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 com pound 2,2-bis[4'-(3 " -dimethylamino- 1 " -propyloxy)phenyl]-5,5-bi-1H-benz imidazole is described. An X-ray crystallographic study of a complex with t he DNA dodecanucleotide sequence d(CGCGAATTCGCG) shows the compound bound i n the A/T minor groove region of a B-DNA duplex and that the head-to-head b isbenzimidazole motif hydrogen-bonds to the edges of all four consecutive A :T base pairs. The compound showed potent growth inhibition with a mean IC5 0 across an ovarian carcinoma cell line panel of 0.31 muM, with no signific ant cross-resistance in two acquired cisplatin-resistant cell lines and a l ow 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.