一种新型、高效的双氰胺氨基甲酸酯前药，无残留副产物释放。
A novel, unusually efficacious duocarmycin carbamate prodrug that releases no residual byproduct.
机构信息
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
出版信息
J Med Chem. 2012 Jun 28;55(12):5878-86. doi: 10.1021/jm300330b. Epub 2012 Jun 12.
Abstract
A unique heterocyclic carbamate prodrug of seco-CBI-indole(2) that releases no residual byproduct is reported as a new member of a class of hydrolyzable prodrugs of the duocarmycin and CC-1065 family of natural products. The prodrug was designed to be activated by hydrolysis of a carbamate releasing the free drug without the cleavage release of a traceable extraneous group. Unlike prior carbamate prodrugs examined that are rapidly cleaved in vivo, the cyclic carbamate was found to be exceptionally stable to hydrolysis under both chemical and biological conditions providing a slow, sustained release of the exceptionally potent free drug. An in vivo evaluation of the prodrug found that its efficacy exceeded that of the parent drug, that its therapeutic window of efficacy versus toxicity is much larger than the parent drug, and that its slow free drug release permitted the safe and efficacious use of doses 150-fold higher than the parent compound.
摘要
一种独特的杂环氨基甲酸酯前药，是 secoCBI-吲哚（2）的前药，不会释放任何残留的副产物，作为天然产物中二羧酸菌素和 CC-1065 家族可水解前药的新成员被报道。该前药通过氨基甲酸酯的水解被设计成激活，释放游离药物而不释放可追踪的外来基团。与之前研究过的在体内迅速裂解的氨基甲酸酯前药不同，环状氨基甲酸酯在化学和生物学条件下都表现出异常稳定的水解，从而提供了游离药物的缓慢、持续释放。体内评估发现，该前药的疗效优于母体药物，其疗效与毒性的治疗窗口比母体药物大得多，其缓慢的游离药物释放允许安全有效地使用比母体化合物高 150 倍的剂量。
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