Structure-dependent aggregation and ROS-generation in aqueous media of new cationic copper(I) complexes based on 1,5,3,7-diazadiphosphacyclooctanes

Abstract

This work presents the synthesis of new cationic bis-(P,P)-chelate copper(I) tetrafluoroborate and hexafluorophosphate complexes with 1,5,3,7-diazadiphosphacyclooctanes with various para-alkylphenyl substituents (alkyl – methyl, isopropyl and octyl) at nitrogen atoms to assess their effect on the therapeutic potential of these complexes. Structure-dependent aggregation of these complexes is observed in the aqueous medium simulating nutrient media, with the octyl-substituted complex exhibiting the most pronounced aggregation. The generation of reactive oxygen species (ROS) by the complexes in an aqueous environment does not correlate with their oxidation potentials but is significantly suppressed by their aggregation. The luminescence of the complexes in the aqueous environment enables the visualization of their cellular uptake. This allows to correlate the cellular uptake of the complexes with their structure-dependent aggregation. The cytotoxicity of the complexes measured in a range of cancer and normal cells depends on their structure, which can be explained by their structure-dependent aggregation and ROS generation. The anticancer specificity of the complexes with isopropylphenyl and methylphenyl substituents are comparable, while these values are higher compared to the octyl-substituted complex. Therefore, these groups are optimal for ensuring the anticancer specificity of Cu(I) bis-chelates, which is likely due to the formation of aggregates with sufficient chemical and colloidal stability in aqueous media.