Josefa María González-Pérez

Three new modes of adenine-copper(II) coordination: interligand interactions controlling the selective N3-, N7- and bridging μ-N3,N7metal-bonding of adenine to different N-substituted iminodiacetato-copper(II) chelates

Abstract The reaction of Cu2CO3(OH)2, various N-substituted-iminodiacetic acids [RN(CH2CO2H)2)] and adenine (AdeH) in water yields crystalline samples of mixed-ligand copper(II) complexes of formulas [Cu(A)(N7AdeH)(H2O)]·H2O (A=N-methyl- or N-ethyl-iminodiacetato(2−); compounds 1 and 2, respectively), [Cu(B)(N3AdeH)(H2O)]·H2O (B=N-benzyl- or N-(p-methylbenzyl)-iminodiacetato(2−); compounds 3 and 4, respectively) as well as [Cu4(pheida)4(μ-N3,N7AdeH)2(H2O)4]·2H2O (pheida=N-phenethyl-iminodiacetato(2−)). Crystal structures of the acid H2pheida and compounds 1–5 are reported. H2pheida acid exhibits a typical zwitterionic structure. Copper(II) compounds were also studied by TG analysis (with FT-IR study of the evolved gasses), IR, electronic and ESR spectra and magnetic susceptibility data. The N-alkyl- or N-benzyl-like-iminodiacetato(2−) ligands (A or B) give complexes with Cu(II)/(A or B)/AdeH equimolar ratio, whereas pheida yields an unexpected tetranuclear compound with a 2:2:1 Cu(II)/pheida/AdeH molar ratio. In 1 and 2 AdeH binds to the metal by N7, whereas in 3 and 4 the N3 atom is used. An unexpected bridging μ-N3,N7AdeHdicopper(II) binding mode is found in the tetra-nuclear compound 5 (without interligand π,π-stacking interactions). These AdeHCu(II) binding modes have not been referred in the literature before. The difference in AdeHCu(II) binding modes in compounds 1 or 2 and 3 or 4 is rationalised on the basis of the absence or presence of a flexible N-benzyl-like substituent in the iminodiacetato(2−) ligand skeleton, which prevents or permits the interligand π,π-stacking interactions.

Synthesis, XRD structures and properties of diaqua(iminodiacetato)copper(II), [Cu(IDA)(H2O)2], and aqua(benzimidazole)(iminodiacetato)copper(II), [Cu(IDA)(HBzIm)(H2O)]

Abstract The stoichiometric reaction of copper(II) hydroxycarbonate with iminodiacetic acid (H2IDA) in water under reduced pressure yields good crystalline samples of [Cu(IDA)(H2O)2] (compound I). Using equimolar amounts of benzimidazole (HBzIm) the above reaction produces crystals of [Cu(IDA)(HBzIm)(H2O)] (compound II). Both compounds were characterised by TG analysis (with IR study of the evolved gasses in the pyrolysis), spectral and/or magnetic properties (IR, electronic, ESR spectrum, magnetic susceptibility in the 1.8–300 K range) and single crystal X-ray diffraction. The structure of I was re-determined (final R1=0.022) and it confirms the earlier reported distorted octahedral Cu(II) coordination (type 4+1+1), the fac-terdentate chelating and bridging roles for IDA ligand, as well as the ‘polymeric’ chain structure, but with a rather different hydrogen bonding network. In compound II (final R1=0.035) the Cu(II) exhibits a square base pyramidal coordination (type 4+1) and the IDA exhibits the mer-terdentate chelating configuration observed earlier for complexes having equimolar Cu(II)/IDA/HIm or HIm-like ratio, but now with a large dihedral angle (31.3°) between basal Cu(II) coordination and HBzIm mean planes.

