RNA-Directed DNA Polymerase - analysis; Zalcitabine - analogs & derivatives; Zalcitabine - chemical synthesis; Zalcitabine - pharmacology; Zidovudine - analogs & derivatives; Zidovudine - chemical synthesis; Zidovudine - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00170a016

1-(3-Azido-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (6, F-AZT) and 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)cytosine (12, F-DDC) were synthesized from the potent antiherpes virus nucleosides 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (1, FMAU) and 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) in the hope that introduction of a 2-"up"-fluoro substituent might potentiate the anti-HIV activity of AZT and DDC. FMAU (1) was converted in three steps into 2,3'-anhydro-1-(2-fluoro-2-deoxy-5-O-trityl-beta-D-lyxofuranosyl)thymine (4), which when treated with NaN3 followed by detritylation afforded 6. F-DDC was prepared by two methods. Tritylation of FIAC followed by treatment of the product with thiocarbonyldimidazole afforded the 5'-O-trityl-3'-O-(imidazolyl)thiocarbonyl nucleoside 9. Upon radical reduction of 9 with Bu3SnH and AIBN, 5'-O-trityl-DDC 10 was obtained. Compound 10 was detritylated to give 12, which (when obtained by this procedure) resisted crystallization, but the diacetate 12' was obtained in crystalline form. Alternatively, FAC (14) was converted into N4,O5'-dibenzoyl derivative 15, which was treated with thiocarbonyldiimidazole. Reduction of 16 with Bu3SnH/AIBN followed by debenzoylation afforded 12, which was obtained in crystalline form. F-AZT did not exhibit any significant activity against the human immunodeficiency virus (HIV) in vitro. F-DDC, however, showed activity against HIV-1, but the therapeutic index is much inferior to that of AZT.