Flavonoid Derivative FMC, as a Potent Cytotoxic and Apoptosis Inducer in Several Human Cancer Cell Lines

Abstract

Synthetic flavonoids with new substitution patterns have attracted attention as potential anticancer drugs. Here, fourteen flavonoids were synthesized and their antiproliferative activities against five human tumour cells were evaluated. These flavonoids derivatives include two cyclic compounds either with or without a furoyl radical. The structure-activity relationship (SAR) revealed that (i) the presence of a 2’ amino group in 4-methoxychalcone generated a more cytotoxic compound than the corresponding 2’-hydroxy against leukemic cells, and (ii) the introduction of a furoyl radical in position 2’ as an ester or an amide group enhanced the cytotoxicity against leukaemia and melanoma cells; and (iii) the substitution of 2’-hydroxy for a 2’-amino group in 3,4,5-trimethoxychalcones enhanced the cytotoxicity but the corresponding furoyl derivatives did not enhance it as in the case of 4-methoxychalcones. The 4-methoxychalcone containing a furoyloxy radical at 2’ on the A ring (FMC) displayed less cytotoxicity against human peripheral blood mononuclear cells and fibroblastlike Vero cells. Treatment of U-937 and HL-60 cells with FMC inhibited colony formation, induced cell cycle arrest at the G2-M phase, an increase in the percentage of sub-G1 and annexin-V positive cells, the release of mitochondrial cytochrome c, activation of caspase and poly (ADP-ribose) polymerase cleavage. In addition, it inhibited tubulin polymerization in vitro in a concentration dependent manner and induced changes in BCL-2 family proteins expression and MAPK activation. Cell death triggered by this chalcone was decreased by a pan-caspase inhibitor and was dependent of the generation of reactive oxygen species.