The effects of two anticancer active copper(II) mixed-ligand complexes of the type [Cu(qui)(mphen)]Y·H2O, where Hqui = 2-phenyl-3-hydroxy- 1H-quinolin-4-one, mphen = bathophenanthroline, and Y = NO3 (complex 1) or BF4 (complex 2) on the activities of different isoenzymes of cytochrome P450 (CYP) have been evaluated. The screening revealed significant inhibitory effects of the complexes on CYP3A4/5 (IC50 values were 2.46 and 4.88 μM), CYP2C9 (IC50 values were 16.34 and 37.25 μM), and CYP2C19 (IC50 values were 61.21 and 77.07 μM). Further, the analysis of mechanisms of action uncovered a non-competitive type of inhibition for both the studied compounds. Consequent studies of pharmacokinetic properties proved good stability of both the complexes in phosphate buffer saline (>96% stability) and human plasma (>91% stability) after 2 h of incubation. Both compounds are moderately metabolised by human liver microsomes (<30% after 1 h of incubation), and over 90% of the complexes bind to plasma proteins. The obtained results showed the potential of complexes 1 and 2 to interact with major metabolic pathways of drugs and, as a consequence of this finding, their apparent incompatibility in combination therapy with most chemotherapeutic agents.

Department of Pharmacology Faculty of Medicine and Dentistry Palacký University in Olomouc Hněvotínská 3 779 00 Olomouc Czech Republic

Institute of Molecular and Translation Medicine Faculty of Medicine and Dentistry Palacký University in Olomouc Hněvotínská 5 779 00 Olomouc Czech Republic

Regional Centre of Advanced Technologies and Materials Palacký University in Olomouc Šlechtitelů 27 779 00 Olomouc Czech Republic

Zobrazit více v PubMed

Rosenberg B., Van Camp L., Krigas T. Inhibition of Cell Division in Escherichia coli by Electrolysis Products from a Platinum Electrode. Nature. 1965;205:698–699. doi: 10.1038/205698a0. PubMed DOI

Johnstone T.C., Park G.Y., Lippard S.J.M. Understanding and Improving Platinum Anticancer Drugs—Phenanthriplatin. Anticancer Res. 2014;34:471–476. PubMed PMC

Wang D., Lippard S.J. Cellular processing of platinum anticancer drugs. Nat. Rev. Drug. Discov. 2005;4:307–320. doi: 10.1038/nrd1691. PubMed DOI

Zhou J., Kang Y., Chen L., Wang H., Liu J., Zeng S. The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents. Front. Pharmacol. 2020;11:343. doi: 10.3389/fphar.2020.00343. PubMed DOI PMC

Jaouen G., Vessieres A., Top S. Ferrocifen type anticancer drugs. Chem. Soc. Rev. 2015;44:8802–8817. doi: 10.1039/C5CS00486A. PubMed DOI

Tabti R., Tounsi N., Gaiddon C., Bentouhami E., Désaubry L. Progress in Copper Complexes as Anticancer Agents. Med. Chem. 2017;7:875–879. doi: 10.4172/2161-0444.1000445. DOI

Munteanu C.R., Suntharalingam K. Advances in cobalt complexes as anticancer agents. Dalton Trans. 2015;44:13796–13808. doi: 10.1039/C5DT02101D. PubMed DOI

Roder C., Thomson M.J. Auranofin: Repurposing an Old Drug for a Golden New Age. Drugs R&D. 2015;15:13–20. doi: 10.1007/s40268-015-0083-y. PubMed DOI PMC

Pragti K., Bidyut K., Mukhopadhyay S. Target based chemotherapeutic advancement of ruthenium complexes. Coord. Chem. Rev. 2021;448:214169. doi: 10.1016/j.ccr.2021.214169. DOI

Leon I.E., Cadavid-Vargas J.F., di Virgilio A.L., Etcheverry S.B. Vanadium, Ruthenium and Copper Compounds: A New Class of Nonplatinum Metallodrugs with Anticancer Activity. Curr. Med. Chem. 2017;24:112–148. doi: 10.2174/0929867323666160824162546. PubMed DOI

Lazarević T., Rilak A., Bugarčić Ž.D. Platinum, palladium, gold and ruthenium complexes as anticancer agents: Current clinical uses, cytotoxicity studies and future perspectives. Eur. J. Med. Chem. 2017;142:8–31. doi: 10.1016/j.ejmech.2017.04.007. PubMed DOI

