Palladium-Mediated Bioorthogonal System for Prodrug Activation of -Benzylbenzamide-Containing Tubulin Polymerization Inhibitors for the Treatment of Solid Tumors.

Bioorthogonal cleavage reactions have been developed as an intriguing strategy to enhance the safety of chemotherapeutics. Aiming to reduce the toxicity and improve the targeted release properties of the colchicine binding site inhibitors (CBSIs) based on previous work, a series of biologically inert prodrugs were further designed and synthesized through a bioorthogonal prodrug strategy. The therapeutic effects of prodrugs could be "turned-on" once combined with palladium resins. Particularly, prodrug was 68.3-fold less cytotoxic compared to the parent compound, while its cytotoxicity was recovered in the presence of palladium resins. Mechanism studies confirmed that inhibited cell growth in the same manner as CBSIs. More importantly, efficacy studies demonstrated the efficient activation of by palladium resins, resulting in significant inhibition of tumor growth (63.2%). These results suggest that prodrug with improved safety and targeted release property catalyzed by a Pd-mediated bioorthogonal cleavage reaction deserves further investigation.