The highest reported denticity of a synthetic nucleoside in the

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Cite This: Cryst. Growth Des. XXXX, XXX, XXX−XXX

Highest Reported Denticity of a Synthetic Nucleoside in the Unprecedented Tetradentate Mode of Acyclovir Inmaculada Peŕ ez-Toro,† Alicia Domínguez-Martín,*,† Duane Choquesillo-Lazarte,‡ Josefa M. Gonzaĺ ez-Peŕ ez,† Alfonso Castiñeiras,§ and Juan Nicloś -Gutieŕ rez† †

Department of Inorganic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain Laboratorio de Estudios Cristalográficos, IACT, CSIC-University of Granada, Avenida de las Palmeras 4, 18100 Armilla, Granada, Spain § Department of Inorganic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain

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‡

S Supporting Information *

ABSTRACT: The unprecedented tetradentate, chelating, and μ3-bridging mode of acyclovir (acv) drives to a 1D-polymeric ribbon in [{Cu2(acv)(μ3-acv)(SO4)(μ2SO4)(H2O)4}·H2O·MeOH]n, stabilized by μ2-SO4 ligands, interligand H-bonds, and anion/π-(SO4/acv) interactions. Stacking π,π-(acv/μ3-acv) interactions play a key role in the crystal packing.

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graphic results regarding the metal-binding role of the O-ribose and related furanose O atoms within nucleosides.1−4 Three main reasons should be kept in mind to understand this fact: (a) the lability of many O-metal bonds, (b) the openingcyclization equilibria of the furanose ring, and/or (c) the Pearson hardness of the O-donors with respect to the borderline or soft Pearson acid character of most metal ions. In fact, all the known O(ribose)-metal binding examples involve hard Pearson’s acids and adenosine (ado)1−3 or guo3,4 derivatives. In these complexes, the purine nucleosides act as (2-) or (3-) anions, binding the metallic centers only as cisdiolate ligands, featuring the bridging μ2-O2′,O3′ mode or, more frequently, the chelating O2′,O3′-diolate mode. On the other hand, synthetic nucleosides such as acyclovir are designed with an acyclic N9-pendant arm. This fact allows avoiding the complexity of the furanose ring; however, the resulting structures are not completely comparable since, obviously, the O-ether in the acyclic chain does not behave as the furanosic oxygen. In acyclovir, the ethylene spacer in the N9-side chain would theoretically let the O(e) and O(ol) atoms to build a five-membered metal chelate ring. Nevertheless, to the best of our knowledge, crystallographic data have never supported such a motif, in any related synthetic nucleoside, or any deprotonated acv species.

cyclovir (acv) is a purine synthetic nucleoside used as a first-line antiviral pro-drug against viruses of the alpha Herpesviridae subfamily. It consists of a guanine moiety attached to an acyclic N9-pendant arm, functionalized with a rather stable O′-ether [hereafter O(e)] and an O″-alcohol [hereafter O(ol)] groups. These latter oxygen atoms would correspond, respectively, to the O-(heterocyclic-furanose) and the O5′-(hydroxy-methyl) atoms within the ribose moiety of related natural nucleosides such as guanosine (guo, see Scheme 1). In the literature, numerous examples can be found where two or more metals per nucleobase are bonded; however, the corresponding information on nucleosides, either natural or synthetic, is very limited. Moreover, there are scarce crystallo-

Scheme 1. Chemical Formula of Guanosine and Acyclovir with Conventional Purine Numbering

Received: June 11, 2018 Published: June 22, 2018 © XXXX American Chemical Society

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DOI: 10.1021/acs.cgd.8b00893 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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Figure 1. Fragment of the 1D-ribbon of the polymer [{Cu2(acv)(μ3-acv)(SO4)(μ2-SO4)(H2O)4}·H2O·MeOH]n. Solvent molecules omitted for clarity. Blue arrows point out the tetradentate role of the μ3-acv ligand. H-bonds depicted as cyan dashed lines. Magenta dashed lines correspond to intrachain anion···π interactions. Bond lengths (Å): Cu1−O1 1.951(5), Cu1−O2 1.951(6), Cu1−N27 2.027(7), Cu1−N7 2.035(7), Cu1−O25 2.416(7), Cu1−O23a 2.476(6), Cu2−O21 1.929(6), Cu2−O3 1.957(6), Cu2−O4 1.970(7), Cu2−O14 1.983(5), Cu2−O6b 2.363(5), and Cu2− O11 2.489(6). Symmetry transformations: a = x, y, z+1; b = x, y, z−1.

