A new class of symmetric bisbenzimidazole-based DNA minor groove-binding agents showing antitumor activity.
The synthesis and evaluation of the novel head-to-head bisbenzimidazole compound 2,2-bis[4'-(3' '-dimethylamino-1' '-propyloxy)phenyl]-5,5-bi-1H-benzimidazole is described. An X-ray crystallographic study of a complex with the DNA dodecanucleotide sequence d(CGCGAATTCGCG) shows the compound bound in the A/T minor groove region of a B-DNA duplex and that the head-to-head bisbenzimidazole motif hydrogen-bonds to the edges of all four consecutive A:T base pairs. The compound showed potent growth inhibition with a mean IC(50) across an ovarian carcinoma cell line panel of 0.31 microM, with no significant cross-resistance in two acquired cisplatin-resistant cell lines and a low level of cross-resistance in the P-glycoprotein overexpressing acquired doxorubicin-resistant cell line. Studies with the hollow fiber assay and in vivo tumor xenografts showed some evidence of antitumor activity.
Mann
J
J
Chemistry Department, Reading University, Whiteknights, Reading RG6 6AD, UK.
Baron
A
A
Opoku-Boahen
Y
Y
Johansson
E
E
Parkinson
G
G
Kelland
L R
LR
Neidle
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C421913:2,2-bis(4'-(3'-dimethylamino-1''-propyloxy)phenyl)-5,5-bi-1H-benzimidazole; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004247:DNA; D002945:Cisplatin