Synthesis and growth inhibitory activity of sinomenine derivatives against cervical cancer SiHa cells through targeting the AKT-CyclinD1-p21/p27 pathway.

Cervical cancer remains a leading cause of female malignancy worldwide, with current therapies limited by systemic toxicity and inadequate efficacy. Sinomenine, a natural isoquinoline alkaloid derived from Sinomenium acutum, exhibits moderate anticancer potential but requires structural modification to enhance its activity. Herein, we synthesized 15 sinomenine derivatives via Ritter reaction-mediated amidation of the C-1 hydroxymethyl group and esterification of the C-4 phenolic hydroxyl group. The in vitro anticancer activities of these derivatives were evaluated against three cervical cancer cell lines (HeLa, SiHa, and C33A) using MTT assay. Among them, compound S14 displayed the most potent cytotoxicity, with IC₅₀ values of 3.32 ± 0.31 µM, 1.96 ± 0.08 µM, and 6.20 ± 0.55 µM against HeLa, SiHa, and C33A cells, respectively. Colony formation, wound healing, and Transwell experiments demonstrated that S14 inhibited the proliferation, migration, and invasion of SiHa cells in a concentration-dependent manner. Flow cytometry assays revealed that S14 induced G₂/M phase cell cycle arrest and late apoptosis in SiHa cells. Mechanistically, Western blot assays indicated that S14 downregulated the expression of AKT, phosphorylated AKT (p-AKT), and CyclinD1, while upregulating the cyclin-dependent kinase inhibitors p21 and p27, suggesting the involvement of the AKT-CyclinD1-p21/p27 signaling pathway. Moreover, AKT silencing via siRNA transfection significantly attenuated S14-induced cell cycle arrest and apoptosis. Collectively, these findings highlight that S14, a structurally optimized sinomenine derivative, exerts anticancer effects by targeting the AKT-CyclinD1-p21/p27 pathway, and thus holds promise as a potential therapeutic candidate for cervical cancer treatment.