氮丙啶基醌对DNA的交联和序列特异性烷基化。1. 醌甲基化物

Cross-linking and sequence specific alkylation of DNA BY aziridinylquinones. 1. Quinone methides.

作者信息

Mayalarp S P, Hargreaves R H, Butler J, O'Hare C C, Hartley J A

机构信息

CRC Department of Biophysical Chemistry, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.

出版信息

J Med Chem. 1996 Jan 19;39(2):531-7. doi: 10.1021/jm950629q.

DOI:10.1021/jm950629q

PMID:8558523

Abstract

The cytotoxicities and DNA cross-linking abilities of 16 1,4-benzoquinones have been investigated. All of the alkylmonoaziridinyl-1,4-benzoquinones were able to interstrand crosslink DNA after reduction and were cytotoxic in vitro. Compounds lacking an aziridine group were unable to cross-link DNA and were less cytotoxic. The methyl analogues were shown to preferentially react at TGC sequences. From comparing the structural requirements for crosslinking and the cytotoxicities, a mechanism has been proposed wherein some hydroquinones can associate and react at TGC sequences in DNA. These hydroquinones can subsequently autoxidize to form a reactive quinone methide which reacts at the opposite strand to form a cross-link.

摘要

对16种1,4 - 苯醌的细胞毒性和DNA交联能力进行了研究。所有烷基单氮丙啶基 - 1,4 - 苯醌在还原后均能够使DNA发生链间交联，并且在体外具有细胞毒性。缺乏氮丙啶基团的化合物无法交联DNA，且细胞毒性较小。甲基类似物显示优先在TGC序列处发生反应。通过比较交联的结构要求和细胞毒性，提出了一种机制，其中一些对苯二酚可以在DNA的TGC序列处缔合并发生反应。这些对苯二酚随后可自动氧化形成反应性醌甲基化物，其在相反链上发生反应以形成交联。