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发现潜在的抗癌多靶点川芎嗪环己酮和肟类似物,克服癌症多药耐药性。

Discovery of potential anticancer multi-targeted ligustrazine based cyclohexanone and oxime analogs overcoming the cancer multidrug resistance.

机构信息

Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan, 430070, PR China.

Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan, 430070, PR China.

出版信息

Eur J Med Chem. 2017 Jul 28;135:34-48. doi: 10.1016/j.ejmech.2017.04.025. Epub 2017 Apr 14.

Abstract

The drug research and development nowadays is focusing on multi-target drugs. In the treatment of cancer, therapies using drugs inhibiting one numerous targets signify a novel viewpoint. In comparison with traditional therapy, multi-targeted drugs directly aim cell subpopulations which are involved in progression of tumor. The current study comprises the synthesis of 34 novel ligustrazine-containing α, β-unsaturated carbonyl-based compounds and oximes. The growth of 5 various cancer cell types was strongly inhibited by ligustrazine-containing oximes as revealed by biological evaluation. A strong SAR was provided by the antiproliferative activity. The mechanistic effects of most active antiproliferative compounds on tubulin polymerization, EGFR TK kinases, KAF and BRAF were investigated, followed by in vitro investigation of reversal of efflux-based resistance developed by cancer cells. EGFR was strongly inhibited by two oximes 7e and 8o. Out of all linkers including positive control, 1-isopropyl-piperidin-4-one linker-bearing compounds showed best inhibition of FAK. The strongest inhibitory activity of BRAF was showed by compound 5e with an IC of 0.7 μM. Analogs such as 5 and 7 (b,e,f) exhibited a dual role as anticancer as well as MDR reversal agents. For understanding the target protein integrations with new compounds, molecular docking studies were also carried out.

摘要

如今,药物研发的重点是多靶标药物。在癌症治疗中,使用抑制多个靶标的药物治疗代表了一种新观点。与传统疗法相比,多靶标药物直接针对参与肿瘤进展的细胞亚群。本研究包括合成 34 种新型含川芎嗪的α,β-不饱和羰基化合物和肟。生物评价结果表明,含川芎嗪的肟强烈抑制 5 种不同类型的癌细胞生长。通过抗增殖活性提供了强烈的 SAR。对最活跃的抗增殖化合物对微管蛋白聚合、EGFR TK 激酶、KAF 和 BRAF 的作用机制进行了研究,随后对癌细胞产生的基于流出的耐药性进行了体外逆转研究。两种肟 7e 和 8o 强烈抑制 EGFR。在包括阳性对照在内的所有连接子中,带有 1-异丙基-哌啶-4-酮连接子的化合物对 FAK 的抑制作用最好。化合物 5e 对 BRAF 的抑制活性最强,IC 为 0.7μM。类似物如 5 和 7(b,e,f)表现出双重作用,既是抗癌剂,也是 MDR 逆转剂。为了了解新化合物与靶蛋白的整合,还进行了分子对接研究。

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