Polybenzamide mustards: structure-activity relationships for DNA sequence-specific alkylation.
A series of cytotoxic polybenzamide mustards targeted to the minor groove of DNA were used to define structure-activity relationships for sequence-specific DNA alkylation. Compounds with an annular structure closely matched to the minor groove of DNA, and with concave-facing, potentially H-bonding NH groups, had a strong preference for alkylating adenines in sequences possessing four or more consecutive adenines. Two compounds whose annular structure matched that of the minor groove better when at least one carboxamide NH group faced outwards showed a high specificity for the consensus sequence (A/T)A(G/C) (A/T)N. Several compounds also alkylated specific guanines, presumably at the N3 position. Modelling studies suggest the most important contribution to sequence-specific alkylation is the H-bonds formed between these compounds and DNA, with factors such as the degree and positioning of cationic charge being less influential.
Turner
P R
PR
Auckland Cancer Society Research Centre, Faculty of Medicine and Health Science, University of Auckland, New Zealand.
Ferguson
L R
LR
Denny
W A
WA
D000225:Adenine / Q000737:chemistry; D000478:Alkylation; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000737:chemistry*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry*; D002417:Cattle; D004247:DNA / Q000737:chemistry*; D018983:DNA Footprinting; D004269:DNA, Bacterial / Q000737:chemistry; D004926:Escherichia coli / Q000187:drug effects; D006147:Guanine / Q000737:chemistry; D020287:In Situ Nick-End Labeling; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D010957:Plasmids / Q000737:chemistry / Q000302:isolation & purification; D013329:Structure-Activity Relationship
D018906:Antineoplastic Agents, Alkylating; D001549:Benzamides; D004269:DNA, Bacterial; D009588:Nitrogen Mustard Compounds; D006147:Guanine; D004247:DNA; D000225:Adenine