Biological activity of mixed chelate copper(II) complexes, with substituted diimine and tridentate Schiff bases (NNO) and their hydrogenated derivatives as secondary ligands: Casiopeína's fourth generation

• Published in: Journal of inorganic biochemistry Vol. 242; p. 112097
• Main Authors: Novoa-Ramírez, Cynthia Sinai, Silva-Becerril, Areli, González-Ballesteros, Mauricio Misael, Gomez-Vidal, Virginia, Flores-Álamo, Marcos, Ortiz-Frade, Luis, Gracia-Mora, Jesús, Ruiz-Azuara, Lena
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2023
• Subjects: cancer; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Copper - chemistry; Crystallography, X-Ray; DNA - chemistry; Electrochemical studies; EPR; HeLa Cells; Humans; Hydrogen Peroxide; Ligands; Mixed copper(II) complexes; Schiff Base; Schiff Bases - chemistry; Schiff Bases - pharmacology; Structure-activity relationship; Electrochemical studies; Schiff Base; cancer; Mixed copper(II) complexes; EPR; Structure-activity relationship
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2022.112097

We synthesize and characterize nine copper(II) compounds. Four with general formula [Cu(NNO)(NO3)] and five mixed chelates [Cu(NNO)(N-N)]+, where NNO corresponds to asymmetric salen ligands (E)-2-((2-(methylamino)ethylimino)methyl)phenolate (L1) and (E)-3-((2-(methylamino)ethylimino)methyl)naphthalenolate (LN1); and their hydrogenated derivatives 2-((2-(methylamino)ethylamino)methyl)phenolate (LH1) and 3-((2-(methylamino)ethylamino)methyl)naphthalenolate (LNH1); and N-N correspond to 4,4′-dimethyl-2,2′-bipiridyne(dmbpy) or 1,10-phenanthroline (phen). Using EPR, the geometries of the compounds in solution in DMSO were assigned, [Cu(LN1)(NO3)] and [Cu(LNH1)(NO3)] a square-planar, [Cu(L1)(NO3)], [Cu(LH1)(NO3)], [Cu(L1)(dmby)]+ and [Cu(LH1)(dmby)]+ a square-based pyramid; and [Cu(LN1)(dmby)]+, [Cu(LNH1)(dmby)]+ and [Cu(L1)(phen)]+ and elongated octahedral. By X-ray it was observed that [Cu(L1)(dmby)]+ and. [Cu(LN1)(dmby)]+ presented a square-based pyramidal, and [Cu(LN1)(NO3)]+ a square-planar geometry. The electrochemical study showed that copper reduction process is a quasi-reversible system, where the complexes with hydrogenated ligands were less oxidizing. The cytotoxicity of the complexes was tested by MTT assay, all the compounds showed biological activity in HeLa cell line, the mixed compounds were the more active ones. Naphthalene moiety, imine hydrogenation and aromatic diimine coordination, increased biological activity. A structure-activity relationships were found: Log(IC50) =  − 1.01(Epc) − 0.35(Conjugated Rings) + 0.87, for Schiff base complexes and Log(IC50) = 0.078(Epc) − 0.32(Conjugated Rings) + 1.94, for hydrogenated complexes; the less oxidizing species with a great number of conjugated rings presented the best biological activity. Complexes-DNA binding constants were obtained by uv-vis studies using CT-DNA, the results suggested that the complexes can interact through the grooves, except the phenanthroline mixed complex that intercalate with DNA. Gel electrophoresis study with pBR 322 showed that compounds can produce changes in the form of DNA and some complexes can cleave DNA in the presence of H2O2. The mixed compounds [Cu(NNO)(N-N)]+ show a greater biological activity in Hela cells compare to the non-mixed ones [Cu(NNO)(NO3)]. A structure-activity relationship was found, the less oxidizing species and complexes with a greater number of conjugated aromatic rings in their ligands, present a better antitumor activity. [Display omitted] •In DMSO the complexes present different geometries, a square-planar, elongated octahedral, and square-base pyramid.•Complexes with hydrogenated ligands were less oxidizing.•The mixed compounds [Cu(NNO)(N-N)]+ were more active.•Naphthalene moiety, Schiff base hydrogenation, and aromatic diimine coordination, increase biological activity in the copper(II) complexes.•A structure-activity relationship was found, the less oxidizing compounds with a greater number of conjugated aromatic rings in the ligands present the best biological activity.