Antitumor Mechanism Study Of Prenylated And Geranylated Chalcone Derivative

Chalcones possess broad pharmacological activities,such as antitumor,anti-oxidant.Chalcones containing prenyl or geranyl groups are an abundant subclass of flavonoids which are widely found in nature and display a variety of biological and pharmacological activities.16 prenyl or geranyl substituted chalcones derivatives were synthesized and evaluated for their anti-tumor activties.Among them,compound 1b exhibited best antitumor activity and low toxicity to normal cells.The study is focused on clarifying the characteristics of the antitumor activity and action mechanism of compound 1b.First,SAR results revealed that there are 6 candidate compounds with better antitumor activity among those 16 newly synthesized chalcones derivatives.Compound 1b is of the best antitumor activity and low toxicity.Next,we tested the effect of the compound 1b on tumor cell proliferation.The result indicated that compound 1b significantly inhibits the proliferation of K562 cells(IC50=3.98?M).Furthermore,compound lb can also inhibit the proliferation of other 10 types of human tumor cell lines,suggesting that compound lb possesses a potent and broad anti-tumor activity.Then we examined the effects of the compound lb on cell cycle transition,apoptosis and mitochondrial membrane potential.Compound lb caused K562 cells a typically apoptotic morphology.Flow cytometric analysis also confirmed the apoptotic result by Annexin-V-FITC and propidium iodide(PI)method.We further found that 4-PBA(the inhibitor of endoplasmic reticulum pathway)and TNF-a(the activator of death receptor pathway)have no effect the cytotoxic when cells wrer previously treated with compound lb.We observed dissipation of the mitochondrial membrane potential,caspase-3 activation,and a reduction of the Bcl-2/Bax ratio in these cells,which suggest that compound lb probably induce the apoptosis of K562 cells through mitochondrial apoptotic pathway.Collectively,our findings demonstrate that compound lb notably induces mitochondrial-mediated apoptosis in K562 cells,indicating its promising anti-cancer activity in leukemia cells in vitro.