Cross-linking and sequence specific alkylation of DNA BY aziridinylquinones. 1. Quinone methides.
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.
Mayalarp
S P
SP
CRC Department of Biophysical Chemistry, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
Hargreaves
R H
RH
Butler
J
J
O'Hare
C C
CC
Hartley
J A
JA
D000478:Alkylation; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA / Q000737:chemistry* / Q000187:drug effects; D006801:Humans; D045563:Indolequinones; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011809:Quinones / Q000737:chemistry* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D045563:Indolequinones; D007211:Indoles; D011809:Quinones; C068040:quinone methide; D004247:DNA