Synthesis And Bioactive Evaluation Of 18?-glycyrrhetinic Acid 3-O-mono-?-D-glucuronide And Its Derivatives

Natural products play a major role in drug discovery,and nearly half of the new drugs introduced into the market over the past two decades are natural products or their derivatives.The roots and rhizomes of licorice(Glycyrrhiza)species have long been used worldwide as a herbal medicine.Glycyrrhizin(Glycyrrhizic acid,GA,18?-GA),the major bioactive compound in licorice,is developed as a drug with mult biological activity effects such as anti-inflammation,antivirus,anti-tumor,etc.GA is a conjugate of an 18?-H-oleanane-type aglycone and two glucuronic acids at the C-3 position,Scientific researchers have done much work on the structure modification of glycyrrhizic acid in the drug research in order to get better active products,includingcomputer-aided design.In this thesis,we effort to leverage molecular modeling in combination with available data to study the effect ofGA analogs on anticancer activity by using the Discovery Studio 3.5,18a-glycyrrhetinic acid mono-glucuronide(18a-GAMG)showed greatest binding affinity to EGFR,which suggested that 18a-GAMG may be developed as a potential anticancer agent.We transformed GA into 18?-glycyrrhetinic acid mono-glucuronide(18?-GAMG)by removing one terminal glucuronic acid.18a-glycyrrhetinic acid mono-glucuronide(18a-GAMG)were synthesized from 18?-GAMG by alkaline isomerization.The results ofvitro anticancer activitiestest with Glycyrrhizin analogs showed that 18a-GAMG exhibited bestin vitro activity with IC50 values of 6.67 ?M against HepG2.To further verify the inhibitory effect of Glycyrrhizin analogs on the growth of tumor cells in vivo,sarcoma cells S180,hepatoma cells HepG2 and Ehrlich ascites cells EAC were selected to evaluate in vivo antitumor effects.The results revealed that the inhibitory rates of GAMGs were higher than those of GAs,while the inhibitory rate of 18a-epimer was higher than that of corresponding 18?-epimer.The most potent activity was showed by 18a-GAMG with inhibitory rates 39.8%and 49.7%for S180 and HepG2 tumor-bearing mice,respectively,and significantly enhanced the survival rate of EAC tumor-bearing mice to 45.4%.We alsosystemic researched thepharmacological and toxicologicaleffects of 18a-GAMG.It was administered to mice via different routes for acute toxicity studies,the LD50in mice werel 6.27 g/kg(po)and 2.31 g/kg(ip).The long-term(13 weeks)toxicity in Wistar rats and Beagle dogs in orally was evaluated on 18a-GAMG,the results ofthis study showed that there was no significant toxicity reaction in rats at dosage of 0.2,0.8 and3.2g/kg for 13 weeks or in Beagle dogs at dosage of 0.04,0.2 and 1.0g/kg for 13weeks,Microscopic histopathological examination did not reveal treatment-related changes..Theresults of safety pharmacology study showed that there are no other undesirable pharmacological effects when 18a-GAMGwhen it exerts its antitumor effects.18a-GAMG was concluded to be very safe.These researches provide acomprehensive theoretical and data support for the 18a-GAMG to develop into new drugs.