Meier Chris, Muus Ulrike, Renze Jürgen, Naesens Lieve, De Clercq Erik, Balzarini Jan
Institut für Organische Chemie, Universität Hamburg, Germany.
Antivir Chem Chemother. 2002 Mar;13(2):101-14. doi: 10.1177/095632020201300204.
A comparative study of three cycloSal-d4TMP 1, 2 and 3 and a variety of bis(benzyl) phosphate triester 4-8 of the antivirally active nucleoside analogue 2',3'-dideoxy-2',3'-didehydrothymidine (d4T) will be described. This study has been initiated by the observation that the introduction of a simple 7-methyl group in the cycloSal-structure (2) led to a completely different hydrolysis pattern as compared to the prototype cycloSal-d4TMP 1. Instead of the selective formation of d4TMP, a phenyl phosphate diester was formed in the case of the 7-methyl-substituted compound 2. The difference in degradation pathway was caused by a change of the reaction mechanism. The phenyl phosphate diester was chemically and enzymatically inert to further cleavage to yield d4TMP. For comparison bis(benzyl)-d4TMP 4, bis(alpha-methylbenzyl)-d4TMP 5, bis(alpha-methoxycarbonylmethyl [MCM]-benzyl)-d4TMP 6 as well as the enzyme-cleavable bis(4-acetoxybenzyl)-d4TMP [bis(AB)-d4TMP(7 and bis(alpha-methoxycarbonylmethyl-4-acetoxybenzyl)-d4TMP [bis(alpha-MCM-AB)-d4TMP] 8 were synthesized. Chemical hydrolysis studies proved that all bis(benzyl) triesters hydrolyze to give the intermediate benzyl phosphate diesters. Moreover, the latter two triesters 7,8 and cycloSal-d4TMPs 1 and 3 led finally to the delivery of d4TMP. The chemical hydrolysis studies allowed a detailed mechanistic interpretation of the degradation pathways of triesters 1-8. Cell extract studies of the bis(benzyl) triesters 4-8 confirmed that only triesters 7 and 8 released d4TMP although with a considerable increase of the reaction rate. Anti-HIV evaluation of the compounds showed that cycloSal-d4TMP 1 and the bis(AB) triesters 7,8 were entirely independent of the presence of cellular thymidine kinase (TK).
将描述三种环胞苷 - d4TMP 1、2和3与多种双（苄基）磷酸三酯4 - 8（抗病毒活性核苷类似物2'，3'-二脱氧-2'，3'-二脱氢胸苷（d4T）的衍生物）的比较研究。该研究始于以下观察结果：与原型环胞苷 - d4TMP 1相比，在环胞苷结构（2）中引入一个简单的7 - 甲基基团导致了完全不同的水解模式。在7 - 甲基取代的化合物2的情况下，形成的不是选择性地形成d4TMP，而是形成了苯基磷酸二酯。降解途径的差异是由反应机制的变化引起的。苯基磷酸二酯在化学和酶促作用下对进一步裂解生成d4TMP是惰性的。为了进行比较，合成了双（苄基）-d4TMP 4、双（α - 甲基苄基）-d4TMP 5、双（α - 甲氧基羰基甲基[MCM] - 苄基）-d4TMP 6以及可酶切的双（4 - 乙酰氧基苄基）-d4TMP [双（AB）-d4TMP（7）和双（α - 甲氧基羰基甲基 - 4 - 乙酰氧基苄基）-d4TMP [双（α - MCM - AB）-d4TMP] 8。化学水解研究证明，所有双（苄基）三酯水解生成中间产物苄基磷酸二酯。此外，后两种三酯7、8以及环胞苷 - d4TMPs 1和3最终导致了d4TMP的释放。化学水解研究允许对三酯1 - 8的降解途径进行详细的机理解释。对双（苄基）三酯4 - 8的细胞提取物研究证实，只有三酯7和8释放d4TMP，尽管反应速率有相当大的提高。对这些化合物的抗HIV评估表明，环胞苷 - d4TMP 1和双（AB）三酯7、8完全不依赖于细胞胸苷激酶（TK）的存在。
