Design, Synthesis, And Sustained-release Property Of1,3-cyclic Propanyl Phosphate Ester Of Pentacyclic Triterpenes And2-indolyl Cyclopent[b]indoles

1. Pentacyclic triterpenes, which have a wide distribution in nature, have variouspharmacological activities, such as hepatoprotective, anti-inflammatory, anti-tumor,anti-virus, anti-ulcer and anti-allergy activity. This kind of natural product is one of the drugresearch hotspots. However, the quick metabolism in vivo limits its clinical applicationas drugs. The structural modification of pentacyclic triterpenes is an effective methodto prolong the mean retention time (MRT) and maintain a stable blood concentration.1,3-cyclic propanyl phosphate ester, a liver-targeted group, has been found havingpotential sustained-release activity. This group may be an appropriate method to alterthe metabolism of pentacyclic triterpenes.In this thesis, a new class of potential prodrugs,1,3-cyclic propanyl phosphateesters of pentacyclic triterpenes, has been designed and synthesized. First,39stereospecific derivatives of18β-glycyrrhetic acid (GA), oleanolic acid (OA) andursolic acid (UA) has been synthesized using substituted acetophenone as startingmaterial via condensation, reduction, trimethyl silylation, ketalization, chiralseparation, hydrolysis, esterification and transesterification. All synthesizedcompounds are new compounds and their structure have been confirmed by NMR,HRMS and polarimetry techniques. Meanwhile, the key step of synthesis,transesterification reaction, has been studied to establish an efficient synthetic method ofthis prodrug. Lithium diisopropylamide (LDA) has been found best alkaline catalystand the optimal ratio is5times of pentacyclic triterpene. has been established. Then,4compouds (P16R, P16S, P17R and P17S) have been chosen to investigate the drugrelease properties in vitro and the sustained-release properties in vivo. The resultsshow that the pentacyclic triterpenes can be released from the prodrugs at a steady rate in rats and the plasma concentrations of GA were nearly stable in36h or even longer.This result indicated that1,3-cyclic propanyl phosphate esters of pentacyclictriterpenes have good sustained-release properties to avoid the quick metabolism ofGA. This kind of prodrugs is highlighted as a hopeful new strategy to improvepentacyclic triterpenes metabolism.2. Bisindole alkaloids form an important family of alkaloids and show importantbioactivities. Yuehchukene is a tetrahydrocyclopenta[b]indole-type bisindole alkaloidwith anti-implantation activity and antitumor activity. The total synthesis, structuralmodification and bioactivity study of this kind of alkaloids have become activeresearch topics. As the core skeleton of yuehchukene,3-indolyl cyclopent[b]indolewhich has potential antitumor activity is a useful bisindole intermediate in thesynthesis of a number of biologically active bisindole alkaloids.[3+2]cyclodimerization reaction is a noval [3+2] cycloaddition reaction, and graduallybecome an efficient method to synthesize many heterocyclic compounds. So thederivatives of3-indolyl cyclopent[b]indole may also be synthesized bycyclodimerization reaction of3-vinylindoles.In this thesis, a new class of2-indolyl cyclopent[b]indoles was designed andsynthesized, and acid mediated cyclodimerization of3-vinylindoles to2-indolylcyclopent[b]indoles was investigated. First, the catalysts and conditions of reactionhave been tested. Trifluoroacetic acid (TFA) carries out to be the best acid reagent, CH2Cl2is an appropriate solvent, and the optimum reaction condition is confirmed. And11stereospecific derivatives of2-indolyl cyclopent[b]indole have been synthesized usingsubstituted3-vinylindoles as starting material via TFA mediated cyclodimerizationreaction. The reaction showed moderate to good yields and high stereoselectivity. Allsynthesized compounds are new compounds except Y01, and their structures havebeen confirmed by NMR, HRMS. Then, the electronic effect of substituent groups,steric hindrance, time, temperature and other influences has been investigated, and astepwise mechanism are given. This reaction provides an efficient synthetic strategy forthe stereoselective synthesis of this kind of bisindole alkaloids. Finally, the inhibition activity of3-indolyl cyclopent[b]indoles on the growth of HL-60cells has been testedand compound Y03, Y06and Y08show moderate activity. The derivates of2-indolylcyclopent[b]indoles is worth further research.