Design And Synthesis Of 18β-glycyrrhetinic Acid And Betulinic Acid Derivatives With Antitumor Activity

Glycyrrhetinic acid (GA) and betulinic acid (BA) are common triterpenoic acidsin plants, both of them show many pharmacological effects, especially antitumor activity. Recently, researchers found that they have antiproliferative activity in various tumor cell lines. However both of them exhibited low cytotoxicity and poor solubility. To ameliorate the antitumor activity, we synthesized a series of analogues of GA and BA.By fusing various five or six-member fused heterocyclicrings at C-2 and C-3 positions,30 novel GA derivatives were obtained. These compounds were tested in a sulforhodamine B (SRB) assay on 8 different cell lines for cytotoxicity. The most active compound 2-60 showed average IC50=8.02μM, which was about 11-fold more potent than the lead compound GA. An apoptotic effect of GA and 2-60 was determined using a flow cytometry assayand trypan blue staining. We also demonstrated here for the first time that GA and the synthetic derivatives exhibited inhibitory effect on migration of the tested tumor cells, especially 2-60 which was about 20-fold more potent than GA on antimetastatic activity.12 novel BA derivatives were obtained by introducing various five or six-membered heterocyclicrings at C-3 via amido bonds and ester bonds. Derivatives with saturated heterocyclics at C-3 had a better cytotoxicity than thoses with heteroaromatics. We also found the amides having more potent antitumor activity than the corresponding esters. The results also showed that more distance between the amido bonds to the NH group of piperidine may afford more antitumor activity.Compound 3-16 had significantly more activity against the tested cancer cell lines than betulinic acid,which IC50 was 0.97μM in HT-29 cell line especially.