Anthony E.J., Bolitho E.M., Bridgewater H.E., Carter O.W., Donnelly J.M., Imberti C., Lant E.C., Lermyte F., Needham R.J., Palau M., et al. Metallodrugs are unique: Opportunities and challenges of discovery and development. Chem. Sci. 2020;11:12888–12917. doi: 10.1039/D0SC04082G. PubMed DOI PMC

Kar K., Ghost D., Kabi B., Chandra A. A concise review on cobalt Schiff base complexes as anticancer agents. Polyhedron. 2022;222:115890. doi: 10.1016/j.poly.2022.115890. DOI

Sainath B.A., Poonam R.I., Mrunalini K., Makarand V.P., Srushti P., Vasudev B. Silver Complexes of N-Heterocyclic Carbenes as Anticancer Agents: A Review. Int. J. Life Sci. Pharma Res. 2022;12:L123–L129. doi: 10.22376/ijpbs/lpr.2022.12.5.L123-129. DOI

Omondi R.O., Ojwach S.O., Jaganyi D. Review of comparative studies of cytotoxic activities of Pt(II), Pd(II), Ru(II)/(III) and Au(III) complexes, their kinetics of ligand substitution reactions and DNA/BSA interactions. Inorganica Chim. Acta. 2020;512:119883. doi: 10.1016/j.ica.2020.119883. DOI

Gasparin C.B., Pilger D.A. 8-hydroxyquinoline, derivatives and metal-complexes: A review of antileukemia activities. ChemistrySelect. 2023;8:e202204219. doi: 10.1002/slct.202204219. DOI

Frezza M., Hindo S., Chen D., Davenport A., Schmitt S., Tomco D., Ping Dou Q. Novel Metals and Metal Complexes as Platforms for Cancer Therapy. Curr. Pharm. Des. 2010;16:1813–1825. doi: 10.2174/138161210791209009. PubMed DOI PMC

Stern B.R., Solioz M., Krewski D., Aggett P., Aw T.C., Baker S., Crump K., Dourson M., Haber L., Hertzberg R., et al. Copper and Human Health: Biochemistry, Genetics, and Strategies for Modeling Dose-response Relationships. J. Toxicol. Environ. Health B. 2007;10:157–222. doi: 10.1080/10937400600755911. PubMed DOI

Ng C.H., Kong K.C., Von S.T., Balraj P., Jensen P., Thirthagiri E., Hamada H., Chikira M. Synthesis, characterization, DNA-binding study and anticancer properties of ternary metal(ii) complexes of edda and an intercalating ligand. Dalton Trans. 2008;8:447–454. doi: 10.1039/B709269E. PubMed DOI

Balsa L.M., Baran E.J., León I.E. Copper complexes as antitumor agents: In vitro and in vivo evidences. Curr. Med. Chem. 2022;30:510–557. doi: 10.2174/0929867328666211117094550. PubMed DOI

Denoyer D., Masaldan S., La Fontaine S., Cater M.A. Targeting copper in cancer therapy: Copper That Cancer. Metallomics. 2015;7:1459–1476. doi: 10.1039/C5MT00149H. PubMed DOI

Santini C., Pellei M., Gandin V., Porchia M., Tisato F., Marzano C. Advances in Copper Complexes as Anticancer Agents. Chem. Rev. 2014;114:815–862. doi: 10.1021/cr400135x. PubMed DOI

Ruiz-Azuara L. Process to Obtain New Mixed Copper Aminoacidate Complexes from Phenylate Phenathrolines to Be Used as Anticancerigenic Agents. EP0434444. European Patent. 1991 June 26;

Ruiz-Azuara L. Copper Amino Acidate Diimine Nitrate Compounds and Their Methyl Derivatives and a Process for Preparing Them. 5,576,326. U.S. Patent. 1996 November 19;

Ruiz-Azuara L. Casiopeina Parenteral Composition and Uses of the Same. MX2017016444A. Mexican Patent. 2019 June 17;

De Vizcaya-Ruiz A., Rivero-Muller A., Ruiz-Ramirez L., Kass G.E.N., Kelland L.R., Orr R.M., Dobrota M. Induction of apoptosis by a novel copper-based anticancer compound, Casiopeina II, in L1210 murine leukaemia and CH1 human ovarian carcinoma cells. Toxicol. In Vitro. 2000;14:1–5. doi: 10.1016/S0887-2333(99)00082-X. PubMed DOI

