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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Demonstration of a pronounced effect of noncovalent binding selectivity on the (+)-CC-1065 DNA alkylation and identification of the pharmacophore of the alkylation subunit.
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Demonstration of a pronounced effect of noncovalent binding selectivity on the (+)-CC-1065 DNA alkylation and identification of the pharmacophore of the alkylation subunit.

机译：证明了非共价结合选择性对（+）-CC-1065 DNA烷基化的显著作用并鉴定了烷基化亚基的药效基团。

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Studies on the structural origin of the DNA alkylation selectivity of the antitumor antibiotic (+)-CC-1065 are detailed. The sites of alkylation of double-stranded DNA were examined for simple derivatives of 7-methyl-1,2,8,8a-tetrahydrocycloprop[1,2-c]pyrrolo[3,2-e]indol- 4(5H)-one (CPI), (+)-CC-1065, and agents incorporating the parent 1,2,7,7a-tetrahydrocycloprop[1,2-c]indol-4-one (CI) left-hand subunit. The CI subunit of the agents is a much more reactive alkylating agent than the natural CPI alkylation subunit of CC-1065. Consequently, simple derivatives of CI were found to alkylate double-stranded DNA under milder conditions than were simple derivatives of CPI, and the marked similarities in the CI and CPI DNA alkylation profiles illustrate that CI represents the minimum pharmacophore of CPI. Comparisons of the DNA alkylation profiles of (+)-N-butyloxycarbonyl-CPI, (+)-N-acetyl-CPI, and (+)-CC-1065 revealed distinctions in the CPI and (+)-CC-1065 sites of alkylation, whereas the incorporation of the reactive CI electrophile into an analog of CC-1065 (CI-CDPI2) (CDPI, N3-carbamoyl-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylic acid) provided an agent that possesses the characteristic CC-1065 DNA alkylation profile (site selectivity and relative site intensity). These observations suggest that the noncovalent binding selectivity of the agents may restrict the number of available DNA alkylation sites and play a productive role in controlling the sequence-selective alkylation by effectively delivering the electrophile to A + T-rich minor groove regions of DNA possessing accessible adenine N-3 alkylation sites. In turn, the noncovalent binding selectivity may be derived from preferential binding within the narrower, sterically more accessible A + T-rich minor groove of double-stranded DNA.
机译：详细研究了抗肿瘤抗生素（+）-CC-1065的DNA烷基化选择性的结构来源。检查了7-甲基-1,2,8,8a-四氢环丙[1,2-c]吡咯并[3,2-e]吲哚-4（5H）-的简单衍生物的双链DNA烷基化位点一个（CPI），（+）-CC-1065和结合了母体1,2,7,7a-四氢环丙[1,2-c]吲哚-4-酮（CI）左手亚基的试剂。这些试剂的CI亚基比CC-1065的天然CPI烷基化亚基具有更高的反应性烷基化剂。因此，发现CI的简单衍生物在比CPI的简单衍生物更温和的条件下将双链DNA烷基化，并且CI和CPI DNA烷基化曲线的显着相似性表明CI代表CPI的最小药效团。 （+）-N-丁氧基羰基-CPI，（+）-N-乙酰基-CPI和（+）-CC-1065的DNA烷基化曲线的比较显示了CPI和（+）-CC-1065位点的区别烷基化，而将反应性CI亲电试剂纳入CC-1065（CI-CDPI2）（CDPI，N3-氨基甲酰基-1,2-二氢-3H-吡咯并[3,2-e]吲哚-7-羧基酸）提供了一种具有CC-1065 DNA烷基化特征（位点选择性和相对位点强度）特征的试剂。这些观察结果表明，这些试剂的非共价结合选择性可能会限制可利用的DNA烷基化位点的数量，并通过有效地将亲电试剂传递到富含A + T的具有可利用性的DNA的小沟区域，从而在控制序列选择性烷基化中发挥生产性作用。腺嘌呤N-3烷基化位点。反过来，非共价结合选择性可以源自在较窄的，空间上更易接近的富含A + T的双链DNA小沟内的优先结合。

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