Antiproliferative Copper(II) Complexes Bearing Mixed Chelating Ligands: Structural Characterization, ROS Scavenging, In Silico Studies, and Anti-Melanoma Activity

Rodica Olar; Catalin Maxim; Mihaela Badea; Mihaela Bacalum; Mina Raileanu; Speranta Avram; Nataša Čelan Korošin; Teodora Burlanescu; Arpad Mihai Rostas

doi:10.3390/pharmaceutics14081692

Antiproliferative Copper(II) Complexes Bearing Mixed Chelating Ligands: Structural Characterization, ROS Scavenging, In Silico Studies, and Anti-Melanoma Activity

Pharmaceutics. 2022 Aug 14;14(8):1692. doi: 10.3390/pharmaceutics14081692.

Authors

Rodica Olar¹, Catalin Maxim¹, Mihaela Badea¹, Mihaela Bacalum², Mina Raileanu^{2

3}, Speranta Avram⁴, Nataša Čelan Korošin⁵, Teodora Burlanescu⁶, Arpad Mihai Rostas⁷

Affiliations

¹ Faculty of Chemistry, Department of Inorganic Chemistry, University of Bucharest, 90-92 Panduri Str., 050663 Bucharest, Romania.
² Horia Hulubei National Institute for Physics and Nuclear Engineering, Department of Life and Environmental Physics, 30 Reactorului Str., 077125 Magurele-Ilfov, Romania.
³ Faculty of Physics, Department of Electricity, Solid State and Biophysics, University of Bucharest, 405A Atomiștilor Str., 077125 Magurele-Ilfov, Romania.
⁴ Faculty of Biology, Department of Anatomy, Animal Physiology and Biophysics, University of Bucharest, 91-95, Splaiul Independenței, 050095 Bucharest, Romania.
⁵ Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia.
⁶ Laboratory of Optical Processes in Nanostructure Materials, National Institute of Materials Physics, 405A Atomiștilor Str., 077125 Magurele-Ilfov, Romania.
⁷ Laboratory of Atomic Structures and Defects in Advanced Materials, LASDAM, National Institute of Materials Physics, 405A Atomiștilor Str., 077125 Magurele-Ilfov, Romania.

Abstract

Melanoma is a skin cancer characterized by rapid growth and spread for which current therapies produce both resistance and increased risk of infection. To develop new anti-melanoma biocompatible species, the series of complexes Cu(N-N)(bzac)(X)⋅nH₂O (N-N: 1,10-phenanthroline/2,2'-bipyridine, Hbzac: 1-phenyl-1,3-butanedione, X: NO₃/ClO₄, and n = 0, 1) was studied. Single-crystal X-ray diffraction revealed a mononuclear structure for all complexes. The ability of the complexes to scavenge or trap reactive oxygen species such as O₂⋅^- and HO⋅ was proved by EPR spectroscopy experiments. All complexes inhibited B16 murine melanoma cells in a dose-dependent and nanomolar range, but the complexes with 1,10-phenanthroline were more active. Moreover, comparative activity on B16 and healthy BJ cells revealed a therapeutic index of 1.27-2.24. Bioinformatic methods were used to calculate the drug-likeness, pharmacokinetic, pharmacogenomic, and pharmacodynamic profiles of the compounds. The results showed that all compounds exhibit drug-likeness features, as well as promising absorption, distribution, metabolism, and excretion (ADME) properties, and no toxicity. The pharmacodynamics results showed that the neutral species appear to be good candidates for antitumor molecular targets (Tyrosyl-DNA phosphodiesterase 1, DNA-(apurinic or apyrimidinic site) lyase or Kruppel-like factor 5). Furthermore, the pharmacogenomic results showed a good affinity of the copper(II) complexes for the human cytochrome. These results recommend complexes bearing 1,10-phenanthroline as good candidates for developing drugs to melanoma alternative treatment.

Keywords: ADME-Tox; Cu(II) complex; ROS; bioinformatics; cytotoxicity; melanoma cells; structure.

Grants and funding

C.M. acknowledge financial support from CNCS-UEFISCDI, project number PN-III-P1-1.1-TE-2019-1345, within PNCD III. The Slovenian author (N.Č.K.) gratefully acknowledges financial support from the Slovenian Research Agency ARRS (Research Core Funding No. P1-0134).