Synthesis and Biological Evaluation of Fatty Acyl Ester Derivatives of (-)-2′,3′-Dideoxy-3′-thiacytidine
Synthesis and Biological Evaluation of Fatty Acyl Ester Derivatives of (-)-2′,3′-Dideoxy-3′-thiacytidine
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DOI：
10.1021/jm300492q
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发表时间：
2012-05-24
影响因子：
7.3
通讯作者：
Parang, Keykavous
中科院分区：
文献类型：
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作者：
Agarwal, Hitesh K.;Chhikara, Bhupender S.;Parang, Keykavous
合成了许多 (-)-2',3'-二脱氧-3'-硫胞苷的脂肪酰基衍生物（拉米夫定，3TC，1）并评估了其抗 HIV 活性。 3TC的单取代5'-O-脂肪酰基衍生物（EC50=0.2-2.3μM）比相应的单取代N-4-脂肪酰基（EC50=0.4-29.4μM）和核苷的5'-O-N-4-二取代（EC50=72.6至>154.0μM）衍生物更有效。 5'-O-肉豆蔻酰 (16) 和 5'-O-12-叠氮十二烷酰衍生物 (17) 被发现是最有效的化合物 (EC50 = 0.2-0.9 μM)，其对无细胞病毒的抗 HIV 活性比 1 (EC50 = 11.4-32.7 μM) 高至少 16-36 倍。 16对B亚型和C亚型临床分离株的EC90值比1低数倍。细胞摄取研究证实，化合物16与CCRF-CEM细胞孵育1小时后在细胞内积累并发生细胞内水解。 1的5'-O-脂肪酰基衍生物表现出比相应的物理混合物针对B亚型病毒显着更高的抗HIV活性。
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 (EC50 = 0.2-2.3 mu M) were more potent than the corresponding monosubstituted N-4-fatty acyl (EC50 = 0.4-29.4 mu M) and 5'-O-N-4-disubstituted (EC50 = 72.6 to >154.0 mu M) derivatives of the nucleoside. 5'-O-Myristoyl (16) and 5'-O-12-azidododecanoyl derivatives (17) were found to be the most potent compounds (EC50 = 0.2-0.9 mu M) exhibiting at least 16-36-fold higher anti-HIV activity against cell-free virus than 1 (EC50 = 11.4-32.7 mu M). The EC90 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.