Water-mediated nuclease activity of [Cu(dmp)2]¬+: Study of mechanism and ROS involved

ROMO A; LEVIN P; LEON I.E ,; LEMUS L.

Simposio; VI Latin American Meeting on Biological Inorganic Chemistry (LABIC); 2018

Coordination compounds able to induce DNA cleavage have been of great interest due todiverse applications in biotechnology and medicine.1 The nuclease activity of the bisphenanthrolineCu(I) complex, [CuI(phen)2]+ (phen=1,10-phenanthroline), has been largelystudied and there is a consensus that the predominant mechanism of DNA damage isthrough the generation of reactive oxygen species, ROS.2Studies on the nuclease activity of Cu(I) coordinated to 2,9-dimethyl-1,10-phenanthroline(dmp), [CuI(dmp)2]+, did not show the same behaviour, and a poor reactivity has beeninformed.2,3 The lower activity of this dmp derivative has been ascribed to the redox stabilityof the 1+ oxidation state, which restricts the ROS-generating cycle.3 In addition, noinformation about the mechanism of DNA cleavage has been reported, meanwhile assays oncell cultures are limited.In this work, we present studies on the nuclease activity of [CuI(dmp)2]+, and the mechanisminvolved in the DNA cleavage. Gel-electrophoresis experiments using radical scavengersand EPR measurements were performed to detect the ROS involved, while hydroxyl radical,HO·, was identified as the responsible of DNA damage.Regarding the redox mechanism involved in the ROS generation, EPR and kinetic methodsallowed to determine that recuperation of the Cu(I) state from the oxidized Cu(II) complex ismediated by water, in absence of common reductants. In addition, MTT assays wereperformed on tumour cells lines MG-63, MDA-231 and MCF-7. Interestingly, the complex[CuI(dmp)2]+ showed a higher anti-tumour activity compared to [CuI(phen)2]+, in agreementwith the higher concentration of intracellular-ROS detected when the cells where incubatedwith [CuI(dmp)2]+. Acknowledgments: To Vice-rectory of postgraduate from University of Santiago of Chile