Elsevier

Polyhedron

Volume 145, 1 May 2018, Pages 218-226
Polyhedron

Copper(II) polyamine chelates as efficient receptors for acyclovir: syntheses, crystal structures and dft study

https://doi.org/10.1016/j.poly.2018.02.011Get rights and content

Abstract

In order to further understand the metal-binding patterns (MBP) of acyclovir (acv), copper(II) and zinc(II) oxo salts (nitrate, sulfate or perchlorate) and tridentate or tripodal-tetradentate chelating-polyamines were reacted with acyclovir to obtain the following compounds: [Cu(dien)(acv)(H2O)]SO4·1.25MeOH·0.5H2O (1), [Cu(dien)(acv)(H2O)]·[Cu(dien)(acv)(H2O)(NO3)](NO3)3]·H2O (2), {[Cu(dien)(µ2-acv)](ClO4)2}n (3), [Zn(dien)(acv)(SO4)] (4), [Cu(pmdta)(acv)](ClO4)2·H2O (5), [Cu(bpa)(acv)(SO4)]·6H2O (6), [Cu(tren)(acv)](NO3)2 (7) and [Cu(tren)(acv)](ClO4)2 (8) (dien = diethylenetriamine, pmdta = N,N,N′,N′,N″-pentamethyl-diethylenetriamine, bpa = bis-(2-picolyl)amine and tren = tris(2-aminoethyl)amine). All the compounds were studied by spectroscopic techniques and single-crystal X-ray diffraction methods. The metal binding pattern of copper(II) compounds 13, 7 and 8 consists of the cooperation of the Cu–N7(acv) bond with an intramolecular interligand (primary/terminal amino)N-H⋯O6(acv) interaction (which is ‘bifurcated’ in 8). Note that in 3 this MBP is embedded within the unusual bridging µ2-N7,O(ol, N9-side chain) mode. On the other hand, the Zn-N7(acv) bond in compound 4 is reinforced with the intramolecular (secondary amino)N-H⋯O6(acv) H-bond. This latest interaction is indeed possible but not displayed in compounds 5 or 6, which feature an asymmetric chelating-N7,O6-acv MBP with O6 acting as an apical/distal Cu(II) donor atom. Remarkably, in compounds 7 and 8, an intricate combination of anion⋯π/π⋯π/π⋯anion interactions generates interesting supramolecular networks that have also been studied theoretically by means of DFT calculations. In addition, these assemblies have been characterized using Bader’s theory of “atoms-in-molecules”.

Graphical abstract

Three different metal binding patterns of acyclovir are described within eight novel metal complexes: (1) the cooperation of a M–N7(acv) bond with an intramolecular interligand N–H⋯O6(acv) interaction; (2) the unusual bridging µ2-N7,O(ol, N9-side chain) mode and (3) the asymmetric chelating-N7,O6-acv mode, with O6 being the apical/distal Cu(II) donor atom.

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Introduction

Acyclovir (also called acycloguanosine, hereafter acv) is one of the most relevant antiviral drugs used worldwide for the treatment of Herpesviridae infections. The similarities of this molecule to the natural nucleoside guanosine (Scheme 1), besides the chemical nature of the acv-N9 pendant arm, encourage the study of the metal binding abilities of this antiviral agent. Sigel et al. studied the stability of different guanosine 5-monophosphate metal complexes in aqueous solutions and revealed the key role of the N7 basicity in the molecular recognition process [1], [2]. According to the well-known coordination preferences of guanosine, the available structural information reveals that the N7 atom is by far the preferred donor atom of acv to bind metal ions. With the sole exception of the outer-sphere complex (H(N7)acv)trans-[RuIICl4(O-dmso)(NO)] [3], the acyclovir metal binding patterns (MBP) described in the literature can be summarized as follows (Scheme 2): (MBP-1) Formation of a single M–N7 bond [4], [5], [6]. (MPB-2) Cooperation between a M–N7(acv) bond and an intramolecular interligand H-bonding interaction type A-H⋯O6(acv), with A = N or O [6], [7], [8], [9], [10], [11], [12], [13], [14]. A striking case is found in the structure of [Pt(en)(acv)2]SO4·2.5H2O [15] where the MBP-1 and MBP-2 modes are both featured in the complex cation. (MBP-3) In 1998, Turel et al. reported the compound trans-[Cu(acv)2(H2O)2](NO3)2 [16]. For a long time, this was the sole example of the asymmetric chelating-N7,O6 acv mode. A series of ternary Cu(II) complexes with NO2+S(thioether or disulfide) chelators were recently reported where this MBP-3 mode was also found [17]. (MBP-4) Another singular metal binding mode of acyclovir is described in the polymer {Cd(μ2-Cl)22-N7,O(ol)-acv)]·H2O}n [8]. Here the synthetic nucleoside displays a bridging mode that involves the Cd–N7 bond and the Cd–O(ol) bond. Within the polymeric chain, the Cd–N7 bond cooperates with an intermolecular acv-O(ol)–H⋯O6-acv H-bond, hence differing from the above referred MBP-2.

