New achievements on biological aspects of copper complexes Casiopeínas®: Interaction with DNA and proteins and anti-Trypanosoma cruzi activity

The mixed-chelate copper(II) complexes Casiopeínas® have been tested in several models in vitro and in vivo, showing promising antitumoral results. However, their mechanism of action remains to be defined. Trying to get a deeper insight into their molecular mode of action, further analyses, including gel electrophoresis, atomic force microscopy and circular dichroism were carried out to study their interaction with DNA and some cytoskeleton proteins. Our results revealed that the interaction of Casiopeínas triggers DNA cleavage by a free radical mechanism. The tested complexes showed a differential response to reducing and scavenger agents. Differences on target preference were also evident using double stranded oligonucleotides as sequence competitors. Surprisingly, distamycin A, a minor groove binder, enhanced the Casiopeínas' action on DNA. On the other hand, the tested Casiopeínas produce strong changes in protein structure of tubulin, integrin and fibronectin. All together these results suggest a multiple mode of action for these metal-based drugs. In addition, since it has been proposed that antitumor drugs efficiently interacting with DNA could also show activity against Trypanosoma cruzi, etiologic agent of Chagas disease, we evaluated the activity of these compounds on this protozoan parasite. The tested complexes showed in vitro anti-T. cruzi activity similar to the anti-trypanosomal reference drug Nifurtimox.

DNA and protein interaction of copper(II) complexes Casiopeínas® was studied through gel electrophoresis, CD and AFM. Antitrypanosomal activity was evaluated.Figure optionsDownload as PowerPoint slideHighlights
► Cu(II) Casiopeínas trigger DNA cleavage by a free radical mechanism.
► Their DNA cleavage ability concurs with their efficiency on tumoral eukaryotic cells.
► Double strand oligonucleotide competitions revealed differences in DNA preferences.
► Interaction with tubulin, integrin and fibronectin was demonstrated by AFM imaging.
► Casiopeínas showed in vitro anti-T. cruzi activities similar to that of Nifurtimox.