Buchtík R., Trávníček Z., Vančo J., Herchel R., Dvořák Z. Synthesis, characterization, DNA interaction and cleavage, and in vitro cytotoxicity of copper(ii) mixed-ligand complexes with 2-phenyl-3-hydroxy-4(1H)-quinolinone. Dalton Trans. 2011;40:9404. doi: 10.1039/c1dt10674k. PubMed DOI

Buchtík R., Trávníček Z., Vančo J. In vitro cytotoxicity, DNA cleavage and SOD-mimic activity of copper(II) mixed-ligand quinolinonato complexes. J. Inorg. Biochem. 2012;116:163–171. doi: 10.1016/j.jinorgbio.2012.07.009. PubMed DOI

Trávníček Z., Vančo J., Hošek J., Buchtík R., Dvořák Z. Cellular responses induced by Cu(II) quinolinonato complexes in human tumor and hepatic cells. Chem. Cent. J. 2012;6:160. doi: 10.1186/1752-153X-6-160. PubMed DOI PMC

Vančo J., Trávníček Z., Hošek J., Dvořák Z. Heteroleptic copper(II) complexes of prenylated flavonoid osajin behave as selective and effective antiproliferative and anti-inflammatory agents. J. Inorg. Biochem. 2022;226:111639. doi: 10.1016/j.jinorgbio.2021.111639. PubMed DOI

Vančo J., Trávníček Z., Hošek J., Malina T., Dvořák Z. Copper(II) complexes containing natural flavonoid pomiferin show considerable in vitro cytotoxicity and anti-inflammatory effects. Int. J. Mol. Sci. 2021;22:7626. doi: 10.3390/ijms22147626. PubMed DOI PMC

Gupte A., Mumper R.J. Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer Treat. Rev. 2009;35:32–46. doi: 10.1016/j.ctrv.2008.07.004. PubMed DOI

Ge E.J., Bush A.I., Casini A., Cobine P.A., Cross J.R., DeNicola G.M., Dou Q.P., Franz K.J., Gohil V.M., Gupta S., et al. Connecting copper and cancer: From transition metal signalling to metalloplasia. Nat. Rev. 2022;22:102–113. doi: 10.1038/s41568-021-00417-2. PubMed DOI PMC

Gul N.S., Khan T.M., Chen M., Huang K.B., Hou C., Choudhary M.I., Liang H., Chen Z.F. New copper complexes inducing bimodal death through apoptosis and autophagy in A549 cancer cells. J. Inorg. Biochem. 2020;213:111260. doi: 10.1016/j.jinorgbio.2020.111260. PubMed DOI

Trejo-Solís C., Jimenez-Farfan D., Rodriguez-Enriquez S., Fernandez-Valverde F., Cruz-Salgado A., Ruiz-Azuara L., Sotelo J. Copper compound induces autophagy and apoptosis of glioma cells by reactive oxygen species and jnk activation. [(accessed on 28 September 2022)];BMC Cancer. 2012 12:156. doi: 10.1186/1471-2407-12-156. Available online: http://www.biomedcentral.com/1471-2407/12/156. PubMed DOI PMC

Marín-Hernández A., Gallardo-Pérez J.C., López-Ramírez S.Y., García-García J.D., Rodríguez-Zavala J.S., Ruiz-Ramírez L., Gracia-Mora I., Zentella-Dehesa A., Sosa-Garrocho M., Macías-Silva M., et al. Casiopeina II-gly and bromo-pyruvate inhibition of tumor hexokinase, glycolysis, and oxidative phosphorylation. Arch. Toxicol. 2012;86:753–766. doi: 10.1007/s00204-012-0809-3. PubMed DOI

Anzenbacher P., Anzenbacherová E. Cytochromes P450 and metabolism of xenobiotics. Cell Mol. Life Sci. 2001;58:737–747. doi: 10.1007/PL00000897. PubMed DOI PMC

Grüner B., Brynda J., Das V., Šicha V., Štěpánková J., Nekvinda J., Holub J., Pospisilova K., Fábry M., Pachl P., et al. Metallacarborane Sulfamides: Unconventional, Specific, and Highly Selective Inhibitors of Carbonic Anhydrase IX. J. Med. Chem. 2019;62:9560–9575. doi: 10.1021/acs.jmedchem.9b00945. PubMed DOI

