RESUMEN
Drug-drug salts are a kind of pharmaceutical multicomponent solid in which the two co-existing components are active pharmaceutical ingredients (APIs) in their ionized forms. This novel approach has attracted great interest in the pharmaceutical industry since it not only allows concomitant formulations but also has proved potential to improve the pharmacokinetics of the involved APIs. This is especially interesting for those APIs that have relevant dose-dependent secondary effects, such as non-steroidal anti-inflammatory drugs (NSAIDs). In this work, six multidrug salts involving six different NSAIDs and the antibiotic ciprofloxacin are reported. The novel solids were synthesized using mechanochemical methods and comprehensively characterized in the solid state. Moreover, solubility and stability studies, as well as bacterial inhibition assays, were performed. Our results suggest that our drug-drug formulations enhanced the solubility of NSAIDs without affecting the antibiotic efficacy.
Asunto(s)
Ciprofloxacina , Sales (Química) , Ciprofloxacina/química , Composición de Medicamentos , Solubilidad , Sales (Química)/química , Antiinflamatorios no Esteroideos , Antibacterianos , Preparaciones FarmacéuticasRESUMEN
Atomic-level control over the position and growth of a single and continuous metal chain is an ambitious goal that often requires complex and costly processes. Herein, we demonstrate that 1Pd-DNA molecules, comprising a continuous single chain of PdII ions, can be prepared by a simple self-assembly reaction between the complex [Pd(Cheld)(CH3 CN)] (1Pd_CH3 CN) (Cheld=chelidamic acid) and single-stranded DNA homopolymers (ss-DNA) containing adenine (A) or 7-deazaadenine (X) bases. The single PdII -base pairs [1Pd(N1-A)] and [1Pd(N1-X)] were synthesized and characterized in solution and solid-state (X-ray diffraction) revealing an arrangement similar to that of natural Watson-Crick base pairs. Subsequently, 1Pd-DNA hybrids were prepared, characterized, and their structures studied by small-angle X-ray scattering (SAXS) and ab-initio calculations. The results indicate that the 1Pd-DNA structures resemble that of double-stranded DNA, with one strand being replaced by a supramolecular stack of continuous PdII complexes.
RESUMEN
The formation of copper(II)-mediated base pairs involving pyridine-2,6-dicarboxylate derivatives and canonical nucleosides has proven to be a smart approach to introduce copper(II) ions at specific locations of DNA duplexes. However, the structural characteristics of these metalized base pairs have not yet been revealed, and their effect on DNA structures is difficult to assess. Herein, for the first time, we report on the different structural details of copper-mediated base pairs formed by themselves and in DNA duplexes. The individual base pairs [Cu(mcheld)(N3-Cyt)(H2O)]·3H2O (1Cu_Cyt), [Cu(mcheld)(N7-Ade)(H2O)2]·2H2O (1Cu_Ade), [Cu(mcheld)(N7-Gua)(H2O)] (1Cu_Gua), and [Cu(mcheld)(N1-7CAde)(H2O)]·H2O (1Cu_7CAde) were obtained from the reaction of the metal complex [Cu(mcheld)(H2O)2] (1Cu) (mcheld = 4-methoxypyridine-2,6-dicarboxylic acid) with model nucleosides (Cyt = N1-methylcytosine, Ade = N9-ethyladenine, Gua = N9-propylguanine, 7CAde = N9-propyl-7-deazaadenine). The crystal structure of the five complexes was determined by means of single-crystal X-ray diffraction. Furthermore, the formation of the 1Cu_Cyt and 1Cu_Gua base pairs in the middle of DNA duplexes, duplex DNA15 (917 atoms) and DNA10 (649 atoms), respectively, was studied using highly demanding ab initio computational calculations. These theoretical studies aimed to validate, from a structural point of view, whether base pairs of the kind 1Cu_nucleosides can be included in a DNA double helix and how this situation affects the double-helical structure. The results indicate that the 1Cu_Cyt and 1Cu_Gua base pairs can be formed in a DNA molecule without significant structural constraints. In addition, the double-helix DNA structure remains virtually unchanged when it contains these Cu(II)-mediated base pairs.
