Research paperDevelopment of copper(II)-diimine-iminodiacetate mixed ligand complexes as potential antitumor agents
Graphical abstract
Cu-iminodiacetate-diimine complexes were studied. They were characterized in solid state, including new crystalline structures, and in aqueous solution. Its DNA binding was studied by UV and CD. The complexes present good cytotoxic activity on MDA-MB-231 tumor cell line.
Introduction
New drugs for the treatment of cancer with better rates of cure and less severe side effects are needed. In this field coordination chemistry has a great potential to offer a wide variety of compounds with different geometry, redox reactivity and a diversity of mechanisms related to DNA binding, some of them unique to metals. The usefulness of coordination metal complexes in cancer chemotherapy has been demonstrated by Cisplatin and other platinum coordination compounds which are amongst the most successfully used anticancer drugs [1]. As a result of an intense and continued research on coordination complexes with antitumor activity, compounds of different metals other than Pt are entering clinical studies.
Copper complexes are studied with promising results. Multiple Cu(II) and Cu(I) compounds have been developed, as reviewed [2], [3], [4]. The copper compound [(Cu(II))(4,4′-dimethyl-2,2′-bipyridine)(acetylacetonate)(NO3)(H2O)] (of the family of Casiopeinas®, developed by L. Ruiz and co-workers) is entering Phase I clinical trials [5], [6]. The phosphine copper(I) complex [Cu(trishydroxymethylphosphine)4][PF6], HydroCuP®, presents highly selective antiproliferative effects, showing promising results in preclinical studies [7], [8].
The mechanism of action of copper compounds is not completely understood to the date. It possibly includes different molecular events [2]. For instance, the proposed mechanism of action of Casiopeinas® complexes includes DNA binding and oxidative damage leading to cell apoptosis [9]. There are also studies that relate antitumor activity with intracellular copper uptake [10], [11].
Our research group is devoted to the development of new copper complexes with antitumor activity [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23]. Among them, the more active were Cu(II)-l-dipeptide–phen complexes. Ternary complexes Cu(II)-l-dipeptide–phen present better cytotoxic activity than both Cu-phen and Cu-l-dipeptide complexes [20], [21], [24], [25], [26], [27], [28]. Their mechanism of action may include DNA binding through the phen moiety. Studies of complexes with phenanthroline derivatives and dipeptides are ongoing.
In this work, in the search of new copper compounds with improved cytotoxic activity we used iminodiacetate (ida) as coligand due to its ability to neutralize the Cu(II) charge and to form stable complexes with metals [29].
Different diimines were studied as presented in Fig. 1: 2,2́-dipyridil-amine (bam), 2,2́-bipyridine (bipy), 4,4́-dimethyl-2,2́-bipyridine (dmb), 1,10-phenanthroline (phen), 4-methyl-1,10-phenanthroline (4met-phen), 5-nitro-1,10-phenanthroline (5nitro-phen), neocuproine (neo) and bathophenanthroline (batho) to assess their influence in the structure and activity of the complexes. [Cu(phen)2]2+ intercalates to the DNA in the minor groove, and shows nuclease activity [30], [31]. Different heteroleptic Cu(II) complexes containing 1,10-phenanthroline interact with DNA through an intercalative mode as well, and present cytotoxic activity [32], [33]. The neocuproine ligand presents cytotoxicity and is a copper chelator that increases copper cellular uptake. Cu(II)-neo complexes are more active than the neo ligand and are able to bind to isolated DNA [11]. The mixed ligand complex [Cu(ida)(phen)] binds to DNA by partial intercalation of the phen moiety as and induces hydrolytic and oxidative double strand cleavage as reported by Selvakumar et al. [34]. To the best of our knowledge no biological studies have been performed for the series of complexes in this study.
The obtained complexes were characterized both in solid state and aqueous solution. Their interaction with isolated DNA was studied in order to assess the effect of the introduction of variations in the diimine. Finally, their cytotoxicity was evaluated against MDA-MB-231 and Vero cell lines.
Section snippets
Synthesis of [Cu(ida)(NN)(H2O)x], x = 0, 1, complexes
Ligands and salts were used as commercially available. Complexes (1) to (8) were synthesized as follows: 15 mmol of H2ida was suspended in 10 mL with 15 mmol of dibasic copper carbonate with constant stirring at 60 °C for 30 min, the excess of copper(II) basic carbonate was filtered and an ethanolic solution of 15 mmol of the diimine (NN) ligand (as presented in Fig. 1) was added and stirred for 15 min at the same temperature. The resulting blue solution was left to slowly evaporate at room
Crystal structure analysis
Eight copper(II) mixed ligand coordination complexes of general formula [Cu(ida)(NN)(H2O)x] with x = 0 or 1 were synthesized and characterized. Suitable single crystals for X-ray diffraction were obtained in all cases. Crystal structures obtained for complexes (1) [35], (2) [36] and (4) [37] were the same as the previously reported and will not be discussed in this section.
The obtained complexes constitute heteroleptic discrete mononuclear molecules. Copper coordination sphere is completed by
Conclusions
Eight ternary copper-iminodiacetate-diimine complexes (five of them new) were synthesized and characterized in solid state and in solution. Five new X-ray structures are reported.
The diimine determines the conformation of the ida (fac or mer). The ida presents facial coordination in complexes with bam, bipy, dmb, phen, 4met-phen, 5nitro-phen and batho. The coordination sphere of the copper center is completed with two N atoms of the diimine and one O from H2O, in an octahedral geometry. The mer
Acknowledgements
Authors thank PEDECIBA Química, ANII and CSIC from Uruguay, CAPES and FAPESP from Brazil for financial support. NA thanks Universidad de la República for a PhD grant. LFSM thanks FAPESP for scholarships (grant numbers 2012/13309-7 and 2017/24669-8.) Authors thank the Crystallography Laboratory at the Facultad de Química, Universidad de la República for the access to the Bruker D8 Venture Diffractometer.
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