Structure-activity relationships reveal a 4-(2-pyridyl)chalcone as a potent cell death inducer

Abstract

Chalcones are biosynthetic precursors of flavonoids and are considered potential anticancer drugs. Here, twentytwo chalcones were synthesized and evaluated for their effects on the viability of eight human leukaemia cells. This series of chalcones was characterized by the presence or absence of a benzyloxy group on the A ring and one or two substituents on the B ring including halogen, methoxy, trifluoromethyl, benzyloxy, morpholine and pyridine in the chalcone skeleton. Chalcones with the lowest IC50 values against leukaemia cells contained a benzyloxy group at position 2 ' on the A ring and one or two halogens, or a 2-pyridyl group at position 4 on the B ring. The chalcone 6 '-benzyloxy-2 '-hydroxy-4-(2-pyridyl)chalcone (BHP) exhibited potency comparable to the antitumor agent etoposide against U-937 cells while showing lower toxicity against human peripheral blood mononuclear cells. BHP-induced viability inhibition was not linked to cell cycle arrest but was associated with apoptosis. Overexpression of the antiapoptotic protein Bcl-2 and the P-glycoprotein did not prevent its activity. In U-937 and HL-60 cells, BHP triggered mitochondrial cytochrome c release, activation of caspases and poly (ADP-ribose) polymerase cleavage and increased annexin-V positive cells. Cell death triggered by BHP was (i) blocked by a pan-caspase inhibitor and by a specific caspase-9 inhibitor, (ii) associated with the phosphorylation of the mitogen-activated protein kinases and (iii) dependent of the generation of reactive oxygen species.