Synthesis And Anti-tumor Activity Of Celastrol Derivatives

Cancer is a life-threatening disease and remains a major health problem around the globe.It is the second most prevalent disease after cardiovascular disease.At present,the most common method for cancer treatment is chemotherapy.However,chemotherapy is becoming less effective because of tumor multidrug resistance.Thus,the development of potent and effective novel anticancer drugs is one of the most intensely pursued goals of contemporary medicinal chemistry.Now,obtain the new drugs by modifications and structure transformation with the natural products as the lead compouds in an important way to the development of new drugs.Celastrol,a quinone methide triterpene,is an active ingredient first extracted from the roots of the Chinese medicinal plant "Thunder of God Vine".A literature survey showed that celastrol can destroy cell lines by activating the classical apoptotic pathway,and it strongly inhibits cell proliferation.It was proven to have several biological activities,such as antitumor,antifungal,antifibrotic,anti-inflammatory,and resistance to neurodegenerative disease activity.Although celastrol has good pharmacological effects,it also has several drawbacks such as poor water solubility,high toxicity,instability,etc.,which restrict its clinical application.Thus,it is very important to improve its solubility and stability and reduce its toxicity by modifying its structure.Previous studies have also suggested that the 20th carboxylic acid position of celastrol can be easily modified,and the derivatives play an important role in anticancer activity.In this paper study,three series of novel celastrol derivatives were designed and synthesised by modifying the carboxylic acid at the 20th position with amino acid,amine,and triazole derivatives.The synthesized 24 compounds were characterized by 1H-NMR,13C-NMR and MS etc.All the synthesised compounds were screened for their anticancer activities using MTT assay against AGS,HeLa,SGC-7901,HCT-116,A549,MGC-803,BEL-7402,and HepG-2 cell lines.Among them,the vast majority of celastrol derivatives exhibited excellent anti-proliferative effects.The best active compound 3-Hydroxy-9?,13?-dimethyl-2-oxo-24,25,26-trinoroleana-1(10),3,5,7-tetraen-29-oic amide,N-(R)-methyl 3-(1H-indol-2-yl)propanoate showed considerable high anticancer activity against AGS cell lines,with an IC50 value of 0.44uM,and considerably higher activities against HCT-116,BEL-7402,and HepG-2 cell lines,with IC50 values of 0.78uM,0.63uM,and 0.76 uM,respectively.Meanwhile,compound 11 induces AGS cell cycle arrest and apoptosis tests indicated that the potent antiproliferative activities of compound 11 were mediated by G1 phase cell cycle arrest and pro-apoptosis.The results of molecular docking study of compound 11 revealed that its mechanism of action with antiproliferative was possibly involved in inducing apoptosis by inducing the activation of caspase-3.