Development of lupeol derivatives based on tubulin-targeting strategy: structural modification and correlation...

Lupeol is a natural pentacyclic triterpenoid compound and exhibits great potential as a lead compound for the development of novel antitumor drugs. To further enhance its antitumor activity and targeting ability, two series of new lupeol derivatives were designed and synthesized in this study, and their antiproliferative activities against three human cancer cell lines (A549, HepG2, and MCF-7) were evaluated. Among these derivatives, compound 5l exhibited more potent in vitro antiproliferative activity against A549 cells, with a half-maximal inhibitory concentration (IC₅₀) of 1.84 ± 0.53 μmol/L and a selectivity index (SI; IC₅₀ of human embryonic lung fibroblast MRC-5 cells/IC₅₀ of A549 cells) of 15.39. Mechanistic studies further revealed that compound 5l is a novel tubulin inhibitor: it can specifically bind to the colchicine-binding site of β-tubulin with a binding energy of -13.40 kcal/mol, effectively inhibit tubulin polymerization, arrest the cell cycle at the G2/M phase, and simultaneously trigger a series of apoptosis-related responses, thereby significantly inducing apoptosis of tumour cells. In the mouse lung cancer model, compound 5l demonstrated significant antitumor activity and a favorable safety profile. Based on these results, compound 5l holds promise as a new tubulin inhibitor for the treatment of non-small cell lung cancer (NSCLC).