Synthesis and anti-HIV activity of several 2'-fluoro-containing pyrimidine nucleosides.
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.
Sterzycki
R Z
RZ
Department of Antiinfective Chemistry, Bristol-Myers Squibb Co., Wallingford, Connecticut 06492-7660.
Ghazzouli
I
I
Brankovan
V
V
Martin
J C
JC
Mansuri
M M
MM
D000970:Antineoplastic Agents; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D005461:Fluorine; D015683:Gene Products, gag / Q000032:analysis; D006678:HIV / Q000187:drug effects* / Q000276:immunology; D015488:HIV Antigens / Q000032:analysis; D016655:HIV Core Protein p24; D006801:Humans; D008264:Macrophages; D015394:Molecular Structure; D009000:Monocytes; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000494:pharmacology*; D013601:T-Lymphocytes; D014407:Tumor Cells, Cultured; D014758:Viral Core Proteins / Q000032:analysis; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D015683:Gene Products, gag; D015488:HIV Antigens; D016655:HIV Core Protein p24; D011741:Pyrimidine Nucleosides; D014758:Viral Core Proteins; C065050:1-(2,3-dideoxy-2-fluoropentofuranosyl)cytosine; D005461:Fluorine; D015215:Zidovudine; D016047:Zalcitabine