The influence of the ancillary ligand on the potential of cobalt(iii) complexes to act as chaperones for hydroxamic acid-based drugs

Abstract

Cobalt( iii) chaperone complexes can modulate the cytotoxicity and subcellular distribution of biologically active hydroxamic acids.

Abstract

Cobalt( iii) chaperones are a promising class of bioreductive prodrugs under investigation for the delivery of cytotoxic ligands to hypoxic solid tumours. Here we investigate a series of cobalt complexes as chaperones for hydroxamic acid ligands, comparing the properties of the cyclic cyclen (1,4,7,10-tetraazacyclododecane) ancillary ligand with the tripodal tpa (tris-(2-pyridylmethyl)amine) and tren (tris-(2-aminoethyl)amine). A small library of complexes containing several different hydroxamic acids, including the MMP inhibitor Marimistat and the fluorescent ligand C343haH ₂, were prepared and their p K _a values, reduction potentials, and in some cases X-ray crystal structures, were determined. The antiproliferative actitivity of the series was evaluated against DLD-1 colon cancer cells and the cellular accumulation of the fluorescent C343haH ₂ complexes was monitored by ICPMS and confocal fluorescence microscopy, revealing that the nature of the ancillary ligand significantly influences the complexes’ properties, cytotoxicity and cellular distribution.