Cross-linking and sequence specific alkylation of DNA by aziridinyl quinones. 2. Structure requirements for sequence selectivity.
The cytotoxicities and DNA sequence selectivity for guanine-N7 alkylation of 22 mono- and disubstituted 2,5-diaziridinyl-1,4-benzoquinones have been investigated. Several quinones produced patterns of alkylation following reduction with a selectivity for 5'-TGC-3' sequences. This sequence selectivity appeared to be dependent only on the presence of a hydrogen in position-6 of the quinone. A computer model, based on published crystallographic data, was used to explain this selectivity. The sequence selective quinones were generally more cytotoxic that the quinones which reacted randomly.
Hargreaves
R H
RH
CRC Department of Biophysical Chemistry, Drug Development, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, U.K.
Mayalarp
S P
SP
Butler
J
J
McAdam
S R
SR
O'Hare
C C
CC
Hartley
J A
JA
D000478:Alkylation; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001388:Aziridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016227:Benzoquinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D006147:Guanine / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D001388:Aziridines; D016227:Benzoquinones; D003432:Cross-Linking Reagents; D006147:Guanine; D004247:DNA