Short-Chain Oleanolic Acid Esters and Furoyl Hybrids: Pharmacological Prediction, ADMETox Profiling, In Vitro...

Background/Objectives: This study aimed to improve the biological profile of oleanolic acid (OA) through structural modification at the C-17 carboxyl group and the C-3 hydroxyl group, with a focus on the design of short-chain alkyl esters and 3-O-furoyl hybrids. Methods: Two series of OA derivatives were synthesized and characterized using spectroscopic methods, including ¹H NMR, ¹³C NMR and MS. In silico structure-activity relationship (SAR) analysis, ADMETox profiling, and molecular docking to the epidermal growth factor receptor (EGFR) tyrosine kinase domain were performed as predictive and hypothesis-generating tools. Anticancer activity was evaluated in vitro using the MTT assay against human cancer cell lines, including HeLa, MCF-7, A-549, SKBR-3, PC-3 and SKOV-3, as well as non-malignant human dermal fibroblasts (HDFs). Antioxidant properties were assessed using cell-free CUPRAC and DPPH assays. Results: The C-17 esterification markedly enhanced cytotoxic potency compared to the parent OA, while the introduction of the 3-O-furoyl moiety further improved antiproliferative activity in several derivatives. Selected compounds showed low-micromolar IC₅₀ values and moderate selectivity toward cancer cells. Molecular docking suggested favorable accommodation of selected derivatives within the EGFR ATP-binding pocket, mainly through hydrophobic and π-related interactions; however, these results do not confirm direct EGFR binding and require experimental validation. The CUPRAC and DPPH assays provided preliminary insight into chemical redox behavior but should not be directly extrapolated to intracellular antioxidant or pro-oxidant activity. Predicted ADMETox profiles indicated moderate permeability and relatively low predicted risk for selected toxicity endpoints, while also highlighting high lipophilicity, poor aqueous solubility and potential metabolic liabilities. Conclusions: Overall, the results identify several OA derivatives as promising anticancer lead compounds for further optimization and mechanistic investigation.