Sequence-selective targeting of long stretches of the DNA minor groove by a novel dimeric bis-benzimidazole.
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-(CH(2))(n)()-X-CH(2))(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.
Joubert
Alexandra
A
INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place de Verdun, 59045 Lille, France.
Sun
Xiao-Wen
XW
Johansson
Eric
E
Bailly
Christian
C
Mann
John
J
Neidle
Stephen
S
D001483:Base Sequence; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D015195:Drug Design; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D013816:Thermodynamics
D001562:Benzimidazoles; D008024:Ligands; C475103:N-methyl-N,N-bis-3,3-(4'-(5' '-(2'-p-methoxyphenyl)-5' -1H-benzimidazolyl)-2' '-1H-benzimidazolyl)phenoxypropylamine; D004247:DNA