Affiliation:
1. School of Chemical Sciences University of Auckland Private Bag 92019 Auckland 1142 New Zealand
2. MacDiarmid Institute for Advanced Materials and Nanotechnology Victoria University of Wellington PO Box 600 Wellington 6140 New Zealand
3. Auckland Cancer Society Research Centre University of Auckland Private Bag 92019 Auckland 1142 New Zealand
4. Maurice Wilkins Centre University of Auckland Private Bag 92019 Auckland 1142 New Zealand
Abstract
AbstractThe clinical use of many potent anticancer agents is limited by their non‐selective toxicity to healthy tissue. One of these examples is vorinostat (SAHA), a pan histone deacetylase inhibitor, which shows high cytotoxicity with limited discrimination for cancerous over healthy cells. In an attempt to improve tumor selectivity, we exploited the properties of cobalt(III) as a redox‐active metal center through stabilization with cyclen and cyclam tetraazamacrocycles, masking the anticancer activity of SAHA and other hydroxamic acid derivatives to allow for the complex to reach the hypoxic microenvironment of the tumor. Biological assays demonstrated the desired low in vitro anticancer activity of the complexes, suggesting effective masking of the activity of SAHA. Once in the tumor, the bioactive moiety may be released through the reduction of the CoIII center. Investigations revealed long‐term stability of the complexes, with cyclic voltammetry and chemical reduction experiments supporting the design hypothesis of SAHA release through the reduction of the CoIII prodrug. The results highlight the potential for further developing this complex class as novel anticancer agents by masking the high cytotoxicity of a given drug, however, the cellular uptake needs to be improved.