Synthesis, activation, and cytotoxicity of aldophosphamide analogues.
Synthesis, activation, and cytotoxicity of aldophosphamide analogues.
复制标题
醛磷酰胺类似物的合成、活化和细胞毒性。
DOI：
10.1021/jm00114a014
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发表时间：
1991
影响因子：
7.3
通讯作者：
Valente,RR
中科院分区：
文献类型：
--
作者：
Borch,RF;Valente,RR
本文合成了一系列醛磷酰胺的全氢恶嗪类似物，并对其~（31）P NMR动力学和体外细胞毒性进行了评价。这些化合物是基于以下想法开发的：开环和互变异构为烯胺中间体可以提供用于释放磷酰胺芥子气的β-消除反应的机械替代方案。4，4，6-三甲基四氢-1，3-恶嗪部分是基于其快速的亚胺离子生成速率和相对缓慢的水解速率来选择的。这些类似物通过三种不同的机制进行二氨基磷酸酯的释放：水解为醛磷酰胺和随后的β-消除;环化产生4-羟基环磷酰胺，其通过开环和消除释放二氨基磷酸酯;和互变异构化为烯胺并快速排出二氨基磷酸酯。动力学研究表明，水解成醛对整个活化过程的贡献最小，烯胺途径是活化的主要途径。对于那些可以进行环化的类似物，该途径有效地与烯胺的释放竞争，并且这些类似物在细胞毒性方面基本上等同于它们的4-羟基环磷酰胺对应物。合成了一系列不能环化的四N-取代磷酰胺类化合物，探讨了环化对这些化合物细胞毒性的影响。四（氯乙基）磷酰二胺在体外对环磷酰胺敏感和耐药的L1210和P388细胞系是非常有效的，这些类似物之一对L1210白血病在体内具有显着的抗肿瘤活性。这些结果表明，烯胺机制提供了一种可行的途径来递送二氨基磷酸酯，并且该方法可用于递送在环磷酰胺抗性细胞系中非交叉抗性的二氨基磷酸酯。
A series of perhydrooxazine analogues of aldophosphamide hasbeen prepared, and their 31P NMR kinetics and in vitro cytotoxicity have been evaluated. These compounds were developed on the basis of the idea that ring opening and tautomerization to an enamine intermediate might provide a mechanistic alternative to the^-elimination reaction for release of phosphoramide mustard. The 4, 4, 6-trimethyltetrahydro-l, 3-oxazine moiety was selected on the basis of its rapid rate of iminium iongeneration and relatively slow rate of hydrolysis. These analogues underwent phosphorodiamidate release by three distinct mechanisms: hydrolysis to aldophosphamide and subsequent ß-elimination; cyclization to produce the 4-hydroxycyclophosphamides, which release phosphorodiamidate by ring opening and elimination; and tautomerization to the enamine with rapid expulsion of phosphorodiamidate. Kinetic studies demonstrated that hydrolysis to the aldehyde contributed minimally to the overall activation process and that the enamine pathway represented the major route of activation. For those analogues that could undergo cyclization, this pathway competed effectively with enamine release, and these analogues were essentially equivalent totheir 4-hydroxycyclophosphamide counterparts in cytotoxicity. A series of tetra-N-substitutedphosphorodiamidates that cannot undergo cyclization was prepared to explore the effects of cyclization on the cytotoxicityof these analogues. The tetrakis (chloroethyl) phosphorodiamidates were highly potent in vitro against both cyclophosphamide-sensitive and-resistant L1210 and P388 cell lines, and one of these analogues had significant antitumor activity against L1210 leukemia in vivo. These results demonstrate that the enamine mechanism provides a viable pathway for delivery of phosphorodiamidates and that this approach can be used to deliver phosphorodiamidates that are non-cross-resistant in cyclophosphamide-resistant cell lines.