Structure-activity relationships reveal a 2-furoyloxychalcone as a potent cytotoxic and apoptosis inducer for human U-937 and HL-60 leukaemia cells

Synthetic flavonoids with new substitution patterns have attracted attention as potential anticancer drugs. Here, twelve chalcones were synthesized and their antiproliferative activities against five human tumour cells were evaluated. This series of chalcone derivatives was characterized by the presence of an additional aromatic or heterocyclic ring linked by an ether, in the case of a benzyl radical, or an ester or amide functional group in the case of a furoyl radical. In addition, the influence on cytotoxicity by the presence of one or three methoxy groups or a 2,4-dimethoxy-3-methyl system on the B ring of the chalcone scaffold was also explored. The results revealed that the most cytotoxic chalcones contain a furoyl substituent linked by an ester or an amide through the 2'-hydroxy or the 2'-amino group of the A ring of the chalcone skeleton, with IC50 values between 0.2 +/- 0.1 mu M and 1.3 +/- 0.1 mu M against human leukaemia cells. The synthetic chalcone 2'-furoyloxy-4-methoxychalcone (FMC) was, at least, ten-fold more potent than the antineoplastic agent etoposide against U-937 cells and displayed less cytotoxicity against human peripheral blood mononuclear cells. Treatment of U-937 and HL-60 cells with FMC induced cell cycle arrest at the G(2)-M phase, an increase in the percentage of sub-G(1) 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. Cell death triggered by this chalcone was decreased by the pan-caspase inhibitor z-VAD-fmk and was dependent of the generation of reactive oxygen species. We conclude that this furoyloxychalcone may be useful in the development of a potential anti-leukaemia strategy.

Automated summary

Synthetic flavonoids with new substitution patterns show potential as anticancer drugs. In this study, twelve chalcones were synthesized and their antiproliferative effects on human tumour cells were evaluated. The most cytotoxic chalcones contained a furoyl substituent linked by an ester or an amide through the 2'-hydroxy or the 2'-amino group of the chalcone skeleton. The synthetic chalcone 2'-furoyloxy-4-methoxychalcone (FMC) displayed higher potency than the antineoplastic agent etoposide and had less toxicity on normal blood cells. The mechanism of action involved cell cycle arrest, induction of apoptosis, and inhibition of tubulin polymerization, and depended on the generation of reactive oxygen species.