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 c...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 44; no. 2; pp. 138 - 144
Main Authors: Mann, J, Baron, A, Opoku-Boahen, Y, Johansson, E, Parkinson, G, Kelland, LR, Neidle, S
Format: Journal Article
Language:English
Published: WASHINGTON Amer Chemical Soc 18.01.2001
Subjects:
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Benzimidazoles - chemical synthesis
Benzimidazoles - chemistry
Benzimidazoles - metabolism
Benzimidazoles - pharmacology
Chemistry, Medicinal
Cisplatin - pharmacology
Crystallography, X-Ray
DNA - metabolism
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Female
Humans
Life Sciences & Biomedicine
Magnetic Resonance Spectroscopy
Mass Spectrometry
Mice
Mice, Nude
Models, Molecular
Pharmacology & Pharmacy
Science & Technology
Structure-Activity Relationship
Transplantation, Heterologous
Tumor Cells, Cultured
PROTEIN
BINDER
RECOGNITION
CRYSTAL-STRUCTURE
DRUGS
TOPOISOMERASE-I
D(CGCGAATTCGCG)2
DERIVATIVES
HOECHST 33258
ISSN:0022-2623, 1520-4804
Online Access:Get more information
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Description
Summary: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.
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content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/jm000297b