title: Synthesis and biological evaluation of fatty acyl ester derivatives of (-)-2',3'-dideoxy-3'-thiacytidine.
abstract: 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.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island , 41 Lower College Road, Kingston, Rhode Island 02881, United States.
authors.forename: Hitesh K
authors.initials: HK
authors.lastname: Agarwal
authors.forename: Bhupender S
authors.initials: BS
authors.lastname: Chhikara
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hanley
authors.forename: Guofeng
authors.initials: G
authors.lastname: Ye
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Doncel
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001386:Azides / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003562:Cytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D024921:Drug Resistance, Multiple, Viral; D004952:Esters; D005227:Fatty Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D006868:Hydrolysis; D019259:Lamivudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C574771:5'-O-(12-azidododecanoyl)-2',3'-dideoxy-3'-thiacytidine; C574770:5'-O-(tetradecanoyl)-2',3'-dideoxy-3'-thiacytidine; D019380:Anti-HIV Agents; D001386:Azides; D004952:Esters; D005227:Fatty Acids; D019259:Lamivudine; D003562:Cytidine