Iron(III) and aluminum(III) complexes with hydroxypyrone ligands aimed to design kojic acid derivatives with new perspectives

With the aim to design new chelators for the clinical treatment of different diseases involving the trivalent metal ions Fe(III) and Al(III), we present the equilibria of kojic acid and its derivative 6-[5-hydroxy-2-hydroxymethyl-pyran-4-one]-5-hydroxy-2-hydroxymethyl-pyran-4-one with these two metal ions. Potentiometric and spectrophotometric techniques for iron, and potentiometry and (1)H NMR for aluminum were used, supported by X-ray, electrospray ionization-mass spectrometry (ESI-MS), calorimetry and quantum chemical calculations. In this work, evidence is given on the formation of MeL, MeL(2), and MeL(3) complexes of both metal ions with kojic acid, confirmed by the X-ray structure of the FeL(3) complex, and of variously protonated Me(2)L(2) and MeL(2) complexes of 6-[5-hydroxy-2-hydroxymethyl-pyran-4-one]-5-hydroxy-2-hydroxymethyl-pyran-4-one. The extremely good pFe value for this second ligand gives confidence to, and opens perspectives for, the search of new kojic acid derivatives.

Inter-ligand interactions and the selective formation of the unusual metal–N3(adenine) bond in ternary copper(II) complexes with N-benzyliminodiacetato(2−) ligands

A novel mixed-ligand copper(II) complex with N-(p-methoxybenzyl)-iminodiacetato(2)) ligand (MOBIDA) and adenine (AdeH) of formula ½CuðMOBIDAÞðAdeHÞðH2OÞ� � H2O has been obtained. Its crystal structure reveals the selective formation of a rare Cu– N3(AdeH) bond, closely related to those reported by first time for compounds of general formula ½CuðBÞðAdeHÞðH2OÞ� � H2O, with B ¼ N-benzyl- or N-(p-methylbenzyl)-iminodiacetato(2)) ligands. Appropriate structural comparison reveals that the copper(II) coordination by less basic N3 heterocyclic donor of the nucleobase is controlled by a molecular recognition process involving the formation of an intra-molecular inter-ligand N7(imidazole-like)–H ��� O(carboxyl) bond and the inter-molecular inter-ligand p,p-stacking interaction between six membered rings of benzyl (MOBIDA) and AdeH. This stack generates multi-stacked infinite chains along the b-axis of the crystal. 2002 Elsevier Science B.V. All rights reserved.

Metal chelates of N-(2-pyridylmethyl)iminodiacetate(2-) ion (pmda). Part I. Two mixed-ligand copper(II) complexes of pmda with N,N-chelating bases. Synthesis, crystal structure and properties of H2pmda·0.5H2O, [Cu(pmda)(pca)]·3H2O (pca=α-picolylamine) and [Cu(pmda)(Hpb)]·5H2O (Hpb=2-(2′-pyridyl)benzimidazole)

N -(2-Pyridylmethyl)iminodiacetic acid hemi-hydrate (H2pmda/0.5H2O) was prepared and characterized by X-ray crystallography (final R 1 � /0.042). The zwitterion H2pmda 9 is intra -stabilized by a trifurcated hydrogen bond. Intermolecular carboxyliccarboxylate hydrogen bonds and the parallel inter-ligand p,p-stacking (3.57(2) A u ) between pyridyl rings from pairs of adjacent zwitterions generate 2D frameworks (bi-layers with the carboxyl groups towards the external surfaces and py � /pmda rings towards the inside). In the crystal, the bi-layered structures are connected by equivalent hydrogen bonds, which link each water molecule to two symmetry related O-carboxylate atoms from the adjacent external faces of two 2D frameworks. The compounds [Cu(pmda)(pca)]/3H2 O( 1) and [Cu(pmda)(Hpb)]/5H2 O( 2) were obtained by stoichiometric reaction of Cu2(CO3)(OH)2, H2pmda/0.5H2O and a-picolylamine (pca) or 2-(2?-pyridyl)benzimidazole (Hpb), respectively, and characterized by single crystal X-ray diffractometry. Compound 2 was also studied by TG analysis (with FTIR study of the evolved gasses in the pyrolysis), magnetic susceptibility at 80 � /300 K range, and FTIR, electronic, ESR spectra. In 1 and 2 the copper(II) atom exhibits a distorted octahedral coordination (type 4� /1� /1) and pmda acts as tripodal tetra-dentate ligand. However, pmda displays different coordination roles. The pmda supplies two N ,O -meridional and two trans -apical N (py),O -donors in 1, whereas links the metal by three N ,N (py),O -meridional and one O -apical atoms in 2 .N op,p-stacking of pyridyl � /(pmda) rings is observed in these complexes. The pyridyl � /(pca) ring of 1 is not involved in ring � /ring stacking interactions, but compound 2 recognizes itself by a roughly antiparallel p,p-stacking of adjacent Hpb ligands (5.38, 3.41(2) A u ) forming pairs of complex units. # 2002 Elsevier Science Ltd. All

