Design,Synthesis And Antitumor Activity Of Novel Flavone Containing Piperazine

Hypoxia microenvironment is common exist in tumor cells,HIF-1? plays a key role in the process that tumor cells adapt to hypoxia environment,if the drug can inhibit the activity of HIF-la,that also can inhibited the tumor cells to adapt to hypoxia Environment,and then can inhibit the growth of the tumor cells.HIF-1? is also involved in the occurrence of tumor cells,progression and metastasis.Therefore,more and more scientific researchers regard HIF-la as a target to develop a series of HIF-la inhibitors,in order to achieve the role of anti-tumor.In recent years,the relationship between the anti-tumor activity of the flavonoid compounds and HIF-1 is gradually being revealed,but the related research is still less.The further research of the relationship between flavonoids and HIF-1 in anti-tumor activity can provide new ideas for the development of new antitumor compounds.In this paper,we use the natural products of baicalein and genistein as the lead compound,through the bio-electronic isotope theory,pharmacokinetics and other drug molecular design theory,design and synthesiz two series of 41 new piperazine ring containing flavonoid compounds.All of the synthetic chemicals were confirmed by nuclear magnetic resonance spectroscopy,nuclear magnetic resonance spectroscopy and mass spectrometry.In order to improve the lipid partition coefficient of the drug,a piperazine ring was add to the structural modification.Through the preliminary screening of the inhibition of proliferation activity of HepG2 cells,we found that some of these derivatives showed a good inhibitory effect on growth activity of tumor cell.For example,compounds ZMY-15 and ZMY-23,the IC50 were 3.38 ?M and 4.46 ?M,respectively.Wherein ZMY-15 shows good inhibitory activity against HepG2 cells.We found that ZMY-15 significantly inhibited the expression of HIF-la protein and inhibited the expression of HIF-la target gene EPO and VEGF mRNA in HepG2 cells,thus promoting the apoptosis of tumor cells and inhibiting its malignant proliferation.The results show that the flavonoid compound ZMY-15,which contains piperazine ring,promotes the apoptosis of tumor cells by inhibiting the expression of hypoxia-inducible factor HIF-1? and its downstream target gene EPO and VEGF mRNA.In this paper,the new compound ZMY-15,which is a structural compound optimized by using the natural compound baicalein and genistein as the lead compound,provides an important research basis for the design of anti-tumor targeting drug.Those compounds have application prospects,and the further research about the anti-tumor mechanism is in progress.