Affiliation:
1. School of Chemical Sciences and National Institute for Cellular Biotechnology, Dublin City University Glasnevin Dublin 9 Ireland andrew.kellett@dcu.ie
2. Department of Physics, Chemistry and Pharmacy, University of Southern Denmark Campusvej 55 5230 Odense M Denmark
Abstract
There have been significant advances in the discovery of developmental copper complexes for the treatment of human cancer. The enzyme-active sites of several copper-containing enzymes suggest a starting point for metallodrug development and successful strategies have, so far, employed phenanthroline or bipyridine ligands to supply two pyridyl donors (modelling histidine residues) along with other oxygen or nitrogen donor ligands that tune specific properties. Suitably designed copper(ii) metallodrugs can generate reactive oxygen species (ROS) and reactive nitrogen species (RNS) that overwhelm innate cellular antioxidant defences to trigger oxidative damage and cell death. Recently, several complexes of this class were screened by the National Cancer Institute's (NCI) Developmental Therapeutics Program (DTP). The 60-cancer cell line screening results indicate copper(ii) metallodrug leads have unique activity and alternative mechanisms to clinically established anticancer agents such as cisplatin and bleomycin. Although DNA is a valid cellular target, mechanistic evidence suggests cell death is triggered by metal-catalysed pro-apoptotic ROS and RNS that damage cytoplasmic, mitochondrial, and genome function. In addition to copper complexes screened within the DTP, a number of other structurally relevant compounds are described, along with mechanistic aspects of their chemotherapeutic activity.
Publisher
The Royal Society of Chemistry
Cited by
25 articles.
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