Short and efficient synthesis of the natural triterpenoids α- and β-amyrins with detailed in silico screening and in vitro anticancer evaluation against breast and prostate cancer cells.

α- and β-Amyrins are biologically important pentacyclic triterpenoids that occur at low levels in natural sources, making their isolation difficult. In this study, a simple and cost-effective semisynthetic route was developed to obtain α- and β-amyrins from ursolic acid and oleanolic acid in three steps, and the products were characterized by NMR, FT-IR, and HRMS. The compounds were evaluated against 32 therapeutically relevant targets using molecular docking, MM-GBSA, and molecular dynamics simulations. Estrogen receptor α (ERα) and androgen receptor (AR) were identified as the most promising targets, with α-amyrin exhibiting the strongest binding toward AR (MM-GBSA = -100.16 kcal/mol) and β-amyrin toward ERα (-91.94 kcal/mol). Stable receptor-ligand complexes were confirmed by 500 ns molecular dynamics simulations. In vitro cytotoxicity studies demonstrated potent antiproliferative activity against MCF-7 and PC-3 cells, with α-amyrin showing the highest activity (IC50 = 7.86 and 6.86 μM, respectively) and favorable selectivity toward cancer cells. DFT analysis indicated similar electronic properties for both isomers and identified the hydroxyl group as the principal reactive site. Overall, α- and β-amyrins, particularly α-amyrin, represent promising lead compounds targeting ERα and AR for the development of therapies against hormone-dependent cancers.