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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.
A new class of symmetric bisbenzimidazole-based DNA minor groove-binding agents showing antitumor activity.,Mann J, Baron A, Opoku-Boahen Y, Johansson E, Parkinson G, Kelland LR, Neidle S J Med Chem. 2001 Jan 18;44(2):138-44. PMID:11170623[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
↑ Mann J, Baron A, Opoku-Boahen Y, Johansson E, Parkinson G, Kelland LR, Neidle S. A new class of symmetric bisbenzimidazole-based DNA minor groove-binding agents showing antitumor activity. J Med Chem. 2001 Jan 18;44(2):138-44. PMID:11170623
