新型咪唑-查尔酮衍生物的设计、合成及抗宫颈癌和顺铂耐药活性研究

摘要 目的 以甘草查尔酮母核为先导化合物骨架，设计、合成一系列新型咪唑-查尔酮衍生物并进行抗宫颈癌活性研究。方法 在查尔酮骨架的B环引入4种咪唑环，在A环分别引入甲氧基、氨基、羟基等活性基团；采用Claisen-Schmidt反应合成系列新型咪唑-查尔酮衍生物，其结构经1H-NMR、13C-NMR和HRMS进行表征。通过MTT、Transwell、流式细胞仪和分子对接实验方法，初步探索目标化合物的抗宫颈癌活性及作用机制。结果 大部分化合物具有一定的抗宫颈癌活性，其中2i较为显著，且对正常细胞的毒性较小。此外，化合物2i能够显著抑制HeLa和HeLa/DDP细胞的迁移和侵袭能力，能够诱导其凋亡，并阻滞HeLa和HeLa/DDP细胞于G2/M期；分子对接模拟显示2i与查尔酮母核和原配体秋水仙碱相比，2i与微管蛋白秋水仙碱结合位点具有较好的结合能力，并能够产生氢键相互作用力。结论 化合物2i具有较显著的抗宫颈癌和抗宫颈癌顺铂耐药活性作用，这可能与其抑制了微管蛋白靶点有关。

Design and synthesis of novel imidazole-Chalcone derivatives and study of their anti-cervical cancer and cisplatin resistance activities

Abstract Objective: To design and synthesize a series of novel imidazole-chalcone derivatives using the parent nucleus of glycyrrhiza chalcone as the backbone of the lead compound and to investigate the anti-cervical cancer activity. Methods: Four types of imidazole rings were introduced into the B-ring of chalcone backbone, while methoxy, amino and hydroxyl groups, respectively, were introduced into the A-ring; a series of novel imidazole-chalcone derivatives were synthesized by Claisen-Schmidt reaction, and their structures were characterized by 1H-NMR, 13C-NMR and HRMS. The mechanism of action of the target compounds and their anti-cervical cancer activity were explored by MTT assays, Transwell assays, flow cytometry and molecular docking techniques. Results: Most of the compounds had anti-cervical cancer activity, among which, 2i was more significant and less toxic to normal cells. In addition, 2i significantly inhibited the migration and invasion of HeLa and HeLa/DDP cells, induced the apoptosis of these cells, and blocked them in G2/M phase; molecular docking simulations showed that 2i had better binding ability to the colchicine binding site on microtubule protein compared with chalcone parent nucleus and protoligand colchicine, and could generate hydrogen bonding interaction. Conclusion: Compound 2i exhibited more significant anti-cervical cancer activity and resistance to cisplatin (a drug used to treat cervical cancer), which may be related to the inhibition of microtubulin targets.