Observation of π-hole interactions in the solid state structures of three new copper(II) complexes with a tetradentate N4 donor Schiff base: Exploration of their cytotoxicity against MDA-MB 468 cells

doi:10.1016/j.poly.2016.11.012

Polyhedron

Volume 123, 17 February 2017, Pages 334-343

https://doi.org/10.1016/j.poly.2016.11.012 Get rights and content

Abstract

A new mononuclear copper(II) complex, [CuL(ClO₄)₂]·CH₃CN (1) has been synthesized from a symmetrical tetradentate di-Schiff base, N,N′-bis(1-pyridin-2-yl-ethylidene)-2,2-dimethylpropane-1,3-diamine (L) and characterized by X-ray crystallography. Reactions of 1 separately with ammonium thiocyanate and sodium azide yielded [CuL(NCS)]ClO₄ (2) and [CuL(N₃)]ClO₄ (3) respectively, both of which have also been characterized by single crystal X-ray diffraction analysis. The ability of the imidic C double bond N bond of the metal-coordinated Schiff base ligand to interact with electron rich atoms in these complexes has also been studied by means of DFT calculations. The complexes showed high in vitro cytotoxic properties against MDA-MB 468 cells. The cells treated with these complexes gave bright green fluorescent light, indicating successful uptake of these complexes inside the nuclei of these cells.

Graphical abstract

π-Hole interactions in solid state structure of three new mononuclear copper(II) complexes have been identified. The energetic features of these interactions have been studied by means of DFT calculations and characterized using Bader’s AIM theory. Cytotoxicity of these complexes has also been explored.

Introduction

Schiff base ligands have been successfully used for many years in inorganic chemistry due to their simple synthesis; versatility and wide range of chelating ability with several transition and non-transition metal ions [1], [2], [3], [4], [5]. The metal ions in such complexes are usually coordinated by the imine nitrogen atom and other donor atoms in the Schiff base molecules. Many such Schiff base complexes have been successfully used in studies of photochromism [6], non-linear optics [7] and magnetism [8], [9], [10], [11]. They can also reversibly bind oxygen in epoxidation reactions and be used as catalyst in hydrogenation of olefins [12]. Encouragement for the synthesis of the symmetrical di-Schiff bases derived from 2-pyridyl carbonyl compounds and for the study of their physical and chemical properties is provided by their potential abilities in various biological modeling applications [13]. On the other hand, copper is one of the most important elements for laboratory and industrial use and also in the field of biological systems [14], [15]. Copper(II), being a d⁹ system, prefers to undergo strong Jahn–Teller distortion, leading to an elongated octahedral or square pyramidal or finally square planar geometry. The structures and functions of many copper containing proteins (e.g. hemocyanin, plastocyanin etc.) and enzymes (e.g. cytochrome c oxidase, ceruloplasmine, amine oxidases, superoxide dismutase etc.) have been investigated by several research groups [16], [17].

The cytotoxicity of many copper(II) complexes have been reported in the literature [18], [19]. Several copper(II) Schiff base complexes have shown promise in the treatment of various cancers [20], [21]. The potential use of these complexes as new therapeutic agents inspires synthetic chemists to search for new copper(II) complexes as bioactive material [22]. Treatment with copper(II) complexes produced remarkable pharmacological effects, which was not observed with parent ligands or bare copper(II) [23]. Copper(II) is crucial for angiogenesis [24]. Keeping this in mind, we prepared three copper(II) complexes with a N₄ donor Schiff base [N,N′-bis(1-pyridin-2-yl-ethylidene)-2,2-dimethylpropane-1,3-diamine] bearing pyridine side arm. Structures were confirmed by X-ray diffraction studies and their cytotoxicity was explored.

Another interesting aspect of this work is the identification of π-hole interactions in the solid state structures of all three complexes. These π-hole interactions demonstrate attraction between positive electrostatic potential of electron deficient π-systems with electron rich species in a directional manner in the solid state [25]. Conventional π-acidic systems are aromatic rings substituted with electron withdrawing subtituents [26]. More unconventional and minimalist π-holes are, for instance, the nitrogen atoms in nitro-compounds such as nitromethane and nitroaromatics [27] the carbon atom in carbonyl groups (e.g. amides) or cyanide, the sulfur atom in SO₃, etc [28]. The ability of the imidic C double bond N bond of the metal-coordinated Schiff base ligand to interact with electron rich atoms in each complex has been studied by means of DFT calculations. This has been evaluated energetically and characterized using the Bader’s theory of atoms in molecules (AIM).

Section snippets

Materials

All chemical reagents used in this study were of analytical grade or above. DMEM, Fetal bovine serum (FBS), penicillin/streptomycin (100 units/ml), DAPI was purchased from Sigma (MO, USA). MTT and Folic acid were obtained from SRL (India). All other chemicals were of reagent grade and used as purchased from Sigma–Aldrich without further purification.

Synthesis

Facile condensation of 2,2-dimethyl-1,3-diaminopropane with 2-acetylpyridine in a 1:2 M ratio furnished the neutral tetradentate ligand, N,N′-bis(1-pyridin-2-yl-ethylidene)-2,2-dimethylpropane-1,3-diamine (L). Reaction of L with Cu(ClO₄)₂·6H₂O in dry methanol yielded neutral copper(II) complex, [CuL(ClO₄)₂] (1). It is to be noted that the same ligand has been used previously to prepare a different coper(II) complex, [CuL(H₂O)](ClO₄)₂, adopting a different procedure [40]. Thus a small change in

Conclusions

The two most important conclusions drawn from this work can be summarized as follows. Firstly, the importance of unconventional O⋯π-hole interactions in the solid state of three new mononuclear copper(II) complexes with a tetradentate N₄ donor Schiff base ligand has been described and the energetic features of these interactions have been studied by means of DFT calculations and characterized using Bader’s AIM theory. The ability of the imidic bond to interact with electron rich atoms in Schiff

Acknowledgements

We thank the EPSRC (UK) and the University of Reading for funds for the Oxford Diffraction Diffractometer. We thank the MINECO of Spain (projects CTQ2014-57393-C2-1-P and CONSOLIDER INGENIO 2010 CSD2010-00065, FEDER funds). We thank the CTI (UIB) for computational facilities.

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Observation of π-hole interactions in the solid state structures of three new copper(II) complexes with a tetradentate N4 donor Schiff base: Exploration of their cytotoxicity against MDA-MB 468 cells

Abstract

Graphical abstract

Introduction

Section snippets

Materials

Synthesis

Conclusions

Acknowledgements

Chem. Phys. Lett.

Polyhedron

Coord. Chem. Rev.

Eur. J. Med. Chem.

J. Inorg. Biochem.

J. Inorg. Biochem.

Chem. Phys. Lett.

Polyhedron

Inorg. Chim. Acta

Inorg. Chim. Acta

Polyhedron

Inorg. Chim. Acta

Inorg. Chim. Acta

J. Mol. Struct.

Polyhedron

Biochim. Biophys. Acta.

Dalton Trans.

Coord. Chem. Rev.

Dalton Trans.

Inorg. Chem.

RSC Adv.

Chem. Soc. Rev.

Chem. Eur. J.

Chem. Commun.

Chem. Commun.

Dalton Trans.

Molecules

Appl. Catal. A

Observation of π-hole interactions in the solid state structures of three new copper(II) complexes with a tetradentate N₄ donor Schiff base: Exploration of their cytotoxicity against MDA-MB 468 cells