Are the duocarmycin and CC-1065 DNA alkylation reactions acid-catalyzed? Solvolysis pH-rate profiles suggest they are not
Are the duocarmycin and CC-1065 DNA alkylation reactions acid-catalyzed? Solvolysis pH-rate profiles suggest they are not
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DOI：
10.1021/jo990762g
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发表时间：
1999-07-23
影响因子：
3.6
通讯作者：
Garbaccio, RM
中科院分区：
文献类型：
--
作者：
Boger, DL;Garbaccio, RM
详细研究了CC-1065/多卡霉素烷基化亚基的两个关键反应性类似物的溶解pH-速率分布。与真正的烷基化亚基和N-BOC-CBI(4)不同，N-BOC-CBQ(5)和N-BOC-CNA(6)在pH值为2-12的范围内都是活性的。此外，它们具有逐渐减少的乙烯基酰胺共轭作用，导致相应的逐渐增加的反应性采用和反映类似于DNA结合的CC-1065的建议的构象。两者都只在较低的pH为2~5时发生了酸催化反应，而在pH大于或等于6时，非催化反应速率占主导地位，说明在pH为7.4时，CC-1065和多卡霉素DNA的烷基化反应不一定是酸催化反应。这些研究进一步提供了有力的证据表明，DNA烷基化反应(pH 7.4)的催化来自于DNA结合引起的试剂的构象变化，这种变化破坏了稳定的烷基化亚单位乙烯基酰胺结合，激活了不依赖于pH的亲核攻击试剂。
A study of the solvolysis pH-rate profiles for two key reactive CC-1065/duocarmycin alkylation subunit analogues is detailed. Unlike the authentic alkylation subunits and N-BOC-CBI (4) which are too stable to establish complete solvolysis ps-rate profiles, the analogues N-BOC-CBQ (5) and N-BOC-CNA (6) are reactive throughout the pH range of 2-12. Moreover, they possess progressively diminished vinylogous amide conjugation resulting in a corresponding progressively increasing reactivity adopting and reflecting conformations analogous to that proposed for DNA-bound CC-1065. For both, the acid-catalyzed reaction was observed only at the lower pH of 2-5, and the uncatalyzed solvolysis reaction rate dominated at pH greater than or equal to 6, indicating that the CC-1065 and duocarmycin DNA alkylation reaction observed at pH 7.4 need not be an acid-catalyzed reaction. The studies provide further strong evidence that catalysis for the DNA alkylation reaction (pH 7.4) is derived from a DNA binding-induced conformational change in the agents that disrupts the stabilizing alkylation subunit vinylogous amide conjugation activating the agents for nucleophilic attack independent of pH.