Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
Bioorg Med Chem Lett. 2012 Sep 1;22(17):5451-4. doi: 10.1016/j.bmcl.2012.07.037. Epub 2012 Jul 17.
Three nucleoside analogues, 3'-fluoro-2',3'-dideoxythymidine (FLT), 3'-azido-2',3'-dideoxythymidine (AZT), and 2',3'-dideoxy-3'-thiacytidine (3TC) were conjugated with three different dicarboxylic acids to afford the long chain dicarboxylate esters of nucleosides. In general, dinucleoside ester conjugates of FLT and 3TC with long chain dicarboxylic acids exhibited higher anti-HIV activity than their parent nucleosides. Dodecanoate and tetradecanoate dinucleoside ester derivatives of FLT were found to be the most potent compounds with EC(50) values of 0.8-1.0 nM and 3-4 nM against HIV-1(US/92/727) and HIV-1(IIIB) cells, respectively. The anti-HIV activity of the 3TC conjugates containing long chain dicarboxylate diester (EC(50)=3-60 nM) was improved by 1.5-66 fold when compared to 3TC (EC(50)=90-200 nM). This study reveals that the symmetrical ester conjugation of dicarboxylic acids with a number of nucleosides results in conjugates with improved anti-HIV profile.
三种核苷类似物，3'-氟-2',3'-二脱氧胸苷（FLT）、3'-叠氮-2',3'-二脱氧胸苷（AZT）和 2',3'-二脱氧-3'-硫代胞苷（3TC）分别与三种不同的二羧酸连接，得到核苷的长链二羧酸酯。通常，FLT 和 3TC 的二核苷酸酯与长链二羧酸的缀合物比其母体核苷具有更高的抗 HIV 活性。发现十二烷酸和十四烷酸二核苷酸酯衍生物的 FLT 是最有效的化合物，对 HIV-1(US/92/727)和 HIV-1(IIIB)细胞的 EC(50)值分别为 0.8-1.0 nM 和 3-4 nM。与 3TC（EC(50)=90-200 nM）相比，含有长链二羧酸二酯的 3TC 缀合物（EC(50)=3-60 nM）的抗 HIV 活性提高了 1.5-66 倍。这项研究表明，用多种核苷对二羧酸进行对称酯键合，得到了具有改善的抗 HIV 特性的缀合物。