terminal nitrogen atoms were substituted for isolobal groups that involve oxygen. Unexpectedly, the isolated compound did not contain coordinated DEA. Like other amines, DEA could have also acted as a weak base. Instead, DEA seems to play a surprising spectator role in the solution. The DEA-free compound 1 crystallizes in the monoclinic system, space group P21. Its structure was solved from data measured at 100 K and refined to a final R1 value of 0.046 (see Supporting Information). In the asymmetric unit, the polymer has two nonequivalent metal centers, Cu1 and Cu2, as shown in Figure 1. Both metal centers exhibit elongated octahedral surroundings, type ∼4 + 2. In addition, two markedly different kinds of acv ligands have been found: monodentate and μ3-bridging tetradentate, and also two distinct sulfate ligands (monodentate and μ2-bridging bidentate) along with one MeOH and one water solvent molecules. Coordination Polyhedron. The trans-Cu1N2O 2+O2 center has two trans-N7 atoms, from a monodentate-acv and a μ3-acv ligand, and two trans-O aqua donors, O1 and O2, as the four closest donors of the metal (with bond distances ∼2 Å). Moreover, two trans-O-sulfate donors are located at the distal sites, pertaining to a monodentate sulfate (O25) and a μ2-sulfate (O23) ligand. On the other hand, the four closest donors of the Cu2O4+O2 chromophore are two trans-O-aqua (O3 and O4) and the O21 μ2-sulfate and the O14(ol) from a μ3-acv. The two additional trans-distal donors in the Cu2 center are built by the longest bonds Cu2−O11(e) and Cu2− O6 (Figure 1), coming from two distinct but symmetry-related μ3-acv ligands. The trans-O6-Cu2-O11(e) angle has a rather low value of 158.26°. The formation of the Cu−O6-acv bond was first documented by Turel et al.11 in the octahedral complex trans-[Cu(acv)2(H2O)2](NO3)2, where both acv display the N7,O6-chelating role (MBP-2). In this latter bis-chelate the Cu−O6 bonds (2.698(2) Å) are far longer than in the reported compound 1, where the Cu2−O6 bond length is 2.363 Å, significantly below the sum of van der Waals radii (2.90 Å).

In a crystal of the human purine nucleoside phosphorylase complex,5 five crucial H-bonds are involved in the pro-drug/ protein molecular recognition involving the O-ribose as Hacceptor. Interestingly, the O(e) and O(ol)-acv atoms have also been observed to play a role as H-acceptor and H-donor, respectively, in the crystal of the 5-fluorocytosine-acv cocrystal.6 Unfortunately, that seems not to be the case of other cocrystals and a salt formed by acv and various organic acids.7 In the crystal of acv6 or acv·0.66 H2O,8 the O(e) atom does not play an H-acceptor role. Metal-binding patterns (MBP) of acv are supported by crystal structures of mixed-ligand metal complexes.9−22 They can be summarized as follows: MBP-1: M-N7 bond together with9,10,12,14−17,19−21 or without11−13,16,18,21 an intramolecular interligand O−H···O6(acv) or N−H···O6(acv) interaction. MBP-2: Chelation-N7,O6.11,21,22 MBP-3: μ2-N7,O″ bridging mode.10,21 Both the highest denticity10,11 and acv/M ratio10,11,13,14,16,17,21,22 are two. With the aim to expand the frontiers of the acv coordination chemistry, we are working on novel mixed-ligand metal complexes that include chelators with N, O, or S. The reaction of equimolar amounts (0.5 mmol) of CuSO4·5H2O, diethanolamine (DEA) and acv in a 40:15 MeOH−DMF mixture (55 mL) affords a light-green turbid solution, which after slow evaporation of solvents and repeated filtration to remove a fine green powder yield lamellar crystals of [{Cu2(acv)(μ3-acv)(SO4)(μ2-SO4)(H2O)4}·H2O·MeOH]n (1); Yield 40%. Elemental analysis (%): Calc. for C17H36Cu2N10O20S2: C 22.90, H 4.07, N 15.70; Found: C 22.87, H 4.12, N 15.63. Diethyl ether was used as antisolvent. The compound formula was first determined by single-crystal X-ray crystallography. Additional crystalline samples were promptly identified as the same compound by additional analyses such as FT-IR, electronic spectra, and coupled thermogravimetry+FT-IR spectroscopy (see Supporting Information). The original purpose of adding DEA was using this ligand as a chelator.23,24 In particular, we were looking for a derivative of diethylenetriamine in which the B



