Synthesis and biological evaluation of 5′-O-dicarboxylic fatty acyl monoester derivatives of anti-HIV nucleoside reverse transcriptase inhibitors
Synthesis and biological evaluation of 5′-O-dicarboxylic fatty acyl monoester derivatives of anti-HIV nucleoside reverse transcriptase inhibitors
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DOI：
10.1016/j.tetlet.2014.02.001
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发表时间：
2014-03-19
影响因子：
1.8
通讯作者：
Parang, Keykavous
中科院分区：
文献类型：
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作者：
Pemmaraju, Bhanu;Agarwal, Hitesh K.;Parang, Keykavous
合成了3‘-叠氮基-3’-脱氧胸苷(Zidovudine，AZT)、2‘，3’-二氢-2‘，3’-二脱氧胸苷(stavudine，d4T)和3‘-氟-3’-脱氧胸苷(alovudine，Flt)的5‘-O-二羧酸脂肪酰基单酯衍生物，以提高亲脂性和潜在的细胞递送能力。对这些化合物的抗艾滋病毒活性进行了评估。用三种不同链长的脂肪酸与核苷进行偶联反应，分别为琥珀酸(辛二酸)、二十二酸(十一酸)和十二烷二酸。对化合物的抗HIV活性和细胞毒性进行了评价。所有核苷二元酸酯结合物的抗HIV活性均显著高于相应的母体核苷类似物。在所有被测试的结合物中，AZT的5‘-O-琥珀酸衍生物(EC50=0.10 NM)被发现是最有效的化合物，其抗HIV活性是AZT的80倍，并且没有任何明显的毒性(TC50和GT；500 NM)。(C)2014爱思唯尔有限公司。保留所有权利。
A number of 5 '-O-dicarboxylic fatty acyl monoester derivatives of 3 '-azido-3 '-deoxythymidine (zidovudine, AZT), 2 ',3 '-didehydro-2 ',3 '-dideoxythymidine (stavudine, d4T), and 3 '-fluoro-3 '-deoxythymidine (alovudine, FLT) were synthesized to improve the lipophilicity and potentially the cellular delivery of parent polar 2 ',3 '-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 '-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). (c) 2014 Elsevier Ltd. All rights reserved.