Dihydropyridine derivatives to overcome atypical multidrug resistance: Design, synthesis, QSAR studies, and evaluation of their cytotoxic and pharmacological activities
Dihydropyridine derivatives to overcome atypical multidrug resistance: Design, synthesis, QSAR studies, and evaluation of their cytotoxic and pharmacological activities
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DOI：
10.1111/j.1747-0285.2007.00569.x
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发表时间：
2007-10-01
影响因子：
3
通讯作者：
Miri, Ramin
中科院分区：
文献类型：
--
作者：
Mehdipour, Ahmad R.;Javidnia, Katayoun;Miri, Ramin
多药耐药(MDR)被定义为肿瘤细胞对化疗中常用的多种结构不同和功能不同的药物的细胞毒作用的耐药性。尽管有迹象表明1，4-二氢吡啶(DHPs)对P-糖蛋白介导的MDR有影响，但到目前为止，还没有证据表明DHPs对非典型MDR的影响。然而，据报道，一种DHP衍生物(右旋尼古地平)通过非竞争性机制抑制人DNA拓扑异构酶I。因此，我们合成了一些DHP的衍生物，并对其逆转非典型MDR的作用进行了评价。结果表明，两种化合物对非典型MDR均有较强的逆转作用。此外，还测定了化合物在四种不同细胞系上的本征细胞毒性。此外，对其钙通道阻断活性进行了评价，根据C-4位的结构-活性关系显示出明显的构效关系(SAR)趋势，证实了C-4位在钙通道阻断中的重要性。
Multidrug resistance (MDR) is defined as resistance of tumor cells to the cytotoxic action of multiple structurally dissimilar and functionally divergent drugs commonly used in chemotherapy. Until now, there is no evidence for the effect of 1,4-dihydropyridines (DHPs) on atypical MDR, although there are some indications about the effect of DHPs on p-glycoprotein-mediated MDR. However, it was reported that a DHP derivative (Dexniguldipine) inhibited human DNA topoisomerase I through a non-competitive mechanism. Therefore, some derivatives of DHP were synthesized and their effect in reversing atypical MDR was evaluated. The results showed that two compounds were the potent reversals of atypical MDR. In addition, the intrinsic cytotoxicity of compounds was determined on four different cell lines. Furthermore, their Ca2+ channel blocking activity was evaluated and showed a clear structure-activity relationship (SAR) trend according to the moieties in C-4 position which confirmed the importance of C-4 moiety on Ca2+ channel blocking.