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Figure 2. Crystal packing of compound 1 and detail of π,π-stacking interactions connecting 1D-polymeric chains in the 2D-framework. Orange centroid corresponds to μ3-acv while green centroid corresponds to monodentate acv ligand. H-bonds are depicted by cyan dotted lines. (Sulfate)anion···π and π,π-stacking interactions are depicted by magenta dashed and dotted lines, respectively. Symmetry transformations: a = x, y, z + 1; d = 2 − x, −1/2 + y, −z; f: 2 − x, 1/2 + y, −z + 1.

the N9-pendant arm of the μ3-acv ligand chelates a different Cu2 center by its O11(e) and O14(ol) donors. As expected, this five-membered chelate ring exhibits a puckered conformation, with the ethylene C12 (+0.50 Å) and C13 (−0.19 Å) atoms at opposite sides of the plane [Cu2, O11, O14]. Sulfate Ligands. The monodentate sulfate ligand binds the Cu1 center by the Cu1−O25 bond, reinforced by the intramolecular interligand interaction (aqua)O1−H1A···O27 (sulfate (2.764(8) Å, 149.2) and an anion···π interaction that connects the O28-sulfate atom with the five-membered ring of the monodentate acv [d(O28···ring centroid-Cg(5) 3.54 Å, angle S2−O28-ring centroid Cg(5) 105.7°)] (Figure 1 and Figure 2). The μ2-sulfate ligand efficiently contributes to the internal stability of the ribbon with two dissimilar Cu1−O23 and Cu2−O21 bonds (Figure 1). From these latter bonds, the shortest is also assisted by an H-bond (aqua)O4−H4A···O24 (2.991(9) Å, 148.5°). Hence, each sulfate ligand shows a Cu− O bond stabilized by interligand (aqua)O−H···O (sulfate, proximal or distal) interactions. Crystal Packing. The acyclic character of the N9-pendant arm of acv hinders the coordination of the purine core and the N9-susbsitutent by the same metal center, therefore promoting the observed μ3-acv bridging role, which features a key role in the polymeric nature of compound 1. The 1D-ribbons extends along the c axis where alternating symmetry related Cu1 and Cu2 centers are connected by a μ3-acv ligand (Cu1···Cu2 8.034(1) Å) and a μ2-sulfate ligand (Cu1···Cu2 4.875(1) Å). The internal stability of these ribbons is additionally reinforced by intramolecular H-bonds involving the aqua ligands and the exocyclic amino groups from the guanine moiety (Figure 2), besides the aforementioned contribution of multiple, although rather weak, anion···π interactions. As shown in Figure 2, the polymeric chains further build 2D layers, parallel to the bc plane, by means of π,π-stacking interactions between the sixmembered rings of the guanine moieties from both acv ligands, monodentate and μ3-acv (intercentroid dc‑c 3.42 Å, interplanar dπ−π 3.29 Å, interplanar dihedral angle 2.78°, slipping angles β or γ 16.5° or 15.1°). Layers are connected along the a axis of the crystal by additional H-bonds.

From the 12 donors of Cu1 and Cu2 centers, ten are O atoms and only two are N atoms. This is in line with the apple-green color of the isolated crystals and the corresponding electronic spectrum, which exhibits an asymmetric and broad d-d band, with λmax at 830 nm (∼12 000 cm−1) and intensity barycenter near 923 nm (10 800 cm−1) (see Supporting Information). The coexistence of monodentate and bridging μ3-acv and μ2sulfate ligands, as well as the presence of water and methanol solvent molecules, leads to a remarkable overlapping of bands in the FT-IR spectrum of 1. Despite this fact, two stretching absorptions for the ν(CO) of acv could be identified: a strong sharp band at 1683 cm−1 and a smooth shoulder near 1675 cm−1, assigned to monodentate acv and μ3-acv. Related copper(II) complexes having solvate and/or coordinated acv ligand also exhibit the ν(CO) band at similar wavelenghth, which has been used with high diagnostic value.12,15,21 In contrast, spectra recorded on various commercial samples of acv·0.66H2O show the corresponding ν(CO) splitted in two partially overlapped bands at 1720 ± 3 and 1695 ± 2 cm−1, which is not observed in the spectrum of 1 (see Supporting Information). Nucleoside Ligand. Interestingly, in 1, two kinds of neutral acyclovir ligands are found in the structure: monodentate and μ3-tetradentate. Neutrality is achieved because the free DEA ligand is not able to deprotonate the hydroxyl group of acv; therefore, the negative charge of sulfate ligands is enough to compensate that of Cu(II) ions. The monodentate acv features a typical acv binding pattern MBP1. The Cu1−N27 bond is reinforced with the (aqua)O2−H2B··· O26 (2.620(8) Å, 159.7°) H-bond. A more complex role is displayed by the μ3-bridging tetradentate acv ligand though. The μ3-acv connects one Cu1 and two different Cu2 centers. The guanine moiety of the μ3acv ligand binds its N7 donor to the Cu1 center and the O6 donor to a Cu2 center. In contrast to the monodentate acv, the Cu1−N7 bond is not assisted by an interligand H-bond, whereas the Cu2−O6 bond is involved in the interligand interaction Cu1−O1−H1B···O6 (2.622(8) Å, 162.2°) providing extra stability to the polymeric chain. On the other hand, C



