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

Chalcones are biosynthetic precursors of flavonoids and are considered potential anticancer drugs. Here, twenty-two 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.