Synthesis and antiviral activity of some 3'-C-difluoromethyl and 3'-deoxy-3'-C-fluoromethyl nucleosides.
The synthesis and antiviral activity of a number of 3'-C-difluoromethyl and 3'-deoxy-3'-C-fluoromethyl nucleosides are reported. The 3'-C-difluoromethyl nucleosides 26a and 26b were obtained by treatment of the corresponding 2',5'-di-O-protected-3'-C-formyl nucleosides 25a and 25b with (diethylamino)sulfur trifluoride (DAST). Removal of the 2'-O-protecting group from 26a and subsequent reaction with DAST furnished the 2'-deoxy-2'-fluoro-beta-D-ribo-pentofuranosyl nucleoside 29. Selective fluorination with DAST of the 5'-O-protected analogues 3'-deoxy-3'-C-hydroxymethyl derivatives 13a and 13b gave the 3'-deoxy-3'-C-fluoromethyl derivatives 30a and 30b, while nonselective fluorination afforded the 2',3'-dideoxy-2'-fluoro-3'-C-fluoromethyl analogues 31a and 31b. The deprotected uracil analogue 17a was iodinated to the 5-iodouracil derivative 18. The fully deprotected fluorinated 3'-C-branched nucleosides 14-18 and 32 were evaluated for their antiviral activity. None were active against human immunodeficiency virus type-1 (HIV-1) at concentrations up to 100 microM. However, 5-iodouracil analogue 18 showed activity, comparable to that of acyclovir, against varicella zoster virus without observed cytotoxicity.
Bamford
M J
MJ
School of Chemistry, University of Birmingham, Edgbaston, England.
Coe
P L
PL
Walker
R T
RT
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D015497:HIV-1 / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis*; D009705:Nucleosides / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D014271:Trifluridine / Q000031:analogs & derivatives
D000998:Antiviral Agents; D006845:Hydrocarbons, Fluorinated; D009705:Nucleosides; D014271:Trifluridine