Design,Synthesis And Anticancer Activity Of Agents Based On Flavonoids Molecular Skeleton

A series of chrysin amino acid derivatives were synthesized to evaluate for their antiproliferative activities against several cancer cell lines.Methods: We synthesized a series of amino acid derivatives of chrysin via modifying the C7-OH group with glycine,alanine,phenylalanine,leucine,isoleucine,methionine and valine by octanoyl groups.All of synthetic compounds were characterized by spectroscopic data.The antiproliferative activities of chrysin derivatives were assessed by MTT assay against several cell lines.In light of the biological observations,potent compound was evaluated for its in vitro cytotoxic activity through the celltiter-glo assay against other types of breast cancer cells MDA-MB-231 and HCC1954.To determine whether potent compound possesses any apoptotic effects and induces cell arrest in breast cancer cells,Flow cytometry were performed on MDA-MB-231 and MCF-7 cells treated with varying concentration of potent compound for 48 h.In order to further study the apoptosis-promoting mechanism of target compound,we evaluated the effects of potent compound on the activation of Akt-mediated pathway and the downstream effector proteins in MCF-7 and MDA-MB-231 cells by western blot analysis.In addition,We measured potent compound activation of capase-3/7 in MAD-MB-231 and MCF-7 cells because caspase-3/7 is a basilic mediator of apoptosis.Results: Among the compounds tested,N-(2-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)octanoyl)-L-leucine methyl ester(5d)presented a good anti-proliferative activity in MDA-MB-231 and MCF-7 cells.Flow cytometry analysis showed that 5d induced apoptosis and prolonged cell cycle progression in MDA-MB-231 and MCF-7 cells.Western blot analysis showed that 5d significantly inhibited Akt phosphorylation(Ser473)in MDA-MB-231 and MCF-7 cells.In addition,5d treatment markedly downregulated Bcl-2 and upregulated Bax in a dose-dependent manner.In vitro caspase activation assay showed that 5d induced apoptosis of MDA-MB-231 cells by enhancing caspase 3/7 activity.The regulatory effect of 5d on apoptosis of MDA-MB-231 and MCF-7 cells may be induced by mitochondrial apoptosis pathway.This study is of great significance for designing and developing more effective chrysin amino acid derivatives.