Enhanced DNA alkylation activities of Hoechst 33258 analogues designed for bioreductive activation.
A series of analogues of Hoechst 33258, designed to be subject to bioreductive activation, were synthesized, and interactions between these compounds and pBR322 DNA were investigated. Compounds containing a quinone group reacted with DNA via two possible pathways in the presence of reductants NADH or NADPH: radical cleavage and DNA alkylation. The corresponding dimethoxy compounds, which are not subject to reduction, showed very weak DNA binding ability. The strength of alkylation reaction of the quinone derivatives is related to leaving group ability. Furthermore, the quinone compounds preferentially alkylate DNA at 5'-CG and TG sequences rather than at the AT sites preferred as binding sites of Hoechst 33258.
Guan
L L
LL
Department of Chemistry, University of Alberta, Edmonton, Canada.
Zhao
R
R
Lown
J W
JW
D000478:Alkylation; D001483:Base Sequence; D001665:Binding Sites; D006690:Bisbenzimidazole / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004229:Dithiothreitol / Q000378:metabolism; D008024:Ligands; D015394:Molecular Structure; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship
D008024:Ligands; D009243:NAD; D009249:NADP; D004247:DNA; D006690:Bisbenzimidazole; D004229:Dithiothreitol