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.
Wang
H
H
Department of Chemistry, University of Alberta, Edmonton, Canada.
Gupta
R
R
Lown
J W
JW
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