Synthesis and anti-cancer activity evaluation of novel prenylated and geranylated chalcone natural products and their analogs

Abstract Four natural chalcones bearing prenyl or geranyl groups, i.e., bavachalcone ( 1a ), xanthoangelol ( 1b ), isobavachalcone ( 1c ), and isoxanthoangelol ( 1d ) were synthesized by using a regio-selective iodination and the Suzuki coupling reaction as key steps. The first total synthesis of isoxanthoangelol ( 1d ) was achieved in 36% overall yield. A series of diprenylated and digeranylated chalcone analogs were also synthesized by alkylation, regio-selective iodination, aldol condensation, Suzuki coupling and [1,3]-sigmatropic rearrangement. The structures of the 11 new derivatives were confirmed by 1 H NMR, 13 C NMR and HRMS. The anticancer activity of these new chalcone derivatives against human tumor cell line K562 were evaluated by MTT assay in vitro . SAR studies suggested that the 5′-prenylation/geranylation of the chalcones significantly enhance their cytotoxic activity. Among them, Bavachalcone ( 1a ) displayed the most potent cytotoxic activity against K562 with IC 50 value of 2.7 μM. The morphology changes and annexin-V/PI staining studies suggested that those chalcone derivatives inhibited the proliferation of K562 cells by inducing apoptosis.