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首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Design, synthesis and biological evaluation of di-substituted noscapine analogs as potent and microtubule-targeted anticancer agents
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Design, synthesis and biological evaluation of di-substituted noscapine analogs as potent and microtubule-targeted anticancer agents

机译：设计，合成和生物评估双取代的Noscapine类似物作为有效的微管靶向抗癌药

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Noscapine is an opium-derived kinder-gentler microtubule-modulating drug, currently in Phase I/II clinical trials for cancer chemotherapy. Here, we report the synthesis of four more potent di-substituted brominated derivatives of noscapine, 9-Br-7-OH-NOS (2), 9-Br-7-OCONHEt-NOS (3), 9-Br-7-OCONHBn-NOS (4), and 9-Br-7-OAc-NOS (5) and their chemotherapeutic efficacy on PC-3 and MDA-MB-231 cells. The four derivatives were observed to have higher tubulin binding activity than noscapine and significantly affect tubulin polymerization. The equilibrium dissociation constant (K-D) for the interaction between tubulin and 2, 3, 4, 5 was found to be, 55 +/- 6 mu M, 44 +/- 6 mu M, 26 +/- 3 mu M, and 21 +/- 1 mu M respectively, which is comparable to parent analog. The effects of these di-substituted noscapine analogs on cell cycle parameters indicate that the cells enter a quiescent phase without undergoing further cell division. The varying biological activity of these analogs and bulk of substituent at position-7 of the benzofuranone ring system of the parent molecule was rationalized utilizing predictive in silico molecular modeling. Furthermore, the immunoblot analysis of protein lysates from cells treated with 4 and 5, revealed the induction of apoptosis and down-regulation of survivin levels. This result was further supported by the enhanced activity of caspase-3/7 enzymes in treated samples compared to the controls. Hence, these compounds showed a great potential for studying microtubule-mediated processes and as chemotherapeutic agents for the management of human cancers. (C) 2015 Elsevier Ltd. All rights reserved.
机译：Noscapine是一种鸦片衍生的Kinder-gentler微管调节药物，目前处于癌症化学治疗的I / II期临床试验中。在这里，我们报告了Noscapine，9-Br-7-OH-NOS（2），9-Br-7-OCONHEt-NOS（3），9-Br-7- OCONHBn-NOS（4）和9-Br-7-OAc-NOS（5）及其对PC-3和MDA-MB-231细胞的化学治疗功效。观察到四种衍生物具有比Noscapine高的微管蛋白结合活性，并显着影响微管蛋白的聚合。发现微管蛋白与2、3、4、5之间相互作用的平衡解离常数（KD）为55 +/- 6μM，44 +/- 6μM，26 +/- 3μM和分别为21 +/- 1μM，与母体类似物相当。这些二取代的Noscapine类似物对细胞周期参数的影响表明，细胞进入静止期而没有进一步的细胞分裂。利用计算机模拟预测模型，合理化了这些类似物的不同生物活性以及母体分子苯并呋喃酮环系统7位上的取代基主体。此外，对用4和5处理的细胞的蛋白裂解物进行的免疫印迹分析表明，它诱导了细胞凋亡，并下调了survivin的水平。与对照相比，处理过的样品中caspase-3 / 7酶的活性增强进一步支持了该结果。因此，这些化合物在研究微管介导的过程以及作为治疗人类癌症的化学治疗剂方面显示出巨大的潜力。 （C）2015 Elsevier Ltd.保留所有权利。

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