Synthesis, superoxide dismutase, nuclease, and anticancer activities of copper(II) complexes incorporating bis(2-picolyl)amine with different counter anions

doi:10.1016/j.molstruc.2011.04.009

Journal of Molecular Structure

Volume 998, Issues 1–3, 13 July 2011, Pages 1-10

https://doi.org/10.1016/j.molstruc.2011.04.009 Get rights and content

Abstract

Interaction of the tridentate ligand bis(2-picolyl)amine L with copper(II) salts gave a series of copper(II) complexes with the formula types: [LCu(X)₂] (X = Cl⁻ 1, = Br⁻ 2), [(LCu(H₂O)(μ-SO₄)(LCu(H₂O)]SO₄ 3, [LCu(OAc)](OAc)H₂O 4, [LCu(H₂O)₂](Y)₂ (Y = ${NO}_{3}^{-}$ 5, = ${ClO}_{4}^{-}$ 6). Their structures and properties were characterized by elemental analysis, thermal analysis (TGA), IR, UV–vis and ESR spectroscopy, electrochemical measurements including cyclic voltammetry and electrical molar conductivity, and magnetic moment measurements. A square pyramidal geometry is proposed for the halogeno complexes 1 and 2 in monomeric structures. For sulfate complex, the sulfate group bridged two copper(II) ions of the two [N₃O] donor units to give the dimeric complex molecule 3 in square pyramidal environment around the copper(II) ions. In the case of complexes 4–6, square planar stereochemistries in monomeric structures are suggested. The SOD biomimetic catalytic activity of the obtained complexes was assessed for their ability to inhibit the reduction of nitroblue tetrazolium (NBT). The catalytic efficiency of $O_{2}^{-}$ scavenging by complexes depends on the nature of the particular acidic anion radical incorporated in the complex molecule and follows the order: ${NO}_{3}^{-}$ > ${ClO}_{4}^{-}$ > Br^- ⩾ Cl⁻ > ${SO}_{4}^{-}$ > AcO^−. A probable mechanistic implications for the catalytic dismutation of $O_{2}^{-}$ by copper(II) complexes are proposed. Furthermore, complex 1 exhibits significant hydrolytic cleavage of the genomic DNA in the absence of any external additives. In addition, the in vitro study of cytotoxicity of complex 1 on colon cancer cell line (Caco-2) indicates that the complex has the potential to act as an effective anticancer drug with IC₅₀ value of 156 ± 0.35 μM.

Highlights

► Synthesis of a series of bis(2-picolyl)amine-based copper(II) complexes with different counter anions (Cl^-, Br^-, SO₄^2-, AcO^-, NO₃^-, and ClO₄^-). ► The SOD-biomimetic catalytic activity of these complexes was assessed for their ability to inhibit the reduction of nitroblue tetrazolium. ► The catalytic efficiency of O₂^- scavenging by these complexes depends on the nature of the particular acidic anion radical incorporated in these complexes. ► The chloride complex exhibits significant hydrolytic cleavage of the genomic DNA in the absence of any external additives. ► The in vitro study of cytotoxicity of the chloride complex on colon cancer cell line (Caco-2) indicates that it has the potential to act as an anticancer drug.