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In conclusion, the unprecedented tetradentate μ3-acv ligand drives the formation of a 1D Cu(II) polymer, in cooperation with μ2-sulfate ligands and (aqua) O−H···OH-bonds. In the crystal, the polymeric chains build a 3D network by means of π,π-stacking interactions between guanine residues of both kinds of acv ligands, besides sulfate anion···π interactions and additional H-bonds.

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(5) dos Santos, D. M.; Canduri, F.; Pereira, J. H.; Vinicius Bertacine Dias, M.; Silva, R. G.; Mendes, M. A.; Palma, M. S.; Basso, L. A.; de Azevedo, W. F.; Santos, D. S. Crystal structure of human purine nucleoside phosphorylase complexed with acyclovir. Biochem. Biophys. Res. Commun. 2003, 308 (3), 553−559. (6) Tutughamiarso, M.; Wagner, G.; Egert, E. Cocrystals of 5fluorocytosine. I. Coformers with fixed hydrogen-bonding sites. Acta Crystallogr., Sect. B: Struct. Sci. 2012, 68 (4), 431−443. (7) Yan, Y.; Chen, J.-M.; Lu, T.-B. Simultaneously enhancing the solubility and permeability of acyclovir by crystal engineering approach. CrystEngComm 2013, 15 (33), 6457−6460. (8) Birnbaum, G. I.; Cygler, M.; Shugar, D. Conformational features of acyclonucleosides: structure of acyclovir, an antiherpes agent. Can. J. Chem. 1984, 62 (12), 2646−2652. (9) Barceló-Oliver, M.; Terrón, A.; García-Raso, A.; Fiol, J. J.; Molins, E.; Miravitlles, C. Ternary complexes metal [Co(II), Ni(II), Cu(II) and Zn(II)] − ortho-iodohippurate (I-hip) − acyclovir. X-ray characterization of isostructural [(Co, Ni or Zn)(I-hip)2(ACV)(H2O)3] with stacking as a recognition factor. J. Inorg. Biochem. 2004, 98 (11), 1703−1711. (10) Garcia-Raso, A.; Fiol, J. J.; Badenas, F.; Cons, R.; Terron, A.; Quiros, M. Synthesis and structural characteristics of metal-acyclovir (ACV) complexes: [Ni(or Co)(ACV)2(H2O)4]Cl2·2ACV, [Zn(ACV)Cl2(H2O)], [Cd(ACV)Cl2]·H2O and [{Hg(ACV)Cl2}]. Recognition of acyclovir by Ni-ACV. J. Chem. Soc., Dalton Trans. 1999, No. 2, 167−174. (11) Turel, I.; Anderson, B.; Sletten, E.; White, A. J. P.; Williams, D. J. New studies in the copper(II) acyclovir (acv) system. NMR relaxation studies and the X-ray crystal structure of [Cu(acv)2(H2O)2](NO3)2. Polyhedron 1998, 17 (23), 4195−4201. (12) Brandi-Blanco, M. d. P.; Choquesillo-Lazarte, D.; DomínguezMartín, A.; González-Pérez, J. M.; Castiñeiras, A.; Niclós-Gutiérrez, J. Metal ion binding patterns of acyclovir: Molecular recognition between this antiviral agent and copper(II) chelates with iminodiacetate or glycylglycinate. J. Inorg. Biochem. 2011, 105 (5), 616−623. (13) Turel, I.; Bukovec, N. a.; Goodgame, M.; Williams, D. J. Synthesis and characterization of copper(II) coordination compounds with acyclovir: crystal structure of triaquabis [9-{(2-hydroxyethoxy)methyl}guanine] copper(II) nitrate (V) hydrate. Polyhedron 1997, 16 (10), 1701−1706. (14) Blažič, B.; Turel, I.; Bukovec, N.; Bukovec, P.; Lazarini, F. Synthesis and structure of diaquadichlorobis {9-[(2-hydroxyethoxy)methyl]guanine} copper(II). J. Inorg. Biochem. 1993, 51 (4), 737− 744. (15) Pérez-Toro, I.; Domínguez-Martín, A.; Choquesillo-Lazarte, D.; Vílchez-Rodríguez, E.; González-Pérez, J. M.; Castiñeiras, A.; NiclósGutiérrez, J. Lights and shadows in the challenge of binding acyclovir, a synthetic purine-like nucleoside with antiviral activity, at an apical− distal coordination site in copper(II)-polyamine chelates. J. Inorg. Biochem. 2015, 148, 84−92. (16) Cini, R.; Grabner, S.; Bukovec, N.; Cerasino, L.; Natile, G. Synthesis and Structural Characterisation of a New Form of Bis(acyclovir)(ethylenediamine)platinum(II) − Correlation between the Puckering of the Carrier Ligand and the Canting of the Nucleobases. Eur. J. Inorg. Chem. 2000, 2000 (7), 1601−1607. (17) Grabner, S.; Plavec, J.; Bukovec, N.; Di Leo, D.; Cini, R.; Natile, G. Synthesis and structural characterization of platinum(II)acyclovir complexes. J. Chem. Soc., Dalton Trans. 1998, 9, 1447−1452. (18) Sinur, A.; Grabner, S. A Platinum(II) Diammine Complex: cis[Pt(C8H11N5O3)2(NH3)2]Cl2.2H2O. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1995, 51 (9), 1769−1772. (19) Turel, I.; Pečanac, M.; Golobič, A.; Alessio, E.; Serli, B.; Bergamo, A.; Sava, G. Solution, solid state and biological characterization of ruthenium(III)-DMSO complexes with purine base derivatives. J. Inorg. Biochem. 2004, 98 (2), 393−401. (20) Turel, I.; Pečanac, M.; Golobič, A.; Alessio, E.; Serli, B. Novel RuIII-DMSO Complexes of the Antiherpes Drug Acyclovir. Eur. J. Inorg. Chem. 2002, 2002 (8), 1928−1931.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.8b00893. Additional structural information, relevant spectral properties, and thermal stability information (PDF) Accession Codes

