Highly water-soluble lipophilic prodrugs of the anti-HIV nucleoside analogue 2',3'-dideoxycytidine and its 3'-fluoro derivative.
Highly water-soluble lipophilic prodrugs of the anti-HIV nucleoside analogue 2',3'-dideoxycytidine and its 3'-fluoro derivative.
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抗 HIV 核苷类似物 2,3-二脱氧胞苷及其 3-氟衍生物的高度水溶性亲脂性前药。
DOI：
10.1021/jm00089a008
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发表时间：
1992
影响因子：
7.3
通讯作者：
Kalman,TI
中科院分区：
文献类型：
--
作者：
Kerr,SG;Kalman,TI
描述了一系列新的抗hiv药物2',3'-二脱氧胞苷（ddC, 1）和3'-氟-ddC(2)的亲脂性前药衍生物的合成，涉及（njv -二烷基胺）亚甲基侧链的n4取代。与亲本药物1和亲本药物2相比，前药系列的分割系数增加幅度分别为1.5 ~ 122倍和1.6 ~ 175倍。在pH 7.4, 37℃条件下，水解时间为2 ~ 52 h，二异丙基衍生物（3d和4d）在该系列中最稳定。3d和4d的水溶性分别是1和2的1.5倍和1.7倍。评价3d、4a、4d的体外抗逆转录病毒活性；结果表明，在实验条件下，前药到药物的转化是有效的。本研究结果表明，通过化学修饰某些溶解度较差的核苷类似物，同时显著提高其脂溶性和水溶性，确实是可行的。
The synthesis of a novel series oflipophilic prodrug derivatives of the anti-HIV drugs 2', 3'-dideoxycytidine (ddC, 1) and 3'-fluoro-ddC (2), involving N4-substitution with (NJV-dialkylamino) methylene side chains, is described. The increase in the partition coefficients for the prodrug series, compared to those of the parent drugs 1 and 2, ranged from 1.5-to 122-fold and from 1.6-to 175-fold, respectively. At pH 7.4, 37 C, the hydrolytic ty2 values ranged from 2 to 52 h, the diisopropyl derivatives (3d and 4d) being most stable in the series. 3d and 4d were> 4-fold and 1.7-fold more soluble in water than 1 and 2, respectively. The in vitro antiretroviral activities of 3d, 4a, and 4d were evaluated; the results indicateefficient prodrug-to-drug conversion under the assay conditions. The results of this investigation demonstrate thatit is indeed feasible to chemically modify certain nucleoside analogues with inferior solubility properties to simultaneouslyachieve significantly enhanced lipid and water solubility.