A new class of symmetric bisbenzimidazole-based DNA minor groove-binding agents showing antitumor activity
A new class of symmetric bisbenzimidazole-based DNA minor groove-binding agents showing antitumor activity
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DOI：
10.1021/jm000297b
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发表时间：
2001-01-18
影响因子：
7.3
通讯作者：
Neidle, S
中科院分区：
文献类型：
--
作者：
Mann, J;Baron, A;Neidle, S
报道了新型头对头双苯并咪唑化合物2,2-双[4′-（3′-二甲氨基-1′-丙氧基）苯基]-5,5-双- 1h -苯并咪唑的合成及评价。对DNA十二核苷酸序列d（CGCGAATTCGCG）配合物的x射线晶体学研究表明，该配合物结合在B-DNA双链的a /T小凹槽区域，并且首尾相连的双苯并咪唑基序氢键与所有四个连续的a:T碱基对的边缘相连。该化合物在卵巢癌细胞系中显示出有效的生长抑制作用，平均IC50为0.31 muM，在两个获得性顺铂耐药细胞系中没有显著的交叉耐药，在p糖蛋白过表达的获得性阿霉素耐药细胞系中没有低水平的交叉耐药。中空纤维试验和体内肿瘤异种移植的研究显示了一些抗肿瘤活性的证据。
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.