Synthesis and anti-HIV activity of several 2'-fluoro-containing pyrimidine nucleosides

• Published in: Journal of medicinal chemistry Vol. 33; no. 8; pp. 2150 - 2157
• Main Authors: Sterzycki, Roman Z, Ghazzouli, Ismail, Brankovan, Vera, Martin, John C, Mansuri, Muzammil M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.08.1990
• Subjects: AIDS/HIV; Antineoplastic Agents; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Carbohydrates. Nucleosides and nucleotides; Cell Line; Cell Survival - drug effects; Chemical Phenomena; Chemistry; Exact sciences and technology; Fluorine; Gene Products, gag - analysis; HIV - drug effects; HIV - immunology; HIV Antigens - analysis; HIV Core Protein p24; Humans; Macrophages; Molecular Structure; Monocytes; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Pyrimidine Nucleosides - chemical synthesis; Pyrimidine Nucleosides - pharmacology; T-Lymphocytes; Tumor Cells, Cultured; Viral Core Proteins - analysis; Zalcitabine - analogs & derivatives; Zalcitabine - chemical synthesis; Zalcitabine - pharmacology; Zidovudine - pharmacology; Virus; Dideoxyribonucleoside; Retroviridae; Lentivirinae; Antiviral; Fluorine Organic compounds; Human immunodeficiency virus; In vitro; Pyrimidine nucleoside; Biological activity; Ethylenic compound
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00170a017

Several 2'-fluoroarabino-2',3'-dideoxy- and 2'-fluoro-2',3'-unsaturated 2',3'-dideoxy pyrimidine nucleoside analogues are reported. The saturated analogues 1-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)thymine (2'-threo-FddT, 33), 1-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)uracil (2'-threo-FddU, 22) were readily prepared from the corresponding 2'-deoxy-2'-fluoroarabinosyl nucleoside analogue by radical deoxygenation of the 3'-OH. The unsaturated compounds 1-(2,3-dideoxy-2-fluoro-beta-D-glycero-pent-2-enofuranosyl)thymine (2'-Fd4T, 40) and 1-[5-O-(mono-methoxytrityl)-2-fluoro-2,3-dideoxy-beta-D-glycero-pen t-2- enofuranosyl]uracil (39) were synthesized by an elimination reaction of the O-2,3'-anhydro-2'-fluoro-lyxo derivatives under basic conditions. The cytidine analogues 28 and 41 were prepared by amination of the corresponding uridine derivatives; compounds 28 and 41 were deprotected to give 1-(2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)cytidine (2'-threo-FddC, 29) and 1-(2,3-dideoxy-2-fluoro-beta-D-glycero-pent-2- enofuranosyl)cytosine (2'-Fd4C, 42), respectively. All of these novel compounds were evaluated in vitro against human immunodeficiency virus (HIV) (LAV isolate). 2'-threo-FddC (29) was the most active of the newly synthesized substances against HIV with an ID50 of 0.8 microgram/mL; ddC had an ID50 of 0.007 micrograms/mL. Because of its potency in the initial tests, 29 was further evaluated in both T cells and macrophage/monocyte cell lines, with several different isolates of HIV. Although 2'-threo-FddC (29) exhibited good antiviral activity in these systems it was less active than AZT in these assays. At 1 microM the inhibition of CFU-GM by 29 was found to be 35-40%; this is slightly higher than seen with AZT.