Synthesis and evaluation of demethylzeylasteral derivatives as potential anticancer therapies for colon cancer: In vitro antiproliferation, cell cycle arrest analyses, network pharmacology investigations, and molecular docking studies.

Abstract

A series of novel demethylzeylasteral derivatives 1-3 was synthesized by performing modifications on the aldehyde groups at the C-4 positions. Subsequently, the anti - proliferative activities of derivatives 1-3 was evaluated using three human cancer cell line models (HCT116, SKOV3, and HepG2) and the CCK - 8 assay. Compared with demethylzeylasteral, derivative 2 exhibited a remarkable inhibitory effect on HCT116 (4.17 ± 0.07 μM), SKOV3 (24.15 ± 1.65 μM), and HepG2 (36.66 ± 0.42 μM), DOX using as a positive control. Treatment with derivative 2 alone led to moderate cell cycle arrest at the S-phase in a concentration- dependent manner. However, when derivative 2 was combined with PTX, it influenced cell cycle arrest at the G1 phase. Meanwhile, treatment with derivative 2 markedly induced apoptosis in tumor cells. When derivative 2 was combined with PTX, it increased the rate of late apoptosis in HCT116 cells. Consistent with this observation, our subsequent network pharmacology analysis showed that TP53 was the most deeply colored and had the most connections with other targets. Then, the docking analysis indicated that derivative 2 could activate TP53 by interacting with the Pro-1537 residues of the protein. Overall, a new series of demethylzeylasteral derivatives with enhanced anti - tumor efficacy compared to their parent compound were developed, indicating derivative 2 has great potential to be used as a candidate anticancer agent in natural - product - based cancer chemotherapy.