Hypoxia-activated dissociation of heteroleptic cobalt(iii) complexes with functionalized 2,2′-bipyridines and a model anticancer drug esculetin

Abstract

A low oxygen level in solid tumors is behind the modern concept of selective chemotherapy by hypoxia-activated prodrugs, such as heteroleptic complexes of transition metals (cobalt(III), iron(III) or platinum(IV)) with bi- or tetradentate ligands and an anticancer drug molecule as a co-ligand. A series of new cobalt(III) complexes [Co(L^R)₂(esc)]ClO₄ with esculetin (6,7-dihydroxycoumarin) and 2,2′-bipyridines (2,2′-bipy) functionalized by different substituents R were probed in the hypoxia-activated delivery of this model anticancer drug. Their combined study by cyclic voltammetry and in situ NMR spectroscopy allowed identifying linear correlations of the electrochemical reduction potentials and the rate of the hypoxia-activated dissociation of [Co(L^R)₂(esc)]ClO₄ with the Hammett constants of the substituents in 2,2′-bipy ligands. The latter, therefore, should be decorated with the most electron-withdrawing groups (unless they preclude the formation of a heteroleptic complex) to promote the drug release and increase the anticancer activity towards, e.g., human epidermoid carcinoma A431.These correlations can be transferred to other types of bi- or tetradentate ligands, thereby paving the way towards the molecular design of cobalt complexes as prodrugs for hypoxia-activated anticancer drug delivery with high therapeutic efficiency.