5'-O-Aliphatic and amino acid ester prodrugs of (-)-beta-D-(2R,4R)-dioxolane-thymine (DOT): synthesis, anti-HIV activity, cytotoxicity and stability studies.
5'-O-Aliphatic and amino acid ester prodrugs of (-)-beta-D-(2R,4R)-dioxolane-thymine (DOT): synthesis, anti-HIV activity, cytotoxicity and stability studies.
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(-)-β-D-(2R,4R)-二氧戊环-胸腺嘧啶 (DOT) 的 5-O-脂肪族和氨基酸酯前药：合成、抗 HIV 活性、细胞毒性和稳定性研究。
DOI：
10.1016/j.bmc.2008.10.078
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发表时间：
2009
影响因子：
3.5
通讯作者：
Chu,ChungK
中科院分区：
文献类型：
--
作者：
Liang,Yuzeng;Sharon,Ashoke;Grier,JasonP;Rapp,KimberlyL;Schinazi,RaymondF;Chu,ChungK
合成了一系列(−)-β-d-(2R,4R)-二氧唑烷-胸腺嘧啶-5′- o -脂肪酸酯和氨基酸酯，作为(−)-β-d-(2R,4R)-二氧唑烷-胸腺嘧啶（DOT）的前药。研究了这些化合物对人外周血单核细胞（PBM） HIV-1LAIin的抗hiv活性以及对PBM、CEM和Vero细胞的细胞毒性。与母体药物相比，化合物2-4（5′- o -脂肪酸酯）的体外抗hiv效力有所提高，但细胞毒性没有增加。研究了前药的化学和酶解作用，发现前药在pH为2.0和7.4的磷酸盐缓冲液下，半衰期为3h ~ 54h，具有良好的化学稳定性。而前药对猪酯酶相对不稳定，半衰期为12.3 ~ 48.0min。
A series of (−)-β-d-(2R,4R)-dioxolane-thymine-5′-O-aliphatic acid esters as well as amino acid esters were synthesized as prodrugs of (−)-β-d-(2R,4R)-dioxolane-thymine (DOT). The compounds were evaluated for anti-HIV activity against HIV-1LAIin human peripheral blood mononuclear (PBM) cells as well as for their cytotoxicity in PBM, CEM and Vero cells. Improved anti-HIV potency in vitro was observed for the compound 2–4 (5′-O-aliphatic acid esters) without increase in cytotoxicity in comparison to the parent drug. Chemical and enzymatic hydrolysis of the prodrugs was also studied, in which the prodrugs exhibited good chemical stability with the half-lives from 3h to 54h at pH 2.0 and 7.4 phosphate buffer. However, the prodrugs were relatively labile to porcine esterase with the half-lives from 12.3 to 48.0min.
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影响因子：
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