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

Joubert, A., Sun, X.W., Johansson, E., Bailly, C., Mann, J. and Neidle, S. (2003) Sequence-selective targeting of long stretches of the DNA minor groove by a novel dimeric bis-benzimidazole. Biochemistry, 42 (20). pp. 5984-5992. 10.1021/bi026926w.

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DOI: 10.1021/bi026926w

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.

Item Type:Article
Additional Information:Full text available in print and electronically from the School of Pharmacy Library.
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Cancer Research UK Biomolecular Structure Group
ID Code:1732
Journal or Publication Title:Biochemistry
Deposited By:Library Staff
Deposited On:11 Aug 2010 10:55
Last Modified:11 Aug 2010 10:55

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