Synthesis,Characterization And Anticancer Activity Of Three Kinds Of Pentacyclic Triterpenoids Nitrogen-Containing Derivatives

Oleanolic acid,Ursolic acid and Asiatic acid are ubiquitous pentacyclic triterpenoids in plant kingdom.A large number of studies have shown that,as long as have the skeletone of triterpenoids have various bioactivities.However,the low water solubility results in the low bioavailability of them,its clinical application is limited.Based on the combination principle of pharmaceutical synthesis,the paper used natural product oleanolic acid,ursolic acid and asiatic acid as starting materials,through a series of structural modification by inducing nitrogen-containing moiety to increase polarity,in order to get pentacyclic triterpenoid derivatives with higher efficiency and lower toxicity.This thesisis divided into three parts:The first part:Briefly introducing the applications for pharmacdogical effects,research progress of three kinds of pentacyclic triterpenoids,and review the developments of amine-containing drugs.The second part:Using ursolic acid,oleanolic acid,and asiatic acid as the lead compounds to induce nitrogen-containing moiety at C-3 and C-28 position in which a series of thirty novel ursolic acid,oleanolic acid,and asiatic acid nitrogen-containing derivatives were designed and synthesized.1.Firstly,protection with acetyl which C-3 oxhydryl of oleanolic acid,ursolic acid and asiatic acid.Then C-28 carboxyl chlorination,condensation with glycolic acid,coupling with Boc-ethylenediamine,Boc-butanediamine and Boc-hexanediamine moiety,after removing the protecting group,eighteen OA,UA and AA derivatives are synthesized（OA-3（a-c）、OA-4（a-c）、UA-3（a-c）、UA-4（a-c）、AA-3（a-c）、AA-4（a-c））;2.Esterification the C-28 carboxyl of oleanolic acid and ursolic acid,introducing connecting moiety succinic acid at C-3 position,then coupling it with Boc-ethylenediamine,Boc-butanediamine and Boc-hexanediamine moiety,after removing the protecting group,twelve OA and UA derivatives are synthesized（OA-7（a-c）、OA-8（a-c）、UA-7（a-c）、UA-8（a-c））;The structures of the compounds were characterized by IR,¹H-NMR and ¹³C-NMR.Parts of compounds were characterized by HR-MS spectrometer and measured value coincide with theoretical value.The third part:OA and UA in vitro anticancer activities towards MCF-7,Hela and A549cell lines were evaluated by a MTT method.The results indicate that the anticancer activities of OA-4b,OA-4c,UA-4a,OA-8a,OA-8b and UA-8a against MCF-7,Hela and A549 cells are obviously better than positive control gefitinib.