Asunto(s)
Emparejamiento Base , Complejos de Coordinación/química , ADN/química , Complejos de Coordinación/síntesis química , Cobre/química , Cristalografía por Rayos X , Modelos Químicos , Estructura Molecular , Nucleósidos/síntesis química , Nucleósidos/químicaRESUMEN
Currently, there is increasing evidence linking diabetes mellitus (especially type 2 diabetes mellitus) with carcinogenesis through various biological processes, such as fat-induced chronic inflammation, hyperglycemia, hyperinsulinemia, and angiogenesis. Chemotherapeutic agents are used in the treatment of cancer, but in most cases, patients develop resistance. Phenformin, an oral biguanide drug used to treat type 2 diabetes mellitus, was removed from the market due to a high risk of fatal lactic acidosis. However, it has been shown that phenformin is, with other biguanides, an authentic tumor disruptor, not only by the production of hypoglycemia due to caloric restriction through AMP-activated protein kinase with energy detection (AMPK) but also as a blocker of the mTOR regulatory complex. Moreover, the addition of phenformin eliminates resistance to antiangiogenic tyrosine kinase inhibitors (TKI), which prevent the uncontrolled metabolism of glucose in tumor cells. In this review, we evidence the great potential of phenformin as an anticancer agent. We thoroughly review its mechanism of action and clinical trial assays, specially focusing on current challenges and future perspectives of this promising drug.
Asunto(s)
Antineoplásicos/farmacología , Fenformina/farmacología , Animales , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Fenformina/química , Factores de RiesgoRESUMEN
The intrinsic acid-base properties of the hexa-2'-deoxynucleoside pentaphosphate, d(ApGpGpCpCpT) [=(A1âG2âG3âC4âC5âT6)=(HNPP)5â»] have been determined by ¹H NMR shift experiments. The pKa values of the individual sites of the adenosine (A), guanosine (G), cytidine (C), and thymidine (T) residues were measured in water under single-strand conditions (i.e., 10% D2O, 47 °C, I=0.1 M, NaClO4). These results quantify the release of H⺠from the two (N7)H⺠(GâG), the two (N3)H⺠(CâC), and the (N1)H⺠(A) units, as well as from the two (N1)H (GâG) and the (N3)H (T) sites. Based on measurements with 2'-deoxynucleosides at 25 °C and 47 °C, they were transferred to pKa values valid in water at 25 °C and I=0.1 M. Intramolecular stacks between the nucleobases A1 and G2 as well as most likely also between G2 and G3 are formed. For HNPP three pKa clusters occur, that is those encompassing the pKa values of 2.44, 2.97, and 3.71 of G2(N7)Hâº, G3(N7)Hâº, and A1(N1)Hâº, respectively, with overlapping buffer regions. The tautomer populations were estimated, giving for the release of a single proton from five-fold protonated H5(HNPP)(±) , the tautomers (G2)N7, (G3)N7, and (A1)N1 with formation degrees of about 74, 22, and 4%, respectively. Tautomer distributions reveal pathways for proton-donating as well as for proton-accepting reactions both being expected to be fast and to occur practically at no "cost". The eight pKa values for H5(HNPP)(±) are compared with data for nucleosides and nucleotides, revealing that the nucleoside residues are in part affected very differently by their neighbors. In addition, the intrinsic acidity constants for the RNA derivative r(A1âG2âG3âC4âC5âU6), where U=uridine, were calculated. Finally, the effect of metal ions on the pKa values of nucleobase sites is briefly discussed because in this way deprotonation reactions can easily be shifted to the physiological pH range.
