Biotin-Linked Ursolic Acid Conjugates as Selective Anticancer Agents and Target-Identification Tools for Cancer Therapy

Ursolic acid (UA), a naturally occurring pentacyclic triterpenoid, exhibits potent anticancer properties; however, its poor solubility and bioavailability limit its therapeutic application. To overcome these challenges and facilitate molecular target identification, a set of biotin-conjugated UA derivatives (<b>5a</b>-<b>d</b>) was synthesized through selective C-28 alkylation and biotinylation. The use of microwave-assisted synthesis significantly enhanced both reaction efficiency and product purity. Among the derivatives, compound <b>5c</b> exhibited increased cytotoxicity and selectivity against bladder cancer cell lines, surpassing UA in its ability to induce apoptosis, generate reactive oxygen species (ROS), and halt cell cycle progression at the G1 phase. Proteomic profiling revealed that <b>5c</b> interacts with proteins involved in ER stress, RNA processing, cytoskeletal remodeling, and metabolic regulation. These findings underscore the potential of biotinylated UA derivatives as multifunctional chemical probes for mechanistic studies in the development of targeted therapies for cancer.