Synthesis and biological evaluation of fatty acyl ester derivatives of (-)-2′,3′-dideoxy-3′-thiacytidine

A number of fatty acyl derivatives of (-)-2′,3′-dideoxy- 3′-thiacytidine (lamivudine, 3TC, 1) were synthesized and evaluated for their anti-HIV activity. The monosubstituted 5′-O-fatty acyl derivatives of 3TC (EC ₅₀ = 0.2-2.3 μM) were more potent than the corresponding monosubstituted N ₄-fatty acyl (EC ₅₀ = 0.4-29.4 μM) and 5′-O-N ₄-disubstituted (EC ₅₀ = 72.6 to >154.0 μM) derivatives of the nucleoside. 5′-O-Myristoyl (16) and 5′-O-12-azidododecanoyl derivatives (17) were found to be the most potent compounds (EC ₅₀ = 0.2-0.9 μM) exhibiting at least 16-36-fold higher anti-HIV activity against cell-free virus than 1 (EC ₅₀ = 11.4-32.7 μM). The EC ₉₀ values for 16 against B-subtype and C-subtype clinical isolates were several folds lower than those of 1. The cellular uptake studies confirmed that compound 16 accumulated intracellularly after 1 h of incubation with CCRF-CEM cells and underwent intracellular hydrolysis. 5′-O-Fatty acyl derivatives of 1 showed significantly higher anti-HIV activity than the corresponding physical mixtures against the B-subtype virus.