Design,Synthesis And Anti-Hepatocellular Carcinoma Activity Study Of 1-Styrenyl Isoquinoline Derivatives About Resveratrol

Liver cancer is the sixth most common cancer and the third most common cancer in the world,which is a serious threat to human health.Resveratrol was attracted the attention of researchers for its extensive physiological activities.However,studies have shown that the antitumor activity of resveratrol still has room to be improved,and the derivative modification of its structure is one of effective ways.Isoquinoline ring widely exists in drug molecules with good antitumor activity,and a number of studies have shown that the combination of resveratrol and isoquinoline alkaloids can achieve synergistic anticancer effects.Our research group designed to introduce isoquinoline rings into the structure of resveratrol,and synthesized 1-styrene isoquinoline compounds.On this basis,two batches of compounds were synthesized and evaluated for their antitumor bioactivity in vitro and in vivo.The specific content is as follows:In the first part（Chapter 2 and 3）,an OH and styrene structure of resveratrol was retained,isoquinoline ring was introduced,and 18 derivatives of1-styrene-isoquinoline were designed and synthesized.The IC₅₀ of compound 1c against Huh7 and SK-Hep-1 cells were 2.52μM and 4.20μM,respectively.Further studies have shown that compound 1c can inhibit cell proliferation,arrest cell cycle in G2/M phase by regulating cell cycling-related proteins,inhibit cell migration and invasion by regulating epithelial–mesenchymal transition（EMT）,and induce cell apoptosis.Notably,compound 1c could damage mitochondrial function,regulate the expression of proteins related to mitochondrial apoptosis pathway,and inhibit the phosphorylation of PI3K/Akt/mTOR signaling pathway.This suggests that compound1c induces apoptosis by triggering the mitochondrial apoptosis pathway.In addition,we found that 1c inhibited SIRT1 protein expression,and showed certain effects on tubulin polymerization.Mice were treated with compound 1c at a single dose of 650mg/kg,and the survival status of mice was good.The in vivo anti-tumor effect of compound 1c was evaluated,and we found that 1c could significantly inhibit the growth of subcutaneous Huh7 liver cancer grafts in nude mice（TGI=41.44%）.In the second part（Chapter 4）,based on the previous work,two modification ideas were proposed:double substitution of-OAc on benzene ring,substituting isoquinoline with other heterocyclic structures.12 compounds were designed and synthesized.MTT assay showed that compound D5 showed good inhibitory effect on LM9 with IC₅₀ value of 1.90μM.We further characterized the activity of D5 on LM9cells.We found that compound D5 can inhibit the proliferation and migration of LM9cells,arrest the cell cycle in G2/M phase.And D5 can induce the eruption of intracellular ROS to induce cell apoptosis.In summary,the two studies in this academic dissertation enrich the molecular library of 1-styrenyl isoquinoline compounds,improve the summary of their SARs,and provide compounds 1c and D5 with good potential for the treatment of liver cancer.