Abstract
Background: Isosteviol, a tetracyclic diterpenoid with a beyerene-type skeleton, exhibited wide pharmacological activities and an inhibitory impact on tumor proliferation in colon cancer; Methods: 22 isosteviol derivatives were synthesized by modifying the C-16 and C-19 position of isosteviol, and then the inhibitory activities of derivatives 2-22 were evaluated by CCK8 method. Next, the structure-activity relationships (SARs) of these isosteviol derivatives in HCT116 cells were discussed in detail. Network pharmacology was employed to predict and analyze the targets of isosteviol in the treatment of colon cancer; Results: The results indicated derivative 8 possessed stronger inhibitory activity against HCT116 and HepG2 cells (IC(50) = 6.20 ± 0.61 μM for HCT116, and IC(50) = 39.84 ± 0.43 μM for HepG2). Additionally, cell cycle analysis indicated that derivative 8 arrested HCT116 cells at the G1 phase and increased the percentage of apoptotic cells. Moreover, the molecular docking showed that derivative 8 could interact with TP53 through its Tyr-1600 and Leu-1534 residues (docking energy: -11.84 kcal/mol); Conclusions: With these results, we can conclude that derivative 8 may be a promising candidate for anticancer chemotherapy.