Ring–ring or nitro-ring π,π-interactions in N-(p-nitrobenzyl)iminodiacetic acid (H2NBIDA) and mixed-ligand copper(II) complexes of NBIDA and imidazole (Him), 2,2′-bipyridine (bipy) or 1,10-phenanthroline (phen). Crystal structures of H2NBIDA, [Cu(NBIDA)(Him)(H2O)], [Cu(NBIDA)(bipy)]·3H2O and [Cu(NBIDA)(phen)]·2H2O

Abstract N-(p-nitrobenzyl)iminodiacetic acid (H2NBIDA) and the mixed-ligand copper(II) complexes with NBIDA and imidazole (Him), 2,2′-bipyridine (bipy) or 1,10-phenanthroline (phen) were prepared and characterised by thermal, spectral, magnetic and X-ray diffraction methods. Our aim is to study various possibilities of the N-(p-nitrobenzyl) arm in the iminodiacetate(2−) ion (IDA) skeleton to be involved in π,π-interactions which contribute to molecular recognition processes and crystal building. Analysis of the shortest aromatic ring–ring interactions were carried out with platon program and let us conclude that in free H2NBIDA acid (1) and [Cu(NBIDA)(Him)(H2O)] (2) only inter-molecular benzyl–benzyl π,π-stacks occur, whereas in [Cu(NBIDA)(bipy)]·3H2O (3) and [Cu(NBIDA)(phen)]·2H2O (4) there are both inter-molecular nitro-benzyl π,π-interactions (instead of benzyl–benzyl π,π-stacks) and α,α′-diimine-α,α′-diimine ring–ring π,π-interactions. In compound 2 NBIDA ligand has a typical mer-NO2 tridentate conformation, whereas in 3 or 4 it exhibits an unusual fac-O2+N(apical) conformation. The molecular recognition pathway in 3 and 4 is discussed on a structural basis, considering a variety of interligand interactions involved in molecular recognition processes to build these and closely related crystals. We conclude that both the presence of a non-coordinating N-substituent in the IDA-like ligand and the chelation of Cu(II) by an aromatic α,α′-diimine (bipy or phen) display active roles for promote a fac-O2+N(apical) conformation and various modes of interligand π,π-stacking interactions.

Synthesis and anticancer activity of (R,S)-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-purines.

A series of eleven 2‐ and 6‐substituted (R,S)‐9‐(2,3‐dihydro‐1,4‐benzoxathiin‐3‐ylmethyl)‐9H‐purine derivatives was obtained by applying a standard Mitsunobu protocol that led to a six‐membered ring contraction from (R,S)‐3,4‐dihydro‐2H‐1,5‐benzoxathiepin‐3‐ol via an episulfonium intermediate. The signal ∼δ=151 ppm, which corresponds to the C4′ carbon atom, is unequivocal proof of the N9′ regioisomer. The potential of the target molecules as anticancer agents is reflected in their activity against the MCF‐7 cancer cell line. The most active compounds have IC50 values of (6.18±1.70) and (8.97±0.83) μM. The results indicate that the anticancer activity for the most active compounds is correlated with their capacity to induce apoptosis.

Synthesis, crystal structure and properties of N-tert-butyliminodiacetic acid (H2TEBIDA), [Cu(TEBIDA)(H2O)2], {[Cu(TEBIDA)(Him)].2H2O}n, {Cu(TEBIDA) (5MeHim).H2O}n, and [Cu(TEBIDA)(2,2'-bipy)(H2O)].4.5H2O, (Him = imidazole, 5MeImH = 5-methylimidazole and 2,2'-bipy = 2,2'-bipyridine)