Introduction

Superoxide dismutases (SODs) are very important antioxidant enzymes that catalyze the conversion of superoxide anion radical $(O_{2}^{-})$ to H₂O₂ and O₂ in the mitochondria [1]. Under normal physiological conditions, mitochondria are the major source of $(O_{2}^{-})$ production. Numerous studies have indicated that SODs play an important role in preventing cells from oxidative stress and inhibiting tumorigenicity [2]. Superoxide dismutases (SODs), with active site copper, iron, manganese, or nickel, are the key cellular antioxidant enzymes. Because of their presumed role in endogenous antioxidant defense, there has been effort to use SOD, primarily CuZn–SOD from bovine or recombinant sources, in therapeutic applications, but proteins have potential limitations as drugs, including difficulties in production and formulation, potential immunogenicity, and poor bioavailability. Such concerns, as well as the lack of clinical success with protein SODs, have fueled efforts to develop synthetic metal coordination complexes as SOD mimetics [3], [4], [5], [6], [7], [8]. The elementary studies in mechanism of some SOD functional models have been elucidated from kinetic studies [9], [10], [11], [11](a), [11](b). The enzymatic reaction consists of a bimolecular reaction with a catalytic cycle involving two distinct half-reactions, an oxidative reaction in which the substrate, $O_{2}^{-}$ , is oxidized to molecular oxygen and a reductive half-reaction in which $O_{2}^{-}$ is converted to H₂O₂ as follows: $O_{2}^{-} + M^{n} -SOD \to O_{2} + M^{(n - 1) +} -SOD (Oxidative reaction)$ $O_{2}^{-} + 2 H^{+} + M^{(n - 1) +} -SOD \to H_{2} O_{2} + M^{n} -SOD (Reductive reaction)$

These two reactions differ in the oxidation state of the metal ion and the involvement of proteins in the reductive half-reaction.

Pyridine derivatives possess a diverse array of bioactivities as well as playing crucial roles for physiological functions. They have been extensively used as ligands in the formation of coordination compounds as medicinal agents [5](b), [5](c), [5](d).

The present article describes the preparation and characterization of a series of copper(II) complexes with bis(2-picolyl) amine L ligand by varying the counter anions and examines their catalytic dismutation of $O_{2}^{-}$ in relation to the effect of the particular coordination environment created by the ligands around copper(II) ions. As well as, the nuclease-like activity and anticancer action of a representative complex 1 will be verified.

Section snippets

Experimental

Caution: Salts of perchlorate and their metal complexes are potentially explosive and should be handled with great care and in small quantities.

Characterization of the copper(II) complexes

The synthesized ligand L behaves as a tridentate ligand in the neutral form. Chemical analysis and some physical properties of the isolated pure complexes are listed in Table 1. The analytical results demonstrate that all the prepared copper(II) complexes have 1:1 (metal/ligand) stoichiometry. The pure solid chelates are various shades of blue. They are freely soluble in H₂O, MeOH, DMSO, and DMF, producing intense blue-colored solutions. The reported microcrystalline complexes are

Conclusion

In the present work, we have reported a series of copper(II) complexes containing bis(2-picolyl) amine and various anions (Cl⁻, Br⁻, ${SO}_{4}^{2 -}$ , CH₃COO⁻, ${NO}_{3}^{-}$ , and ${ClO}_{4}^{-}$ ). Their structures and properties were characterized by several physicochemical methods. A square pyramidal geometry is proposed for complexes 1–3, while a square planar stereochemistry in a monomeric structure was suggested for complexes 4–6. These complexes represent suitable functional model of the enzyme superoxide dismutase

Acknowledgement

This work was financially supported by Taif University, Saudi Arabia, Project No.: 1/1431/702.

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Synthesis, superoxide dismutase, nuclease, and anticancer activities of copper(II) complexes incorporating bis(2-picolyl)amine with different counter anions

Abstract

Highlights

Introduction

Section snippets

Experimental

Characterization of the copper(II) complexes

Conclusion

Acknowledgement

J. Biol. Chem.

J. Inorg. Biochem.

Eur. J. Med. Chem.

Molecules

Molecules

J. Inorg. Biochem.

Immunol. Methods

Inorg. Chem.

Eur. J. Med. Chem.

Trans. Met. Chem.

J. Inorg. Biochem.

Spectrochem. Acta A

Polyhedron

J. Chem. Soc., Chem. Commun.

Trans. Met. Chem.

Coord. Chem. Rev.

Carcinogenesis

Cancer Res.

Medicinal Inorganic Chemistry

Polyhedron

Trace Element Med. Biol.

Inorg. Chem. Commun.

J. Am. Chem. Soc.

Polyhedron

Inorg. Chem.

Inorg. Chem. Acta

J. Immunol.