Background: The structural modification of natural products with the aim to improve the anticancer activity is a popular current research direction. The pentacyclic triterpenoid compounds oleanolic acid (OA) and glycyrrhetinic acid (GA) are distributed widely in nature. Methods: In this study, various oleanolic acids and glycyrrhetinic acids were designed and synthesized by using the combination principle. The in vitro anticancer activities of new OA and GA derivatives were tested by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) method with SGC-7901 (gastric cancer), MCF-7 (breast cancer), Eca-109 (esophageal cancer), HeLa (cervical cancer), Hep-G2 (hepatoma cancer) and HSF (normal human skin fibroblast) cells. Results and conclusion: The screening results showed that the compound 3m presented the highest inhibitory activities against SGC-7901, MCF-7 and Eca-109 cell lines with IC₅₀ values of 7.57±0.64 µM, 5.51±0.41 µM and 5.03±0.56 µM, respectively. In addition, this compound also showed effective inhibition of Hep-G2 cells with an IC₅₀ value of 4.11±0.73 µM. Moreover, compound 5b showed the strongest inhibitory activity against Hep-G2 cells with an IC₅₀ value of 3.74±0.18 µM and compound 3l showed strong selective inhibition of the HeLa cells with the lowest IC₅₀ value of 4.32±0.89 µM. A series of pharmacology experiments indicated that compound 5b could induce Hep-G2 cells autophagy and apoptosis. These compounds will expand the structural diversity of anti-cancer targets and confirm the prospects for further research.

Glycyrrhetinic acid (GA) is a natural product with certain antitumor activity. In order to enhance the cytotoxicity, a total of eighteen derivatives of GA were designed and synthesized. Their cytotoxicity against MDA-MB-231cells (human breast cancer cells) and HeLa cells (human cervical cancer cells), were evaluated by the MTT method (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide). The results indicated that these target compounds have a wide molar activity range and some of them show better activity than the commercial drugs gefitinib and doxorubicin. Compound 6g induces apoptosis of 7, 10 and 44% of MDA-MB-231 cells at 5, 10, and 20 µM, respectively.

Triple negative breast cancer (TNBC) is the most aggressive cancer in women, and despite improved treatments, it remains a major cause of morbidity and mortality. We and others have demonstrated that different hybrid compounds targeting PARP/MAPK or other pathways to inhibit cancer progression may lead to promising therapeutic results. We introduced fluorine to alter the physical properties of the compounds. TSC-3C was one of the generated compounds. Upon treatment with TSC-3C, MDA-MB-231 cell proliferation, invasion, and migration were inhibited. TSC-3C induced MDA-MB-231 cell mitochondrial dysfunction and apoptosis, which may be caused by reducing the level of phosphorylated p44/42 MAPK (ERK1/2) and increasing the level of p-JNK. The present study may help to elucidate the role of the MAPK pathway in the development of breast cancer and may promote further research on halogenated heterocyclic compounds for the treatment of breast cancer.

A series of new glycyrrhetinic acids and oleanolic acids has been designed and synthesized based on the principles of combinatorial chemical synthesis. Their anticancer activities were further studied by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method with hepatocellular carcinoma (Hep-G2), breast cancer (MCF-7) cell lines and a normal hepatic cell (LO2). Cytotoxicity tests (in vitro) indicated that compound 6a showed the highest cytotoxicity with the lowest IC50 values of 23.34 µM on Hep-G2 cells, 12.23 µM on MCF-7 cells, and 44.47 µM on LO2, which would widen the structural diversity of these anticancer targets and confirm the perspectives of further investigations.