新型吡咯烷-查尔酮类衍生物的设计、合成及抗宫颈癌活性研究

Design, Synthesis and Anti-cervical Cancer Activity of Novel Pyrrolidine-chalcone Derivatives

关键词:  先导化合物  查尔酮类衍生物  宫颈癌  顺铂耐药宫颈癌  新型分子靶向

Key words:  lead compound  chalcone derivatives  cervical cancer  cisplatin-resistant cervical cancer  novel molecular targeting

摘要:

目的 设计、合成系列新型氮杂查尔酮类衍生物并研究其抗宫颈癌活性和作用机制。方法 以甘草查尔酮为先导化合物，以VEGFR-2和P-gp为靶点，采用活性亚结构拼接原理，设计并合成一系列新型查尔酮类衍生物，利用¹H-NMR、¹³C-NMR和HR-MS对结构进行表征。采用MTT、ELISA、联合顺铂用药、Western blotting和分子对接试验，初步评价了目标化合物对宫颈癌和顺铂耐药宫颈癌细胞的增殖抑制活性及作用机制。结果 化合物7h具有一定的抗肿瘤活性和逆转顺铂耐药作用，对VEGFR-2及下游PI3K/AKT信号通路蛋白的磷酸化具有一定的抑制作用，并在0.5，1.0，1.5 μmol·L^?1浓度内对P-gp蛋白表达量与空白组相比无显著性差异。结论 化合物7h的抗宫颈癌活性和逆转顺铂耐药作用，可能与其抑制了VEGFR-2和P-gp靶点有关。

Abstract:

OBJECTIVE To design and synthesize of a series of novel azachalcone derivatives and study of their anti-cervical cancer activity and mechanism of action. METHODS A series of novel chalcone derivatives were designed and synthesized by using glycyrrhiza chalcone as the lead compound and VEGFR-2 and P-gp as the target sites using the active substructure splicing principle, and the structures were characterized by ¹H-NMR, ¹³C-NMR and HR-MS. MTT, ELISA, co-dosing with cisplatin, Western blotting and molecular docking assays were used to preliminarily evaluate the proliferation inhibitory activity and mechanism of action of the target compounds on cervical cancer and cisplatin-resistant cervical cancer cells. RESULTS Compound 7h showed some antitumor activity and reversal of cisplatin resistance, and had some inhibitory effects on phosphorylation of VEGFR-2 and downstream PI3K/AKT signaling pathway proteins, with no significant differences on P-gp protein expression compared with the blank group in the concentration range of 0.5, 1.0, 1.5 μmol·L^?1. CONCLUSION The anti-cervical cancer activity and reversal of cisplatin resistance of compound 7h may be related to its inhibition of VEGFR-2 and P-gp targets.