Asunto(s)
Aptámeros de Nucleótidos/química , Nucleósidos/química , Ácidos/química , Adenosina/química , Álcalis/química , Guanosina/química , Hexosaminidasa A , Concentración de Iones de Hidrógeno , Isomerismo , Espectroscopía de Resonancia Magnética , Metales/química , ARN/química , Timidina/química , Temperatura de TransiciónRESUMEN
7-Deaza-8-aza-adenine, namely 4-aminopyrazolo[3,4-d]pyrimidine (H4app), is a bioisoster of adenine (Hade) resulting from the translocation of N7 and C8 atoms on the purine moiety. With the aim of studying the influence of this translocation on the metal binding abilities of H4app, we have prepared and structurally characterized two ternary copper(II) complexes having H4app and one N-benzyl-iminodiacetate chelator (MEBIDA or FBIDA, with a methyl or fluoro group in para- of the benzyl aromatic ring): [Cu(2)(MEBIDA)(2)(µ(2)-N1,N8-H4app)(H(2)O)(2)]·4H(2)O (1) and [Cu(4)(FBIDA)(4)(µ(2)-N8,N9-H4app)(2)(H(2)O)]·3.5H(2)O (2). Furthermore, thermal, spectral, and magnetic properties have been also investigated. In 1, H(N9)4app is disordered over two equally pondered positions and the µ(2)-N1,N8 coordination mode is assisted by N6-H···O and N9-H···O intramolecular interactions, respectively. The acyclic nonlinear molecular topology of 2 is strongly influenced by two intramolecular H-bonding interactions (O-H···O-carboxylate) involving the apical aqua ligand of a terminal Cu(II) atom. Thus, both compounds have in common the Cu-N8 bond. In order to better understand our limited structural information, DFT calculations for the individual tautomers of H4app as well as mononuclear Cu(II) model systems have been carried out. According to previous results, we conclude that H(N9)4app is the most stable tautomer followed by H(N8)4app. When N9 and N8 are metalated, then the tautomer H(N1)4app can come into play as observed in compound 2. Likewise, the findings concerning compound 1 suggest that the formation of a Cu-N1 bond in H4app results was favored compared to neutral adenine, for which only one case has been reported with such coordination despite the large variety of related Cu(II)-Hade described in the literature.
Asunto(s)
Adenina/química , Cobre/química , Compuestos Organometálicos/química , Adenina/análogos & derivados , Modelos Moleculares , Estructura Molecular , Compuestos Organometálicos/síntesis química , Teoría CuánticaRESUMEN
According to the World Health Organization, more than 422 million people worldwide have diabetes. The most common oral treatment for type 2 diabetes is the drug metformin (MTF), which is usually formulated as a hydrochloride to achieve higher water solubility. However, this drug is also highly hygroscopic, thus showing stability problems. Another kind of worldwide prescribed drug is the non-steroidal anti-inflammatory drug (NSAID). These latter, on the contrary, show a low solubility profile; therefore, they must be administered at high doses, which increases the probability of secondary effects. In this work, novel drug-drug pharmaceutical solids combining MTF-NSAIDs have been synthesized in solution or by mechanochemical methods. The aim of this concomitant treatment is to improve the physicochemical properties of the parent active pharmaceutical ingredients. After a careful solid-state characterization along with solubility and stability studies, it can be concluded that the new molecular salt formulations enhance not only the stability of MTF but also the solubility of NSAIDs, thus giving promising results regarding the development of these novel pharmaceutical multicomponent solids.
RESUMEN
Pharmaceutical multicomponent solids have proved to efficiently modulate the physicochemical properties of active pharmaceutical ingredients. In this context, polyphenols are interesting coformers for designing pharmaceutical cocrystals due to their wide safety profile and interesting antioxidant properties. The novel 6-propyl-2-thiouracil multicomponent solids have been obtained by mechanochemical synthesis and fully characterized by powder and single-crystal X-ray diffraction methods. The analysis of supramolecular synthons has been further performed with computational methods, with both results revealing a robust supramolecular organization influenced by the different positions of the hydroxyl groups within the polyphenolic coformers. All novel 6-propyl-2-thiouracil cocrystals show an enhanced solubility profile, but unfortunately, their thermodynamic stability in aqueous media is limited to 24 h.
