Synthesis, DNA binding, sequence preference and biological evaluation of minor groove-selective N1-alkoxyalkyl-bis-benzimidazoles.
The synthesis and characterization of two groups of N1-alkoxyalkyl-bis-benzimidazoles are described. These groups of agents, that differ in the orientation of the N3-alkoxyalkyl group with respect to the minor groove of the DNA receptor, were designed to examine the structural requirements of molecular recognition of these minor groove-selective anticancer agents. The relative binding of the 12 agents to poly(dA-dT), determined by ethidium displacement in C50 values, ranged from 0.62 to 14.20 micrograms/ml. Sequence-preferential binding, established by complementary strand MPE.Fe(II) footprinting, was predominantly AT selective, but with significantly enhanced GC recognition in the cases of those ligands bearing an accessible pyridine N directed inwards to the minor groove. Binding site sizes were generally 5 +/- 1 base pairs. Cytotoxicities against KB human tumor cells ranged from 0.93 to 46.59 micrograms/ml. The most potent agent 6c, which also showed the strongest DNA binding, is of the 'r-inward-directed' type. The stringent structural requirements within the alkoxyalkyl R group for potency suggest additional specific interactions or chemical reaction of 6c within the groove that more than compensate for the increased steric hindrance.
Department of Chemistry, University of Alberta, Edmonton, Canada.
H
H
Wang
R
R
Gupta
J W
JW
Lown
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001483:Base Sequence; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D006801:Humans; D007624:KB Cells / Q000187:drug effects; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004247:DNA