Study On The Synthesis Of Tripterygium Wilfordii Derivatives And Its Anti-tumor Mechanism

Celastrol is a quinone methyl pentacyclic triterpenoid,it looks like red needle crystal.The molecular formula is C29H38O4 and relative molecular weight is 450.Celastrol mainly in the Tripterygium wilfordii HooK has lots of bioactivities,such as anti-inflammation,anti-tumor,anti-oxidant,anti-angiogenesis,anti-liver fibrosis,anti-neurodegenerative diseases and so on.Although celastrol has significant bioactivities,its low bioavailability and high toxicity restrict its therapeutic applications.Therefore,a series of celastrol derivatives were synthesized and biologically evaluated.These researches were carried out on CM,one of Celastrol derivatives.Meanwhile,we compared absorption and metabolism of CM and celastrol on zebrafish models in order to provide evidence to reveal mechanism of drug action.Firstly,several kinds of amino acid were linked to celastrol at C-28,and then C-3 were esterified.After structure confirmation and purity study,Gastric and liver cancer cell lines were used to evaluate their cytotoxic activities.As a result,we found CM has higher bioactivities and lower toxicitythan both celastrol and other derivatives.Secondly,we elucidated the effects of CM and C on the liver cancer cells and their underlying mechanisms.Consequently,we indicated that C and CM efficiently inhibited proliferation,induced apoptosis and arrested cell cycle in G2/M phase.Besides these,C and CM had the ability to suppress constitutive STAT3 activation in liver cancer cells.C and CM also modulated the expressions of STAT3-regulated factors,including Bcl-2,c-Myc,Bax,MMP-2 and MMP-9.Therefore,we considered that C and CM are novel inhibitors of JAK2-STAT3 and has the potential in liver cancer prevention and therapy.Addtionally,absorption and metabolism studies were carried out on zebrafish.A reliable HPLC method was established to measure the content of CM and celastrol in zebrafish.The results showed the absorption of CM and celastrol in zebrafish were in a time-dependent manner.When the concentration of CM and celastrol increased to the highest degree,the consuming time was almost the same.The absorption and metabolism studies of CM and celastrol provided a theoretical basis for revealing the mechanism of drug action.Finally,in this study,we made a lot of researches on celastrol and its derivatives in pharmacochemistry、pharmacology and pharmacokinetics aspects,which provided structure transformation of celastrol and activity evaluation of its derivatives with guidance in future.