Anticancer Effect And Mechanism Of Novel Pentacyclic Triterpenoids And Deoxycholic Acid Derivatives

From a biological perspective,the class of pentacyclic triterpenoids(PTs),bearing a basic molecular structure with five rings,have broad spectrum of pharmacological activities,such as anticancer,anti-inflammatory,immunomodulatory,anti-oxidant,antiviral,antimicrobial,antidiabetic,hepato-and cardio-protective effects,etc.PTs,having anticancer activity,include oleanolic,glycyrrhetinic,ursolic and asiatic acids,among others.Bile acids(BAs)are steroidal molecules synthetized from cholesterol in the liver of mammals.Bile acids play a major role in the absorption of fat metabolism in the organism.Cholesterol catabolism is the prime source of primary bile acids in bile canaliculus and digestive tract.BAs can be categorized into three groups: primary,secondary,and tertiary.Deoxycholic acid,belonging to the secondary BAs,has broad spectrum of pharmacological activities,such as treating liver disease,gallstones,antibacterial,antimalarial,anti-cancer,etc.Most of the anti-cancer drugs have side effects.Chemical treatment of cancer is still lack of an antitumor drug which can protect normal cells.This dissertation adopted the splice theory used in drug,guided by organic chemical theory,combined the achievements of biological activity test.A series of new derivatives of pentacyclic triterpenoids and deoxycholic acid bearing biological and pharmacological activities were prepared by modification with active groups or amino acids to expect improving anticancer activities.In this dissertation,the research work can be divided into two parts:Firstly,considering the anticancer activities of pentacyclic triterpenoids,piperazine and succinic acid were introduced into the hydroxyl group of pentacyclic triterpenoids to synthetise a series of novel derivatives.The antiproliferative activities studies were evaluated by MTT method.The results show that novel synthetic derivatives have certain anticancer effects.Secondly,various functional groups were added to deoxycholic acid.In vitro antiproliferative activities of the compounds were evaluated by MTT method.The results showed that novel synthetic derivatives have inhibitory effect on cancer cells.Then a series of deoxycholic acid(DCA)derivatives bearing amino acid moiety has been synthesized and investigated for their potential antiproliferative activities.Compounds showed significant antiproliferative effect,compared with the original compound DCA.Compound DCA5 b showed the greatest cytotoxic activity on human cancer cell lines.Using western blotting,the results showed that DCA5 b could induce apoptosis of cancer cells.The novel deoxycholic acid compounds,especially DCA5 b may be promising candidates as an anticancer drug of monotherapies or combined antitumor therapies.The mechanism of its action and in vivo experiments need to be further studied.