RESUMEN
The X-ray diffraction structural results of 23 ternary compounds, type M(II)(iminodiacetate-like)(hypoxanthine) [M = Co, Ni, Cu, or Zn], show that the iminodiacetate moiety conformation (mer-NO(2) or fac-NO(2)) is able to drive the M-hypoxanthine binding patterns displaying the M-N9 or M-N3 bond, cooperating with a N9-H···O intramolecular interaction, respectively.
Asunto(s)
Quelantes/química , Química Orgánica/métodos , Hipoxantina/química , Metales/química , Quelantes/metabolismo , Cristalografía por Rayos X , Hipoxantina/metabolismo , Ligandos , Metales/metabolismo , Modelos Moleculares , Conformación MolecularRESUMEN
The synthetic nucleoside acyclovir is considered an outstanding model of the natural nucleoside guanosine. With the purpose of deepening on the influence and nature of non-covalent interactions regarding molecular recognition patterns, three novel Cu(II) complexes, involving acyclovir (acv) and the ligand receptor N-(2-hydroxyethyl)ethylenediamine (hen), have been synthesized and thoroughly characterized. The three novel compounds introduce none, one or two acyclovir molecules, respectively. Molecular recognition has been evaluated using single crystal X-ray diffraction. Furthermore, theoretical calculations and other physical methods such as thermogravimetric analysis, infrared and UV-Vis spectroscopy, electron paramagnetic resonance and magnetic measurements have been used. Theoretical calculations are in line with experimental results, supporting the relevance of the [metal-N7(acv) + H-bond] molecular recognition pattern. It was also shown that (hen)O-H group is used as preferred H-donor when it is found within the basal coordination plane, since the higher polarity of the terminal (hen)O-H versus the N-H group favours its implication. Otherwise, when (hen)O-H occupies the distal coordination site, (hen)N-H groups can take over.
RESUMEN
Any time the pharmaceutical industry develops a new drug, potential polymorphic events must be thoroughly described, because in a crystalline pharmaceutical solid, different arrangements of the same active pharmaceutical ingredient can yield to very different physicochemical properties that might be crucial for its efficacy, such as dissolution, solubility, or stability. Polymorphism in cocrystal formulation cannot be neglected, either. In this work, two different cocrystal polymorphs of the non-steroidal anti-inflammatory drug niflumic acid and caffeine are reported. They have been synthesized by mechanochemical methods and thoroughly characterized in solid-state by powder and single crystal X-ray diffraction respectively, as well as other techniques such as thermal analyses, infrared spectroscopy and computational methods. Both theoretical and experimental results are in agreement, confirming a conformational polymorphism. The polymorph NIF-CAF Form I exhibits improved solubility and dissolution rate compared to NIF-CAF Form II, although Form II is significantly more stable than Form I. The conditions needed to obtain these polymorphs and their transition have been carefully characterized, revealing an intricate system.
