DNA alkylation by minor groove-binding N1-alkoxyalkyl-bis-benzimidazoles.
Two groups of isomeric N1-alkoxyalkyl-bis-benzimidazoles differing in the orientation of the N-alkoxyalkyl group (R) with respect to the DNA minor groove have been examined as to their reaction with DNA. Agarose gel mobility shift assay demonstrates that the 'R-inward' isomers alkylate and cause thermally induced strand breakage, in contrast to a much weaker reaction of the 'R-outward' isomers. Complementary studies using high-resolution polyacrylamide gel electrophoresis confirmed relatively weak but definite alkylation-induced thermal cleavage at all available G base sites, but at selected A sites. The alkylation reaction is interpreted in terms of an SN2 displacement of the alkoxy group by nucleophiles within the groove, in contrast to the complete lack of such nucleophilic displacement of these drugs in bulk solution. Reaction with all available Gs is interpreted in terms of nucleophilic strength within the DNA minor groove whereas, in contrast, reaction at the A residues appears to be determined primarily by initial molecular recognition of a DNA site by the drug, followed by an SN2 displacement. The relative cytotoxic potencies of these drugs against KB human tumor cells may be explained on the basis of this mechanism.
Gupta
R
R
Department of Chemistry, University of Alberta, Edmonton, Canada.
Huang
L
L
Wang
H
H
Lown
J W
JW
D000478:Alkylation; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry* / Q000633:toxicity; D001483:Base Sequence; D001562:Benzimidazoles / Q000737:chemistry*; D006690:Bisbenzimidazole / Q000737:chemistry*; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry*; D006801:Humans; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D018736:DNA Adducts; D004247:DNA; D006690:Bisbenzimidazole