Evaluation of cobalt(III) complexes as potential hypoxia-responsive carriers of esculetin

Abstract

Differentiation between hypoxic and normoxic tissues have been exploited for the development of selective chemotherapeutic agents. In this context, cobalt(III)-based coordination compounds have been designed and investigated as prospective hypoxia-responsive drug delivery systems. Three cobalt(III) complexes, namely [Co^III(esc)(py₂en)]ClO₄·(CH₃OH)₂ (1) [Co^III(esc)(TPA)]ClO₄·3H₂O (2) and [Co^III(bipy)₂(esc)]ClO₄·2.5H₂O (3) (py₂en = N,N'-bis(pyridin-2-ylmethyl)ethylenediamine, TPA = tris(2-pyridylmethyl)amine, bipy = 2,2'-bipyridine and esc = 6,7-dihydroxycoumarin or esculetin), were prepared and investigated as potential carriers of esculetin. The spectroscopic and electrochemical properties of 1-3 were investigated and compared. Reactions of the complexes with biologically relevant reducing agents, viz. ascorbic acid, cysteine and glutathione, were monitored spectroscopically for 24 h, in pH 6.2 and 7.4 PBS phosphate buffer saline (PBS) solutions at 37 °C, under air, argon and dioxygen atmospheres. Dissociation of esculetin was observed upon Co³⁺/Co²⁺ reduction preferably under hypoxic conditions, with more effective conversion rates for 3 > 2 > 1. These results illustrate the importance to modulate the Co³⁺/Co²⁺ redox potential through the donor-acceptor properties of the ancillary ligands. Complex 3 is cytotoxic against HCT-116 but not against HT-29 and HEK-293 cells. In addition, DNA-binding studies indicate that interactions of 1 and 3 with the biomolecule are electrostatic.

Keywords: Anticancer drugs; Cobalt(III) complexes; Esculetin; Hypoxia-activated drug delivery; Redox potential tuned by ancillary ligands; Solid tumors.