A new class of symmetric bisbenzimidazole-based DNA minor groove-binding agents showing antitumor activity
MetadataShow full item record
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 IC50 across an ovarian carcinoma cell line panel of 0.31 muM, 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.
License start date
JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 pp. 138 - 144