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

•Four natural chalcones bearing prenyl or geranyl groups were synthesized.•Eleven 3′ or/and 5′-prenylated/geranylated chalcones analogs were prepared.•5′-prenylation/geranylation of the chalcones enhanced the cytotoxicy 7–10 folds.•These chalcone derivatives inhibited K562' proliferation by inducing apoptosis.

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 1H NMR, 13C 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 IC50 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.

Graphical abstractA series of prenyl and geranyl substituted chalcone natural products and their derivatives were synthesized. The anti-cancer activity evaluation results revealed these chalcone derivatives inhibit K562 proliferation by inducing apoptosis.Figure optionsDownload full-size imageDownload as PowerPoint slide