Mechanism of Action of AminoCBIs: Highly Reactive but Highly Cytotoxic Analogues of the Duocarmycins
Mechanism of Action of AminoCBIs: Highly Reactive but Highly Cytotoxic Analogues of the Duocarmycins
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AminoCBI 的作用机制：多卡霉素的高反应性但高细胞毒性类似物
DOI：
10.1002/cbic.201402256
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发表时间：
2014
期刊：
影响因子：
3.2
通讯作者：
Sonia Alix
中科院分区：
文献类型：
--
作者：
M. Tercel;F. Pruijn;Patrick D. O’Connor;H. Liyanage;G. Atwell;Sonia Alix
双霉素是一种具有高度细胞毒性的天然产物，具有开发成为抗癌药物的潜力。在这里，我们描述了提议的但以前未确定的DNA烷基化亚基的NH类似物，并通过溶剂化研究、核磁共振和计算模型来表征这些类似物。结果表明，这些化合物是SECO前驱体溶剂分解的唯一中间体，除了具有异常高的碱度外，还具有与被广泛研究的氧基类似物非常相似的结构特征。测得的pKa为10.5，表明NH化合物在生理条件下是完全质子化的。值得注意的是，它们极高的反应性(质子化NH的计算水解率是中性O类似物的108倍)仍然与强大的细胞毒性相容，只要活性物种是在细胞存在的情况下形成的。这些令人惊讶的发现与以多卡霉素为基础的肿瘤选择性治疗的设计有关。
Duocarmycins are highly cytotoxic natural products that have potential for development into anticancer agents. Herein we describe proposed but previously unidentified NH analogues of the DNA‐alkylating subunit and characterise these by solvolysis studies, NMR and computational modelling. These compounds are shown to be the exclusive intermediates in the solvolysis of their seco precursors and to possess very similar structural features to the widely studied O‐based analogues, apart from an unusually high basicity. The measured pKa of 10.5 implies that the NH compounds are fully protonated under physiological conditions. Remarkably, their extremely high reactivity (calculated hydrolysis rate 108 times higher for protonated NH compared to the neutral O analogue) is still compatible with potent cytotoxicity, provided the active species is formed in the presence of cells. These surprising findings are of relevance to the design of duocarmycin‐based tumour‐selective therapies.
影响因子：
7.3
作者：
MacMillan KS;Boger DL
通讯作者：
Boger DL
( )-CC-1065-DNA 加合物的结构：有序水分子的关键作用以及对磷酸盐催化参与共价反应的影响。
影响因子：
2.9
作者：
Lin,CH;Beale,JM;Hurley,LH
通讯作者：
Hurley,LH
影响因子：
3.6
作者：
Boger, DL;Hughes, TV;Hedrick, MP
通讯作者：
Hedrick, MP