Cervical cancer remains one of the greatest life threatening diseases for women worldwide. Although chemotherapy is considered as a standard treatment for advanced cervical cancers, there are still some drawbacks in this procedure including side effects and acquired drug resistance, which necessitate further research on development of more effective agents with less side effects. Among natural compounds, coumarin derivatives have shown anticancer properties on various cancerous cells and coumarin ring has proven to have a paramount role in development of anticancer drugs.Here, we aimed to establish the structure-activity relationships of eighteen O-prenylated coumarin derivatives and determined their anticancer properties on HeLa cervical cancer and HDF normal cells by MTT assay. Moreover, the mechanism of cell death induced by these compounds and their effects on cell cycle were studied using flow cytometry. MTT results indicated that twelve O-prenylated coumarin derivatives exhibited selective toxicity on HeLa cells, while they had no significant toxic effects on normal cells. Besides, flow cytometric analyses, showed that the selected compounds induced apoptosis in HeLa cells, and could also result to G1 cell cycle arrest.In conclusion, analyzing structural–activity relationships revealed that a prenylation substitution at position 6 of the coumarin ring greatly improved anticancer properties of these agents. As these derivatives exerted their cytotoxic effects via apoptosis and were not toxic on normal cells, they can be considered as effective anticancer agents for further preclinical experiments

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