Synthesis And Anticancer Activity Of Glycyrrhetinic Acid Compounds

Objective:To synthesis of12Glycyrrhetinic Acid (GA) derivatives in using itshepatocyte-targeting property, and then, these compounds were used as drug carrier, combined withdichloro phosphorus nitrogen mustard (DPNM), the active metabolite of anticancer drugcyclophosphamide and Cis-Platine (CDDP) for preparing4anti-cancer target compounds; thierchemical structures were characterised; their in vitro antitumor activities were studied. Methods:Firstly, the optical isomer18α-GA was prepared form18β-GA, by the reaction of epimerization andchiral seperation;12semi-synthetic GA derivatives were prepared using GA as starting compound, bythe reactions of chemical reduction and esterification; two different reduction systems—the Red-al andNaBH4/I2system were used respectively for the reductive modification, the procedure of theirpreparation technology were optimized by factor analysis method; we choosed three derivatives astargeting carrier (according to their chamical reactivity and stability), combined respectively with theanticancer moity--DPNM and CDDP to preparing4new liver targeting anticancer compounds; theirphysico-chemical properties and spectrometerical characteristics were studied. The in vitro antitumoractivity of these compounds was studied using human hepatocarcinoma cell line Belle7402. TheMTT method was used for evaluating their capacity to inhibit tumor cell proliferation. Cis-platinwas used as positive reference. Results: We obtained12glycyrrhetinic acid derivatives as drug carrier,two anticancer moities and4target anticancer compounds by above chemical synthesis. Thierpreparation technologys were investigated and optimized; spectrometrical and physico-chemicalproperties were characterized. The initial biological data showed that compound3(18α-GA) and21(GA-DPNM complex) exhibited relatively strong antitumor activities, at a concentration range of5～500μg/mL, they inhibited cancer cell proliferation by2.6%～86%and1.3%～50.1%,respectively. In the same conditions, the reference compound cis-platin inhibited cell proliferationby20.0%～73.41%. Conclusions: The selevtive chemical reduction of GA by NaBH4/I2reductivesystem was an effective method with the advantages such as higher yield, simplified synthesis andpurification procedures. In the preparation of target compounds by phosphoryl esterification reaction,the control of reaction condition (such as anhydrous condition, the rario of reactants1:2.5, temperature 65℃and reaction time3-4h) is the key points for their synthesis. The biological results suggest that,the compounds3and21have similar cancer cell inhibiting activities as cis-platin at the middleand higher concentration. Furthermore, the optical conversion and binding with antitumor moietycan significantly increase the antitumor potency of glycyrrhetinic acid derivatives. This work couldprovide substancial bases for the pharmacological screening of new anticancer compounds withhep-directing potency from the glycyrrhetinic acid derivatives.