Synthesis Of 11-deoxo-Glycyrrhetinic Acid-Nitrogen Mustard Anticancer Compounds And Content Determination Of Glabridin In Licorice

Objective:(1) To synthesis of six Glycyrrhetinic Acid (GA) derivatives in using its hepatocyte-targeting property, and then, the six compounds will be used as drug targeted carrier, combined with dichloro phosphorus nitrogen mustard (DPNM, the active metabolite of anticancer drug cyclophosphamide) for preparing anti-cancer pro-drug; thier structural characteristics were identified. (2) To determine the content of isoflavone ingredient glabridin in different sources of licorice. Methods (1) 18α-Glycyrrhetinic Acid (compoundⅡ) was prepared form its optical isomer 18β-Glycyrrhetinic Acid (compoundⅠ) as a starting compound, by the reaction of optical configuration transformation and chiral seperation; The carbonyl group in C11 position of compoundⅠandⅡwere reduced by chemical reaction for preparing two 11-deoxo-derivatives (compoundⅢandⅣ) and its methyl ester (compoundⅤandⅥ) were also prepared by esterification of C30-carboxyl group; the compoundⅠwas modified by the reaction of reduction for obtaining two optical isomers-11α-hydroxi-glycyrrhetol (compoundⅦ) and 11β-hydroxi-glycyrrhetol (compoundⅧ); the hydrochloride nitrogen mustard was transformed to dichloro-phosphorus nitrogen mustard (compoundⅩ), the active metabolite of anticancer drug cyclophosphamide; two targed compounds---18αand 18β-methy glycyrrhetinic acid-phosphorus nitrogen mustard ester (compoundⅪandⅫ) were prepared by the reaction of combination respectively between two targeted carrier (compoundⅢandⅣ) with compoundⅩ. The four spectroscopies and related methodologies were used for structural identification and physicochemical characterization of above twelve compounds. (2) The active ingredien glabridin contents in four different origin of licorice waste residues were evaluated by reverse phase high performance liquid chromatography (RP-HPLC) method.Results:(1) Finnaly, we prepared seven glycyrrhetinic acid derivatives as drug carrier, two anticancer moities and two target prodrugs by above chemical modifications. Thier preparation technologys were investigated and optimized; spectral and physico-chemical properties were characterized and described; (2) Among the four kinds of liquorice residues, glabridin contents are:0.225%,0.290%,0.211%,0.218%; In the preparation of glabridin extract, the yield of methanol extraction method was higher tha other methods.Conclusion:(1) The work of the preparation of Glycyrrhetinic Acid carriers and anti-cancer prodrug may provide a substancial bases for the pharmacological study of new anticancer compounds with hep-directing potency. (2) Among the four kinds of Glycyrrhiza glabra, the glabridin content in Xinjiang Hejing licorice is higher than those of other sources. Furthermore, the RP-HPLC method is simple and convenient, reproduction quality is excellent, and suitable for determination of glabridin content and quality control of licorice raw material and its pharmaceutical preparation. This study has important reference value in the basic research of new type hepatocyte-targeting anti-cancer drugs and innovation of the development of resources of xinjiang liquorice research.