4,5-Di-substituted benzyl-imidazol-2-substituted amines as the structure template for the design and synthesis of reversal agents against P-gp-mediated multidrug resistance breast cancer cells
4,5-Di-substituted benzyl-imidazol-2-substituted amines as the structure template for the design and synthesis of reversal agents against P-gp-mediated multidrug resistance breast cancer cells
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4,5-二取代的苄基-咪唑-2-取代胺作为设计和合成针对P-gp介导的多药耐药性乳腺癌细胞的逆转剂的结构模板
DOI：
10.1016/j.ejmech.2014.06.016
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发表时间：
2014-08-18
影响因子：
6.7
通讯作者：
Jiang, Tao
中科院分区：
文献类型：
--
作者：
Zhang, Nan;Zhang, Zhaohui;Jiang, Tao
p -糖蛋白（P-gp）是一种主要的多药转运蛋白，位于质膜上，其过表达在细胞毒性化疗的多药耐药（MDR）中起重要作用。纳米脒是一类从海绵中分离出来的海洋咪唑类生物碱，具有y形支架。基于本课组已开发的第三代MDR调制剂ONT-093及其他调制剂的研究结果，以纳米酰胺支架为结构模板，设计合成了一系列新型4,5-二取代苄基-1-甲基- 1h -咪唑-2取代胺。随后，在p- gp介导的多药耐药乳腺癌细胞系MDA435/LCC6MDR中评估了它们对紫杉醇耐药的逆转活性。具有y形支架的化合物12c和具有x形支架并在芳基环B上具有4-二乙胺基的化合物17c是最有效的P-gp调节剂。化合物12c和17c在1 μ M浓度下对LCC6MDR细胞紫杉醇的增敏率分别为26.4倍和24.5倍，EC50分别为212.5和210.5 nM。这两种化合物的效力大约是维拉帕米的5-6倍（RF = 4.5）。化合物12c和17c对癌细胞和正常小鼠成纤维细胞系均无明显的细胞毒性。本研究表明，合成的萘脒类似物可以作为p- gp介导的耐药癌细胞的有效、安全的调节剂。(C) 2014 Elsevier Masson SAS。版权所有。
Over-expression of P-glycoprotein (P-gp), a primary multidrug transporter which is located in plasma membranes, plays a major role in the multidrug resistance (MDR) of cytotoxic chemotherapy. Naamidines are a class of marine imidazole alkaloids isolated from Leucetta and Clathrina sponges, possessing a Y-shaped scaffold. Based on the results previously obtained from the third-generation MDR modulator ONT-093 and other modulators developed in our group, we designed and synthesized a series of novel 4,5-di-substituted benzyl-1-methyl-1H-imidazol-2-substituted amines using the Naamidine scaffold as the structure template. Subsequently, their reversing activity for Taxol resistance has been evaluated in P-gp-mediated multidrug resistance breast cancer cell line MDA435/LCC6MDR. Compounds 12c with a Y-shaped scaffold, and compound 17c which is 'X-shaped' scaffold and possesses a 4-diethylamino group at aryl ring B, turned out to be the most potent P-gp modulators. It appears that compounds 12c and 17c at 1 mu M concentration can sensitize LCC6MDR cells toward Taxol by 26.4 and 24.5 folds, with an EC50 212.5 and 210.5 nM, respectively. These two compounds are about 5-6 folds more potent than verapamil (RF = 4.5). Moreover, compounds 12c and 17c did not exhibit obvious cytotoxicity in either cancer cell lines or normal mouse fibroblast cell lines. This study has demonstrated that the synthetic Naamidine analogues can be potentially employed as effective, safe modulators for the P-gp-mediated drug resistance cancer cells. (C) 2014 Elsevier Masson SAS. All rights reserved.