Abstract: OBJECTIVE To design, synthesis, and screen of chalcone derivatives with anti-breast cancer activity. METHODS The series of chalcone were synthesized by Claisen-Schmidt aldol condensation reaction, and the anti-breast cancer activity was assessed by MTT. RESULTS Thity six chalcone compounds were synthesized. All the target compounds had been confirmed by ¹H-NMR and ¹³C-NMR spectra. The preliminary biological results showed that most of chalcone derivatives displayed significant antiproliferative effect on MCF-7 breast cancer cells, which also showed moderate inhibitory activity, against MDA-MB-231 cell lines; specifically, compound 27(IC₅₀=11.3 μmol·L^-1) showed about 1.5-fold potency of tamoxifen, against MCF-7 cell lines, and these chalcone derivatives were not toxic to normal cells. CONCLUSION This study provides information and basis for development of chalcone compounds with anti-breast cancer activity.