Preparation Of Glycyrrhetinic Acids Anticancer Compounds And Study On Extraction Process Of Flavonoids In Xinjiang Glycyrrhiza Glabra

Objective:(1) To synthesize11glycyrrhetinic acid (GA) derivatives as potentialliver-targeting carriers, and to combine with the anti-cancer drugs dichlorophosphorousnitrogen mustard (DPNM) and5-FU (fluorouracil) respectively, for preparing selectivelyanticancer compounds with liver-targeting potency; and to study their in vitro anti-canceractivity;(2) To study the technology of preparation of total flavonoids from Glycyrrhizaglabra in Xinjiang origin, and to determine the flavonoid content and those of the activeingredient isoflavone glabridin. Method:(1)18α-GlycyrrhetinicAcid (18α-GA) wasprepared form18β-GA by the reaction of optical epimerization and chiral seperation;18β-GA and18α-GA were used as starting materials to synthesize another10glycyrrhetinic acid derivatives by chemical modification methods including deoxidizationat the carbonyl group in C11-position, oxidation at the hydroxide radical in C3-position,esterification and amidation at the carboxyl group in C30-position of18β-GA and18α-GA;we selected some of them and linked with anticancer moities DPNM and5-FUrespectively to prepare four new anticancer pro-drugs; the chemical structure of17compounds was elucidated by spectrometry;(2) The in vitro antitumor activity of thesecompounds were studied using human hepatocarcinoma cell line Belle7402; the MTTmethod was used for evaluating the capacity to inhibit tumor cell proliferation; cis-platinwas used as positive reference;(3) The technology of extraction and content measurementof total flavonoid in Glycyrrhiza glabra was established by the method of single factoranalysis and orthogonal test; the glabridin content in licorice residue and licorice extractwas determined by RP-HPLC method. Result:(1)11glycyrrhetinic acid derivative carriers,2anticancer drug moieties and4potential liver-targeting anti-cancer compoundswere prepared by chemical modification method through the optimized process, and theirphysico-chemical properties and spectral features were described; The initial biologicaldata showed that compound1and15exhibited relatively strong antitumor activities;(2)According to the analysis of single factor and orthogonal tests, we determined the optimalextraction process of flavonoids and glabridin content in licorice and its extract (ethanolreflux extracton, flavonoids content1.99%, glabridin content0.18%). Conclusion:(1) Inthe synthesis of C-30acylated glycyrrhetinic acid derivatives, the use of catalytic systemHOBt/EDCI can significantly improve the condensation reaction yield and product purity;The optimal control of preparation conditions of target compound--glycyrrhetinic acid-fluorouracil conjugate (anhydrous condition, reactants ratio1:1.25, solvent DMF, catalyticsystem DCC/DMAP, RT/24h) is the key point of the synthetic reaction. The biologicalresults suggest that, the compounds1and15have similar cancer cell inhibiting activitiesas cis-platin at the middle and higher concentration. Furthermore, the optical conversionand binding with antitumor moieties can significantly increase the antitumor potency ofglycyrrhetinic acid derivatives.(2) The use of RP-HPLC method for the determination ofglabridin content was a simple operation with the good reproductibility. This method wassuitable for the content determination and quality control ofglabridin in licorice rawmaterial and its pharmaceutical preparations.