Sequence-selective targeting of long stretches of the DNA minor groove by a novel dimeric bis-benzimidazole.

Abstract

A dimeric bis-benzimidazole molecule has been designed by computer modeling to bind to a DNA sequence via the DNA minor groove that covers a complete turn of B-DNA. A series of bis-benzimidazole dimers incorporating a −O−(CH2)n−X−CH2)n−O− linker, with n = 2 or 3 and X = O or N+H(Me), were screened for their capacity to fit the DNA minor groove. The modeling studies enabled an optimal linker to be devised (n = 3, X = N+H(Me)), and the synthesis of the predicted “best” molecule, N-methyl-N,N-bis-3,3-{4‘-[5‘‘-(2‘‘‘-p-methoxyphenyl)-5‘‘‘-1H-benzimidazolyl]-2‘‘-1H-benzimidazolyl}phenoxypropylamine (5), is reported. The optimized linker permits the two symmetric bis-benzimidazole motifs to maintain hydrogen-bonded contacts with the floor of the DNA minor groove. DNase I footprinting studies have shown that this ligand binds with high affinity to sequences representing approximately a complete turn of B-DNA, represented by the [A·T]4-[G·C]-[A·T]4 motif, and only poorly to sequences of half this site size, in accord with the computer modeling studies. Compound 5 does not show acute cellular cytotoxicity, in contrast with its monomeric bis-benzimidazole precursors, yet is rapidly taken up into cells.