Design,Synthesis And Hypoxia-inducible Factor-1α Inhibitory Activity Evaluation Of Celastrol

Objective:In recent years,with the increasing incidence of caner year by year,the number of patients dying from malignant tumors has risen to the second place among all causes of death in the world,which is a serious threat to human health.Compared with normal cells,tumor cells have the characteristics of unlimited proliferation and rapid division,and the unlimited proliferation of tumor cells often requires a large amount of oxygen and nutrients.As a result,hypoxia is the norm in tumor tissues and cells.This local hypoxic environment will promote the formation of new blood vessels around the tumor tissue,and the tumor tissue can continue to grow infinitely fast due to more adequate oxygen and nutrients.In the process of tumor angiogenesis induced by hypoxia-inducible environment,hypoxia-inducible factor(HIF-1)is the key transcriptional regulator in the reaction process.HIF-1 expression in tumor cells is continuously high under the induction of anoxic environment,thus relieving hypoxia and starvation in tumor tissues.Therefore,hypoxic signaling pathway blockers based on HIF-1 target can inhibit the occurrence and development of tumors with high efficiency and low toxicity,and have become the focus of anti-tumor drug research and development.Methods:Celastrol is a quinone methylated triterpene,which is a natural product with a variety of biological activities.Modern research shows that it has a strong antioxidant,anti-tumor,anti-inflammation,anti-fungal,anti-fibrosis and other biological activities.Pharmacological activity studies have shown that tripterine can will inhibit HIF-1 expression in human liver cancer(Hep3B)cells without obvious cytotoxicity.Therfore,Celastrol has the potential to specifically inhibit the growth of tumor cells and is an ideal lead compound.However,like many natural products,Celastrol has the disadvantages of poor water solubility,narrow therapeutic window,high toxicity,poor stability and low bioavailability.Therefore,it is necessary to reduce its cytotoxicity and improve its bioavailability through structural modification.Result and discussion:In this paper,the carboxyl group of Celastrol C20 was modified by the principle of pharmaceutical chemical composition.The structures of all target compounds were confirmed by nuclear magnetic hydrogen spectrum(1H-NMR),nuclear magnetic carbon spectrum(13C-NMR)and high resolition mass spectormetry(HR-MS).In this paper,the HIF-1 inhibition activity of these 32 derivatives was tested for the first time in order to obtain a more effective ang less toxic HIF-1 inhibitor.Celastrol was used as the positive control drug.Hep3B cells were used under low oxygen conditions to test the inhibitory activity of all compounds on HIF-1 expression by luciferase reporter gene method.Exciting,the cytotoxicity of all the synthesized compounds was improved,and the HIF-1 activity of 13 compounds was superior to that of the positive control.More importantly,compound 15 echibited the strongest HIF-1 inhibitory activity(IC50=0.053 μM),which increased the activity by more than 4 times and was concentration-dependent.Conclusion:Compound 15(3-quinoline oxyethyl derivative introduced on the C20 carboxyl group of Celastrol)has the value of further modification or development.