RESUMEN
Four ternary metal-complexes with Cu(II) or Zn(II), 2,6-pyridine-dicarboxylate (pdc) or glycyl-glycinate (GG) and the synthetic nucleoside 9-(2-hydroxyethyl)adenine (9heade) have been synthesized and studied by single-crystal X-ray diffraction and other physical methods. Relevant supramolecular assemblies found in the solid state structures have been further studied using density functional theory (DFT) calculations. In addition, the energetic features of the non-covalent interactions as well as the cooperativity effects have been calculated and characterized using the non-covalent interaction plot computational tool. Compounds trans-[Cu(pdc)(9heade)(H2O)2]·3H2O (1a) and [Cu(pdc)(9heade)(H2O)]·H2O (1b), trans-[Zn(pdc)(9heade)(H2O)2] (2), share the same molecular recognition pattern consisting in the cooperation of the metal-N7(9heade) bond and an interligand (9heade)N6-H···O(pdc) interaction, regardless of the nature of the metal, the coordination environment and the water content. At a supramolecular level, these compounds exhibit pairs of complex molecules linked by H-bonds and interesting anion-π/π-π/π-anion assemblies (in 1a and 1b) or the unprecedented π-π interactions (in 2), involving the purine moieties or the exocyclic -6NH2 purine groups, respectively. Compound 3, {[Cu(GG)(9heade)(H2O)·Cu(GG)(µ2-9heade)]·8H2O}n, consists in asymmetric dinuclear complex units (Cu···Cu 7.83â¯Å) that connect with adjacent ones by pairs of very weak Cu-O(carboxylate) bonds (Cu···Cu 3.81â¯Å) building a polymeric chain. The supramolecular transition from a single molecule to dinuclear units and finally a polymeric chain is also observed in the electron paramagnetic resonance spectra and discussed from a structural point of view as well as by DFT calculations. The unprecedented N7 and µ-N7,O(ol) metal binding patterns of 9heade differs from that recently reported (µ-N1,N7) in a Cd(II) polymer.
Asunto(s)
Adenosina/química , Quelantes/síntesis química , Complejos de Coordinación/síntesis química , Cobre/química , Compuestos Organometálicos/síntesis química , Zinc/químicaRESUMEN
Zn(II) is an inhibitor of SARS-CoV-2's RNA-dependent RNA polymerase, and chloroquine and hydroxychloroquine are Zn(II) ionophores-this statement gives a curious mind a lot to think about. We show results of the first clinical trials on chloroquine (CQ) and hydroxychloroquine (HCQ) in the treatment of COVID-19, as well as earlier reports on the anticoronaviral properties of these two compounds and of Zn(II) itself. Other FDA-approved Zn(II) ionophores are given a decent amount of attention and are thought of as possible COVID-19 therapeutics.
RESUMEN
The study of the metal binding pattern of N-methyladenines (1-, 3-, 7- or 9-Meade) towards CuII-iminodiacetate-like chelates is addressed on the basis of XRD crystal structures of sixteen novel ternary compounds. Except for three compounds, all others feature an square-based Cu(II) coordination, type 4â¯+â¯1, and the efficient cooperation of a CuN7 bond with an intra-molecular N6-Hâ¯O(coord. carboxylate) interligand interaction as the major metal-binding pattern. The three referred exceptions to this behavior are: (1) the compound [Cu(MIDA)(7Meade)(H2O)]·4H2O, which evidence the CuN3 binding pattern; the (2) [Cu(IDA)(1Meade)(H2O)2]·4H2O, which molecular recognition consist in the CuN9 bond and a (distal aqua)â¯â¯N3(1Meade) intra-molecular interaction, within an octahedral Cu(II) center; and (3) [Cu(IDA)(9Meade)(H2O)2]·3H2O, also with a 4â¯+â¯1â¯+â¯1 Cu(II) coordination, where the CuN7 bond exists along with an extremely weak N6-Hâ¯O(coord. carboxylate) interaction (3.33â¯Å, 140.2°). This former interaction is determined by packing forces that promote the participation of the N6H group in a 'trifurcated' H-bond. In conclusion, the cooperation between the CuN7 bond (not possible for 7Meade) and the intra-molecular N6-Hâ¯O interaction is clearly favored (a) by the H-accepting role of the O-coordinated carboxylate atoms from the iminodiacetate ligands in mer-NO2 conformation and (b) in compounds where the Cu(II) atom exhibits an elongated square-base pyramidal coordination, type 4â¯+â¯1.
