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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Benzo(b)acronycine derivatives: a novel class of antitumor agents.
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Benzo(b)acronycine derivatives: a novel class of antitumor agents.

机译：苯并（b）阿卡洛霉素衍生物：一类新的抗肿瘤药。

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摘要

A hypothesis of bioactivation of the antitumor alkaloid acronycine by transformation of the 1,2-double bond into the corresponding epoxide in vivo and the suggestion that acronycine could interact with DNA, led to develop 1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine diesters (1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]p yrano[3,2-h]acridin-7-one diesters) as new anticancer drug candidates. Compared to acronycine these compounds were markedly more potent, both in terms of cytotoxicity and antitumor activity. The biological activity of these compounds was strongly related with their ability to give covalent adducts with purified as well as genomic DNA. Formation of those adducts involves alkylation of the exocyclic N-2 amino groups of guanines exposed in the minor groove of double helical DNA by the carbocation produced by the elimination of the acyloxy leaving group at position 1 of the drug. A transesterification process of the ester group from position 2 to position 1 accounted for the intense activity of cis-1-hydroxy-2-acyloxy-1,2-dihydrobenzo[b]acronycine derivatives. Cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine, which displays a particularly impressive broad antitumor spectrum, is currently developed by Servier Laboratories under the code S23906-1.
机译：通过体内将1,2-双键转变成相应的环氧化物来抗肿瘤生物碱丙烯醛生物活化的假说，并暗示丙烯醛可以与DNA相互作用，从而导致开发1,2-二羟基-1，2-二氢苯并[ b]丙ron酸二酯（1,2-二羟基-6-甲氧基-3,3,14-三甲基-1,2,3,14-四氢-7H-苯并[b] p吡喃并[3,2-h] h啶- 7位二酯）作为新的抗癌药物候选者。与丙烯醛相比，这些化合物在细胞毒性和抗肿瘤活性方面均显着更有效。这些化合物的生物学活性与它们与纯化的以及基因组DNA产生共价加合物的能力密切相关。这些加合物的形成涉及通过消除药物第1位上的酰氧基离去基团而产生的碳正离子化作用，使双螺旋DNA小沟中暴露的鸟嘌呤的环外N-2氨基烷基化。酯基团从位置2到位置1的酯基转移反应说明了顺式-1-羟基-2-酰氧基-1，2-二氢苯并[b]环丙氨酸衍生物的强烈活性。 Servier Laboratories当前正在开发Sis-1,2-diacetoxy-1,2-dihydrobenzo [b] acronycine，它具有特别令人印象深刻的广谱抗肿瘤谱，编码为S23906-1。

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