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 (<b>6a</b>-<b>i</b>, <b>9a</b>-<b>i</b>, and <b>12a</b>-<b>i</b>) 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 <b>12i</b> exhibited significant activity against the HepG2 cell line, with an IC₅₀ value of 4.40 μM, which is 9.9-fold more potent than lupeol (IC₅₀ = 43.62 μM). Mechanistic studies suggested that <b>12i</b> 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 <b>12i</b> can upregulate Bax expression, downregulate Bcl-2 expression, and activate the mitochondria-mediated apoptotic pathway. Collectively, compound <b>12i</b> is worthy of further investigation to support the discovery of effective agents against cancer.