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.

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.