Borkova L., Frydrych I., Jakubcová N., Adamek R., Lišková B., Gurská S., Medvedíková M., Hajduch M., Urban M. Synthesis and biological evaluation of triterpenoid thiazoles derived from betulonic acid, dihydrobetulonic acid, and ursonic acid. Eur. J. Med. Chem. 2020;185:111806. doi: 10.1016/j.ejmech.2019.111806. PubMed DOI

Phillips I., Shephard E., Ortiz De Montellano P. Cytochrome P450 Protocols. 3rd ed. Volume 987. Humana; New York, NY, USA: 2013. Methods in Molecular Biology (Clifton, NJ, USA)

Kumar Singh J., Olanki A. Rapid Equilibrium Dialysis (RED): An In-vitro High-Throughput Screening Technique for Plasma Protein Binding using Human and Rat Plasma. J. Bioequivalence Bioavailab. 2012;S14:1–4. doi: 10.4172/jbb.S14-005. DOI

Di L., Kerns E. Profiling drug-like properties in discovery research. Curr. Opin. Chem. Biol. 2003;7:402–408. doi: 10.1016/S1367-5931(03)00055-3. PubMed DOI

Schenkman J., Jansson I. Spectral Analyses of Cytochromes P450. Methods Mol. Biol. 2005;320:11–18. doi: 10.1385/1-59259-998-2:11. PubMed DOI

Spartan 14. Wavefunction, Inc.; Irvine, CA, USA: 2013. version 1.1.4.

Nassar A.F., Hollenberg P.F., Scatina J. Drug Metabolism Handbook: Concepts and Applications. Wiley; Hoboken, NJ, USA: 2009.

Skolnik S., Lin X., Wang J., Chen X., He T., Zhang B. Towards Prediction of In Vivo Intestinal Absorption Using a 96-Well Caco-2 Assay. J. Pharm. Sci. 2010;99:3246–3265. doi: 10.1002/jps.22080. PubMed DOI

Daly A., Rettie A., Fowler D., Miners J. Pharmacogenomics of CYP2C9: Functional and Clinical Considerations. J. Pers. Med. 2018;8:1. doi: 10.3390/jpm8010001. PubMed DOI PMC

Bu H.Z. A Literature Review of Enzyme Kinetic Parameters for CYP3A4-Mediated Metabolic Reactions of 113 Drugs in Human Liver Microsomes: Structure- Kinetics Relationship Assessment. Curr. Drug. Met. 2006;7:231–249. doi: 10.2174/138920006776359329. PubMed DOI

Hendrychová T., Anzenbacherová E., Hudeček J., Skopalík J., Lange R., Hildebrandt P., Otyepka M., Anzenbacher P. Flexibility of human cytochrome P450 enzymes: Molecular dynamics and spectroscopy reveal important function-related variations. Biochim. Biophys. Acta. 2011;1814:58–68. doi: 10.1016/j.bbapap.2010.07.017. PubMed DOI

Campero-Peredo C., Bravo-Gómez M.E., Hernández-Ojeda S.L., del Rosario Olguin-Reyes S., Espinosa-Aguirre J.J., Ruiz-Azuara L. Effect of [Cu(4,7-dimethyl-1,10-phenanthroline)(acetylacetonato)]NO3, Casiopeína III-Ea, on the activity of cytochrome P450. Toxicol. In Vitro. 2016;33:16–22. doi: 10.1016/j.tiv.2016.02.008. PubMed DOI

Jefcoate C.R. Measurement of substrate and inhibitor binding to microsomal cytochrome P-450 by optical-difference spectroscopy. Methods Enzymol. 1978;52:258–279. doi: 10.1016/s0076-6879(78)52029-6. PubMed DOI

Kastritis P., Bonvin A. On the binding affinity of macromolecular interactions: Daring to ask why proteins interact. J. R. Soc. Interface. 2013;10:20120835. doi: 10.1098/rsif.2012.0835. PubMed DOI PMC

Jelesarov I., Bosshard H.R. Isothermal titration calorimetry and differential scanning calorimetry as complementary tools to investigate the energetics of biomolecular recognition. J. Mol. Recognit. 1999;12:3–18. doi: 10.1002/(SICI)1099-1352(199901/02)12:1<3::AID-JMR441>3.0.CO;2-6. PubMed DOI