| Abstract
| - As 2‘,3‘-didehydro-2‘,3‘-dideoxy-2‘-fluoronucleosides have exhibited interesting antiviral effectsagainst HIV-1 as well as HBV, it is of interest to synthesize the isosterically substituted 4‘-thionucleosides in which 4‘-oxygen is replaced by a sulfur atom. To study structure−activityrelationships, various pyrimidine and purine nucleosides were synthesized from the keyintermediate (2R,4S)-1-O-acetyl-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-2-fluoro-2-phenylselenyl-4-thio-β-d-ribofuranoside 8, which was prepared from the 2,3-O-isopropylidene-d-glyceraldehyde 1 in 13 steps. The antiviral activity of the synthesized compounds were evaluatedagainst HIV-1 in human peripheral blood mononuclear (PBM) cells, among which cytidine 17,5-fluorocytidine 18, adenosine 24, and 2-fluoroadenosine 32 showed moderate to potent anti-HIV activities (EC50 1.3, 11.6, 8.1, and 1.2 μM, respectively). It is noteworthy that 2-fluoroadenosine analogue 32 showed antiviral potency as well as high cytotoxicity (IC50 1.5, 1.1, and7.6 μM for PBM, CEM, and Vero, respectively) whereas no other compound showed cytotoxicityup to 100 μM. The cytidine 17 and 5-fluorocytidine 18 analogues showed significantly decreasedantiviral activity against the clinically important lamivudine-resistant variants (HIV-1M184V),whereas the corresponding d-2‘-Fd4 nucleosides showed limited cross-resistance. Molecularmodeling studies demonstrated that the larger van der Waals radius as well as the closeproximity to Met184 of the 4‘-sulfur atom of d-2‘-F-4‘-Sd4C (17) may be the reasons for thedecreased antiviral potency of synthesized 4‘-thio nucleosides against the lamivudine-resistantvariants (HIV-1M184V).
|
