Thiazolidinedione-Conjugated Lupeol Derivatives as Potent Anticancer Agents Through a Mitochondria-Mediated Apoptotic Pathway.

To improve the potential of lupeol against cancer cells, a privileged structure, thiazolidinedione, was introduced into its C-3 hydroxy group with ester, piperazine-carbamate, or ethylenediamine as a linker, and three series of thiazolidinedione-conjugated compounds (-, -, and -) were prepared. The target compounds were evaluated for their cytotoxic activities against human lung cancer A549, human breast cancer MCF-7, human hepatocarcinoma HepG2, and human hepatic LO2 cell lines, and the results revealed that most of the compounds displayed improved potency over lupeol. Compound exhibited significant activity against the HepG2 cell line, with an IC value of 4.40 μM, which is 9.9-fold more potent than lupeol (IC = 43.62 μM). Mechanistic studies suggested that could induce HepG2 cell apoptosis, as evidenced by AO/EB staining and annexin V-FITC/propidium iodide dual staining assays. Western blot analysis suggested that compound can upregulate Bax expression, downregulate Bcl-2 expression, and activate the mitochondria-mediated apoptotic pathway. Collectively, compound is worthy of further investigation to support the discovery of effective agents against cancer.