Synthesis and biological evaluation of 5鈥?O-dicarboxylic fatty acyl monoester derivatives of anti-HIV nucleoside reverse transcriptase inhibitors

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• 作者：Bhanu Pemmaraju^a ; Hitesh K. Agarwal^a ; Donghoon Oh^a ; Karen W. Buckheit^b ; Robert W. Buckheit Jr.^b ; Rakesh Tiwari^a ; ^c ; Keykavous Parang^a ; ^c ; ^{kparang@uri.edu" class="auth_mail}
• 关键词：Anti-HIV agents ; Fatty acids ; Lipophilicity ; Nucleosides ; Reverse transcriptase
• 刊名：Tetrahedron Letters
• 出版年：19 March, 2014
• 年：2014
• 卷：55
• 期：12
• 页码：1983-1986
• 全文大小：306 K

文摘

A number of 5鈥?O-dicarboxylic fatty acyl monoester derivatives of 3鈥?azido-3鈥?deoxythymidine (zidovudine, AZT), 2鈥?3鈥?didehydro-2鈥?3鈥?dideoxythymidine (stavudine, d4T), and 3鈥?fluoro-3鈥?deoxythymidine (alovudine, FLT) were synthesized to improve the lipophilicity and potentially the cellular delivery of parent polar 2鈥?3鈥?dideoxynucleoside (ddN) analogs. The compounds were evaluated for their anti-HIV activity. Three different fatty acids with varying chain length of suberic acid (octanedioic acid), sebacic acid (decanedioic acid), and dodecanedioic acid were used for the conjugation with the nucleosides. The compounds were evaluated for anti-HIV activity and cytotoxicity. All dicarboxylic ester conjugates of nucleosides exhibited significantly higher anti-HIV activity than that of the corresponding parent nucleoside analogs. Among all the tested conjugates, 5鈥?O-suberate derivative of AZT (EC₅₀ = 0.10 nM) was found to be the most potent compound and showed 80-fold higher anti-HIV activity than AZT without any significant toxicity (TC₅₀ >500 nM).