Abstract: A total synthesis of dehydrocurvularin (DCV) demethylated derivatives and structure modification have been completed using a Friedel-Crafts reaction and a highly olefin metathesis reaction. All compounds were identified by NMR, HRMS, etc. Their antitumor activity with high expression of ATP-citrate lyase was evaluated by CCK-8 assay in MDA-MB-231 and HepG2 cells. The structure activity relationship studies were also investigated. Among them, compound 7e showed better antitumor activity than DCV, and could significantly induce apoptosis in MDA-MB-231 cells. These results represent a step toward the development of novel and improved DCV derivatives.