Mechanistic investigation of developmental copper chemotherapeutics

Abstract

The quest for new metal-based anticancer agents, alternative to clinically established chemotherapeutics, has been motivated by deficiencies observed in current treatment regimes. Coupled with the approach of sophisticated and targeted drug design, there is a clear need for comprehending the underlying biomolecular and cellular responses of new developmental therapeutics. Reported herein is a detailed analysis of redox active developmental metallodrugs containing 1,10-phenanthroline (Phen) ligands and their action as novel cytotoxins of human cancers. This body of research describes mechanistic investigations into the oxidative nuclease activity and redox-targeting properties of new Cu(II) and Mn(II) phenanthroline chemo-types. A number of the Cu(II) complexes have been developed and examined, in collaboration with the National Cancer Institute, USA, for their ability to induce cytotoxicity within a wide variety of cancer cells. To uncover these properties, a range of molecular biology and biophysical techniques were employed including, flow cytometry, confocal microscopy, electrophoresis, and immunohistochemistry. Replacing auxiliary 1,10-phenanthroline with phenazine-type (N,Nʹ) ligands in mononuclear systems, [Cu(N,Nʹ)(Phen)]2+ , was found to enhance intercalation and oxidative DNA scission in vitro. Alternatively, incorporation of dicarboxylates (O,Oʹ) has shown to increase redox potential and stability, thereby targeting both mitochondrial and genomic DNA in human ovarian cancer cells, SKOV3. Increased nuclearity and varying rigidity was explored in dinuclear chemo-types ([Cu2(O,Oʹ)(Phen) 4 ]2+) through the addition of aliphatic and aromatic bridging dicarboxylate ligands. In combination with NCI-60 analysis, the dinulcear complexes were shown to enhance both geno- and cyto-toxic effects when compared to the mononuclear analogue, leading to an apoptotic mode of cellular death; activated through intrinsic mitochondrial machinery. Finally, exchange of the metal centre in the form of di-manganese(II) complex significantly influenced the mode of programmed cell death, activating autophagic catabolism and self-digestion