CCDC 1828231 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Telephone: +34 958 24 8589. Fax: +34 958 24 62 19. ORCID

Alicia Domínguez-Martín: 0000-0001-8669-6712 Duane Choquesillo-Lazarte: 0000-0002-7077-8972 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the Excellence Network “Metal Ions in Biological Systems” MetalBio CTQ15-71211-REDT (Plan ́ Estatal de Investigación Cientifica y Técnica y de Innovación 2013-2016) and the Research group FQM-283 (Junta de ́ is gratefully acknowledged. D.CH.L. acknowledges Andalucia) funding by the Excellence Network of Crystallography and Crystallization “Factoriá de Cristalización” FIS2015-71928REDC supported by Spanish MINECO and the Intramural CSIC (201730I019) project.

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ABBREVIATIONS Acv, acyclovir; MBP, metal binding pattern; MeOH, methanol; DMF, dimethylformamide REFERENCES

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(21) Pérez-Toro, I.; Domínguez-Martín, A.; Choquesillo-Lazarte, D.; García-Rubiño, M. E.; González-Pérez, J. M.; Castiñeiras, A.; Bauzá, A.; Frontera, A.; Niclós-Gutiérrez, J. Copper(II) polyamine chelates as efficient receptors for acyclovir: syntheses, crystal structures and dft study. Polyhedron 2018, 145, 218−226. (22) González-Pérez, J. M.; Choquesillo-Lazarte, D.; DomínguezMartín, A.; Vílchez-Rodríguez, E.; Pérez-Toro, I.; Castiñeiras, A.; Arriortua, O. K.; García-Rubiño, M. E.; Matilla-Hernández, A.; Niclós-Gutiérrez, J. Metal binding pattern of acyclovir in ternary copper(II) complexes having an S-thioether or S-disulfide NO2Stripodal tetradentate chelator. Inorg. Chim. Acta 2016, 452, 258−267. (23) Pratt, H. D.; Leonard, J. C.; Steele, L. A. M.; Staiger, C. L.; Anderson, T. M. Copper ionic liquids: Examining the role of the anion in determining physical and electrochemical properties. Inorg. Chim. Acta 2013, 396, 78−83. (24) Dey, B.; Mukherjee, P.; Mondal, R. K.; Chattopadhyay, A. P.; Hauli, I.; Mukhopadhyay, S. K.; Fleck, M. Femtomolar level sensing of inorganic arsenic(iii) in water and in living-systems using a non-toxic fluorescent probe. Chem. Commun. 2014, 50 (96), 15263−15266.

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The highest reported denticity of a synthetic nucleoside in the

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