Multitargeted Platinum(IV) Anticancer Complexes Bearing Pyridinyl Ligands as Axial Leaving Groups
Qiyuan Zhou, Shu Chen, Zoufeng Xu, Gongyuan Liu, Shuyuan Zhang, Zhigang Wang, Man‐Kit Tse, Shek-Man Yiu, Guangyu Zhu
Abstract
Abstract Although multitargeted Pt IV anticancer prodrugs have shown significant activities in reducing drug resistance, the types of bioactive ligands and drugs that can be conjugated to the Pt center remain limited to O‐donors. Herein, we report the synthesis of Pt IV complexes bearing axial pyridines via ligand exchange reactions. Unexpectedly, the axial pyridines are quickly released after reduction, indicating their potential to be utilized as axial leaving groups. We further expand our synthetic approach to obtaining two multitargeted Pt IV prodrugs containing bioactive pyridinyl ligands: a PARP inhibitor and an EGFR tyrosine kinase inhibitor; these conjugates exhibit great potential for overcoming drug resistance, and the latter conjugate inhibits the growth of Pt‐resistant tumor in vivo. This research adds to the array of synthetic methods for accessing Pt IV prodrugs and significantly increases the types of bioactive axial ligands that can be conjugated to a Pt IV center.