Abstract N-tert-butyliminodiacetic acid (H2TEBIDA, compound 1) has been prepared and characterised by thermogravimetric analysis, FT-IR and NMR spectra, and X-ray crystallography (final R1=0.04). The zwitterion H2TEBIDA± is intra-stabilised by a hydrogen bond, and H-bonded chains of zwitterions form supramolecular 2D bilayers with tert-Bu groups towards the external faces. Compounds [Cu(TEBIDA)(H2O)2] (2), {[Cu(TEBIDA)(Him)]·2H2O}n (3) {[Cu(TEBIDA)(5MeHim)]·H2O}n (4) [Cu(TEBIDA)(bipy)]·4.5H2O (5) were also obtained and studied by thermal, (FT-IR, reflectance and ESR) spectral, magnetic and X-ray diffraction methods. Compound 2 has a molecular structure and TEBIDA with mer-NO2 tridentate conformation in contrast with that reported for {[Cu(IDA)(H2O)2]}n (polymeric chains, elongated octahedral Cu(II) coordination and fac-NO+O(apical) IDA conformation). Compounds 3 and 4 form zig–zag polymeric chains and follow all structural co-relations reported for complexes with equimolar Cu(II)/iminodiacetato (IDA)/N-heterocyclic donor ratio (Cu(II) coordination type 4+1, mer-NO2 TEBIDA conformation and N(Him-like) donor in trans to the Cu–IDA-like bond). However, compound 5 has an unexpected fac-O2+N(apical) TEBIDA conformation, with the aqua ligand (instead of one N-heterocyclic donor) in the trans-site of the CuN(IDA-like) bond, in contrast with structural co-relations for complexes with Cu/(IDA or IDA-like)/N-heterocyclic donor ratio 1/1/2 and closely related compounds (fac-NO+O(apical) IDA-like conformation and one N-heterocyclic donor in the trans-site to the CuN(IDA-like) bond). These findings are attributed to the influence of π,π-stacking interactions involving both rings of two 2,2′-bipy ligands in the molecular recognition process, forming pairs of complex molecules which probably build the crystal of compound 5 with non-coordinated water.

Metal ion binding patterns of acyclovir: molecular recognition between this antiviral agent and copper(II) chelates with iminodiacetate or glycylglycinate.

In order to deepen on metal-binding patterns of acyclovir (acv), {[Cu(IDA)(acv)]·2MeOH}(n) (1) and [Cu(glygly)(acv)]·H(2)O (2) compounds have been synthesized and investigated by X-ray crystallography as well as spectral and thermal methods. These compounds have been chosen upon the assumption that iminodiacetate (IDA) and glycylglycinate (glygly) chelating ligands would bind copper(II) with mer-tridentate conformation, supplying two terminal H-acceptor carboxylate groups (IDA) or one H-acceptor carboxylate and one H-donor primary amino group (glygly). The main aim of this work was to clarify if the amino group of glygly can build an intra-molecular interligand H-bonding interaction to reinforce the Cu-N7(acv) bond. Our results are discussed in the context of an up-to-date critical look regarding the related structural information. From the viewpoint of molecular recognition, the structure of 1 shows that the chelate-nucleoside recognition only involves the Cu-N7(acv) coordination bond. In contrast, the molecular complex of 2 exhibits the Cu-N7(acv) coordination bond reinforced by an intra-molecular (glygly)N-H···O6(acv) interaction (2.961(3)Å, 140.5°).

Searching for new aluminium chelating agents: a family of hydroxypyrone ligands.

Attention is devoted to the role of chelating agents in the treatment of aluminium related diseases. In fact, in spite of the efforts that have drastically reduced the occurrence of aluminium dialysis diseases, they so far constitute a cause of great medical concern. The use of chelating agents for iron and aluminium in different clinical applications has found increasing attention in the last thirty years. With the aim of designing new chelators, we synthesized a series of kojic acid derivatives containing two kojic units joined by different linkers. A huge advantage of these molecules is that they are cheap and easy to produce. Previous works on complex formation equilibria of a first group of these ligands with iron and aluminium highlighted extremely good pMe values and gave evidence of the ability to scavenge iron from inside cells. On these bases a second set of bis-kojic ligands, whose linkers between the kojic chelating moieties are differentiated both in terms of type and size, has been designed, synthesized and characterized. The aluminium(III) complex formation equilibria studied by potentiometry, electrospray ionization mass spectroscopy (ESI-MS), quantum-mechanical calculations and (1)H NMR spectroscopy are here described and discussed, and the structural characterization of one of these new ligands is presented. The in vivo studies show that these new bis-kojic derivatives induce faster clearance from main organs as compared with the monomeric analog.