新型三氟甲基查耳酮类衍生物的设计、合成及体外抗宫颈癌活性
Design, synthesis and anti-cervical cancer activity of novel trifluoromethyl chalcones derivatives
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摘要: 查耳酮类化合物是一种多酚类黄酮物质，具有多种药理活性，毒性较低。本研究以天然甘草查耳酮母核为先导化合物骨架，设计合成了15个新型三氟甲基查耳酮类衍生物（3a ~ 3o）。目标化合物结构经1H NMR、13C NMR和HRMS进行确认。采用MTT法测定化合物3a ~ 3o、甘草查耳酮、顺铂和Nutlin3a对SiHa、HeLa、C-33A等3种人宫颈癌细胞和H8、HaCaT等两种正常细胞的增殖抑制活性，并进行构效关系分析；采用Transwell法和流式细胞仪法评价目标化合物抑制癌细胞迁移侵袭、促凋亡、阻滞细胞周期的能力。通过分子对接技术研究目标化合物与Akt-MDM2-p53通路中MDM2蛋白的结合特征。结果显示，目标化合物对3种宫颈癌细胞的增殖具有不同程度的抑制活性。其中，化合物3n对HeLa细胞的活性最强（IC50 = 11.69 μmol/L），明显优于先导化合物，并对两种正常细胞的毒性较低；化合物3n能显著抑制HeLa细胞的迁移和侵袭，诱导癌细胞凋亡，并将细胞周期阻滞在G2/M期。分子对接结果显示，化合物3n能与MDM2蛋白有效结合（结合能为-38.1 kJ/mol），具有抑制MDM2蛋白作用。本研究为新型有效低毒的查耳酮类抗肿瘤候选药物筛选提供了实验依据。Abstract: Chalcones are polyphenolic flavonoid substances with various pharmacological effects and low toxicity.In this study, 15 novel trifluoromethyl chalcone derivatives (3a-3o) were designed and synthesized using the chalcone nucleus of natural licorice chalcone as the lead compound skeleton in order to find the candidate drugs with high efficiency and low toxicity against cervical cancer.The structures of the target compounds were confirmed by 1H NMR, 13C NMR and HRMS. The inhibitory activities of compounds 3a-3o, licorice chalcone, cisplatin and Nutlin3a on SiHa, HeLa and C-33A human cervical cancer cells and H8 and HaCaT normal cells were determined by MTT assay, and the structure-activity relationship was analyzed.Transwell and flow cytometry methods were used to assess the target compounds' ability to inhibit cell migration and invasion, promote apoptosis, and arrest the cell cycle.Molecular docking technology was used to further study the binding characteristics of the target compound with MDM2 protein.The results showed that the compounds had different degrees of inhibitory activity against the three types of cervical cancer cells.Compound 3n showed the strongest activity against HeLa cells (IC50 = 11.69 μmol/L), which was superior to the lead compound, and had lower toxicity against the two normal cells.Compound 3n was found to significantly inhibit the migration and invasion of HeLa cells, induce apoptosis and arrest the cell cycle at G2/M phase.The results of molecular docking showed that the effective binding of compound 3n to MDM2 protein may be one of its anti-tumor mechanisms.This study provides an experimental basis for the screening of new anti-cervical cancer candidate drug from chalcone derivatives.
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Keywords:
- chalcone derivatives /
- synthesis /
- cervical cancer /
- proliferation inhibition /
- apoptosis /
- anti-tumor activity
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