In past years, our research group has been devoted to providing a clear picture of acv metal binding abilities [6], [13], [14], [17]. Thus, the main aim of this work is to deepen the understanding on the role of copper(II) chelates with tridentate and tripodal tetradentate amines as potential acv receptors. In addition, we examine the detailed structural features of the tren complexes (78) as well as the energetic features of the referred assemblies.

Section snippets

Materials

The oxo salts (Cu(NO3)2·3H2O, Cu(ClO4)·6H2O, CuSO4·5H2O and ZnSO4·7H2O) and acyclovir were purchased, already purified, from various commercial sources, e.g. Merck (former Sigma–Aldrich), and used as received. Anhydrous acv (225.21 MW) and various acyclovir hydrates have been previously crystallized [13] and their structures reported in the Cambridge Structural Database (CSD database). The specific hydrated form of acyclovir used in this work was identified by powder-XRD, FT-IR spectroscopy and

Results and discussion

The reported compounds were crystallized in aqueous-methanol solutions. Methanol was selected as the preferred solvent for crystallization due to its polarity [6], while the water content was reduced to the small amounts provided by acv·0.66H2O and the hydrated oxo salts used for the synthesis. Eventually, the formation of colorless crystals, identified as acv·0.66H2O by FT-IR spectroscopy, was observed. On appearing, these crystals were removed by filtration without vacuum and the mother

[Cu(dien)(acv)(H2O)]SO4·1.25MeOH·0.5H2O (1)

This Cu-dien-acv complex is a salt with sulfate as the counter-anion. In the complex cation [Cu(dien)(N7-acv)(H2O)]2+, dien adopts its most common mer-conformation. This fact enables the coordination of the N7-acv atom amongst the four closest copper(II) coordination sites. The Cu(II) center is strongly influenced by the Jahn–Teller effect (3d9), featuring a distorted square-base pyramidal coordination (type 4 + 1). The Cu–N7(acv) coordination bond is reinforced by the intramolecular

[Cu(pmdta)(acv)](ClO4)2·H2O (5)

The complete methylation of all the amino groups in diethylenetriamine affords the ligand N,N,N′,N′,N″-pentamethyl-diethylenetriamine (pmdta). Interestingly, the pmdta ligand cannot build intramolecular interligand interactions of the type (chelating amine)N-H⋯O6(acv), as reported in the previous metal complexes (Table 1). Single crystals of compound 5 were isolated and its structure solved according to the formula [Cu(pmdta)(N7,O6-acv)](ClO4)2·H2O. The asymmetric unit contains twice the

[Cu(tren)(acv)](NO3)2 (7)

In the complex cation, the copper(II) atom is N5-five coordinated, showing a distorted trigonal bipyramidal coordination (Table 1). The tren ligand forms three rather similar Cu–N bonds of ∼2.05 Å and one long Cu1–N23 (2.15 Å) bond. The shortest coordination bond is Cu1–N7(acv) (Fig. 3a). This bond is reinforced by an intramolecular H-bond (amino primary tren)N–H⋯O6(acv) (Table 1). Interestingly, the amino tertiary N10(tren) and N7(acv) atoms act as trans-apical donors, leading to a

Theoretical study

We have focused our theoretical study on analyzing the energetic features of the interesting supramolecular assemblies observed in the solid state of compounds 7 and 8. The theoretical model used to evaluate the interactions is shown in Fig. 4. Here, the tren ligand chelates the Cu(II) ion. The [Cu(tren)(acv)]2+ complex cation, common to compounds 7 and 8, acts as a host for the nitrate/perchlorate counter ions due to its enhanced capability of establishing hydrogen bonds, π⋯π and anion⋯π

Conclusions

Tridentate or tripodal-tetradentate polyamine copper(II) chelates are suitable receptors for acyclovir. Cu-dien-acv and Zn-dien-acv complexes differ in the dien conformation, but all exhibit a metal-N7 bond efficiently reinforced by an appropriate intramolecular interligand N–H⋯O6 interaction. Likewise, the tripodal-tetradentate tren ligand binds acyclovir assisting the Cu–N7(acv) bond with one or two N–H⋯O6 interactions. This metal binding pattern is the most commonly reported for acv and is

Acknowledgements

Financial support from the Network of Excellence “Metal Ions in Biological Systems” MetalBio CTQ15-71211-REDT (Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016) and the Research group FQM-283 (Junta de Andalucía) is gratefully acknowledged.

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