Design,Synthesis And Anti-fibrotic Activity Of Novel Flavonoid Derivatives

Hepatic fibrosis is a complication of many chronic liver diseases.It has received widespread attention in the public health field worldwide due to the large number of people affected.The therapeutic strategy of liver fibrosis is closely related to the reversal stage of liver fibrosis,while the current research and development of targeted new drugs around anti-fibrosis are rare.Flavonoids can protect the liver through multiple pathways in the process of liver fibrosis.However,as a drug,it has disadvantages such as poor water solubility and high cytotoxicity,which is not conducive to subsequent development.Based on the flavonoid parent structure,this paper designed and synthesized four series of compounds through rational drug design principles such as pharmacokinetics and bioelectronics.The structures of the 66 compounds synthesized were all confirmed by structural identification methods such as NMR and MS.All compounds had novel structures and independent intellectual property rights.First,hepatic stellate cells(HSCs)survival rate experiments were performed on the two series of synthesized compounds to achieve a preliminary drug screening and preliminary discussion of the structure-activity relationship of cytotoxicity.After screening eight compounds that had no significant toxicity to normal HSCs,protein level experiments were performed to examine their effects on various indexes after Transforming growth factor-β(TGF-β)-induced HSC activation.The results showed that the four compounds synthesized(WB-24,WB-27,WB-42,WB-53)could significantly reduce the expression of various indicators of liver fibrosis,and could inhibit the activation of HSCs in addition to promoting the degradation of extracellular matrix(ECM)by inhibiting the expression of tissue inhibitor of metalloproteinases(TIMPs)and increasing the expression of matrix metalloproteinases(MMPs),thereby playing an important role for anti-fibrotic effects.Immunofluorescence staining analysis were performed on the four compounds to confirm the effect of the compounds.The research on the specific action mechanism of related signal pathways for compounds to work is still underway.In summary,four hit compounds were obtained by reasonable structure modification and activity screening using flavonoids as the parent,which provided an important theoretical basis for clarifying the structure-activity relationship of this series of derivatives and promoting the development of new drugs against liver fibrosis.Such compounds had certain application prospects,and further optimization and transformation as well as in-depth research on the mechanism of action are underway.