Isolation and synthesis of rocaglaol derivatives by inhibiting Wnt/β-catenin and MAPK signaling pathways against colorectal cancer

Eight rocaglaol derivatives with good cytotoxic activity (IC50: 0.013 ∼ 5.82 μM) were isolated from Aglaia odorata. Then, a series of novel derivatives with modifications on C3 of rocaglaol were designed, synthesized, and screened for their antitumor activities against three tumor cell lines (HEL, MDA-MB-231, and HCT116). A total of 44 derivatives exhibited significant cytotoxic activity with IC50 values lower than 1 μM. In particular, four derivatives (14, 20, 22j, and 22r) exhibited the best cytotoxic activity against HCT116 cells, with an IC50 value of 70 nM. Compound 22r with relatively low toxicity against normal cells and the best cytotoxic activity against HCT116 cells was selected for further study. Subsequent cellular mechanism studies showed that compound 22r induced apoptosis and G1 cell cycle arrest in HCT116 cells. Moreover, compound 22r inhibited both the Wnt/β-catenin and MAPK signaling pathways via key proteins, such as the phosphorylation of p38 and JNK, GSK-3β, Axin-2, etc. Therefore, our present results suggest that compound 22r is a potential candidate for developing novel anti-colorectal cancer agents in the future.