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

Li, Jinlong; Zhang, Tong; Wu, Di; He, Chen; Weng, Haoxiang; Zheng, Tiandong; Liu, Jie; Yao, Hong; Chen, Jichao; Ren, Yansong; Zhu, Zheying; Xu, Jinyi; Xu, Shengtao

Abstract

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 2b was 68.3-fold less cytotoxic compared to the parent compound, while its cytotoxicity was recovered in situ in the presence of palladium resins. Mechanism studies confirmed that 2b inhibited cell growth in the same manner as CBSIs. More importantly, in vivo efficacy studies demonstrated the efficient activation of 2b by palladium resins, resulting in significant inhibition of tumor growth (63.2%). These results suggest that prodrug 2b with improved safety and targeted release property catalyzed by a Pd-mediated bioorthogonal cleavage reaction deserves further investigation.

Citation

Li, J., Zhang, T., Wu, D., He, C., Weng, H., Zheng, T., Liu, J., Yao, H., Chen, J., Ren, Y., Zhu, Z., Xu, J., & Xu, S. (2024). Palladium-Mediated Bioorthogonal System for Prodrug Activation of N-Benzylbenzamide-Containing Tubulin Polymerization Inhibitors for the Treatment of Solid Tumors. Journal of Medicinal Chemistry, 67(21), 19905-19924. https://doi.org/10.1021/acs.jmedchem.4c02419

• Journal Article Type: Article
• Acceptance Date: Oct 22, 2024
• Online Publication Date: Nov 1, 2024
• Publication Date: Nov 14, 2024
• Deposit Date: Nov 24, 2024
• Publicly Available Date: Nov 2, 2025
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 67
• Issue: 21
• Pages: 19905-19924
• DOI: https://doi.org/10.1021/acs.jmedchem.4c02419
• Keywords: Assays; Organic polymers; Palladium; Pharmaceuticals; Toxicity
• Public URL: https://nottingham-repository.worktribe.com/output/42468850
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c02419