Design, Synthesis and Biological Evaluation of Novel Osthole Derivatives as Potential Agents for the Treatment of Cancer

Aim: Osthole, an ingredient of Traditional Chinese Medicine (TCM) from natural product Cnidium monnieri (L.) Cusson, showed many biological activities related to the treatment of cancer. However, the comparatively weak activity hinders its further application in clinical. Therefore, the aim of the present study was design and synthesis of a series of novel osthole derivatives by introducing different secondary amine groups at 7-O position of coumarin ring to improve its anticancer activity. Method: After the demethylation of osthole, the target derivatives 4a-l were successfully synthesized through two steps in high yield. The structures of the synthesized compounds were confirmed by 1H and 13C NMR. The antiproliferative activity of these compounds was evaluated against four selected cancer cell lines (SGC7901, MCF-7, HCT116 and HepG2) using MTT method, and the most potent compound was selected for Hoechst 333258 staining assay to further investigate its possible mechanism on cancer cells. Results: Twelve osthole derivatives were synthesized and their structures were identified. Biological studies showed that most of them showed moderate to good growth inhibition against all the tested cancer cells. Especially, compound 4l displayed the most potent activity with IC50 values of 37.57 μM, 25.12 μM, 46.54 μM and 18.39 μM against SCG7901, HCT116, MCF-7 and HepG2, respectively, which was more potent than those of its parent compound osthole and the anticancer agent 5-Fu. The Hoechst 33258 staining assay revealed that compound 4l could induce cell apoptosis in HepG2 cells. Conclusion: The modification of osthole to improve its activity is feasible, and compound 4l can be considered as a potential agent for the treatment of cancer