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Adenina/química , Complejos de Coordinación/química , Cobre/química , AlquilaciónRESUMEN
A comprehensive study of the protonation equilibria of a series of polyamine ligands along with their complex formation equilibria with Cu2+ and Zn2+ is reported in this work. The primary aim of this study has been the achievement of homogeneous thermodynamic data on these ligands, in order to evaluate their influence on the homeostatic equilibria of essential metal ions (Cu2+ and Zn2+) in biological fluids. These polyamines are largely used as linkers in the building of chelating agents for iron overload. Potentiometric and spectrophotometric techniques were used for the characterization of protonation and complex formation constants. In addition, the characterization of the formed complexes is discussed together with selected solid-state crystal structures, remarking the influence of the length of the chain and of the linear or tetradentate tripod nature of the polyamine ligands on the stability of the complexes.
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Quelantes/química , Complejos de Coordinación/química , Cobre/química , Poliaminas/química , Zinc/química , Ligandos , Protones , TermodinámicaAsunto(s)
Química Bioinorgánica , Complejos de Coordinación , Antineoplásicos , Antioxidantes , ADN , Nanoestructuras , EspañaRESUMEN
Several nucleic acid components and their metal complexes are known to be involved in crucial metabolic steps. Therefore the study of metal-nucleic acid interactions becomes essential to understand these biological processes. In this work, the synthetic purine-like nucleoside acyclovir (acv) has been used as a model of guanosine recognition with copper(II)-polyamine chelates. The chemical stability of the N9-acyclic arm in acv offers the possibility to use this antiviral drug to deepen the knowledge of metal-nucleoside interactions. Cu(II) chelates with cyclam, cyclen and trien were used as suitable receptors. All these copper(II) tetraamine chelates have in common the potential ability to yield a Cu-N7(apical) bond assisted by an appropriate (amine)N-Hâ¯O6(acv) intra-molecular interligand interaction. A series of synthesis afforded the following compounds: [Cu(cyclam)(ClO4)2] (1), {[Cu(cyclam)(µ2-NO3)](NO3)}n (2), {[Cu(cyclam)(µ2-SO4)]·MeOH}n (3), {[Cu(cyclam)(µ2-SO4)]·5H2O}n (4), [Cu(cyclen)(H2O)]SO4·2H2O (5), [Cu(cyclen)(H2O)]SO4·3H2O (6), [Cu(trien)(acv)](NO3)2·acv (7) and [Cu(trien)(acv)]SO4·0.71H2O (8). All these compounds have been characterized by X-ray crystallography and FT-IR spectroscopy. Our results reveal that the macrochelates Cu(cyclen)(2+) and Cu(cyclam)(2+) are unable to bind acv at an apical site. In contrast, the Cu(trien)(2+) complex has proved to be an efficient receptor for acv in compounds (7) and (8). In the ternary complex [Cu(trien)(acv)](2+), the metal binding pattern of acv consists of an apical Cu-N7 bond assisted by an intra-molecular (primary amino)N-Hâ¯O6(acv) interligand interaction. Structural comparisons reveal that this unprecedented apical role of acv is due to the acyclic nature of trien together with the ability of the Cu(trien)(2+) chelate to generate five-coordinated (type 4+1) copper(II) complexes.
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Aciclovir/química , Complejos de Coordinación/química , Cobre/química , Poliaminas/química , Aciclovir/metabolismo , Antivirales/química , Antivirales/metabolismo , Quelantes/química , Quelantes/metabolismo , Complejos de Coordinación/metabolismo , Cobre/metabolismo , Cristalografía por Rayos X , Ciclamas , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/metabolismo , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Nucleósidos/química , Nucleósidos/metabolismo , Poliaminas/metabolismo , Purinas/química , Purinas/metabolismo , Espectroscopía Infrarroja por Transformada de Fourier , Termogravimetría , Trientina/química , Trientina/metabolismoRESUMEN
Five novel ternary copper(II) complexes with the N,O2,S-tripodal tetradentate chelators N,N-bis(carboxymethyl)-S-benzylcysteaminate(2-) ion (BCBC) or N,N,N',N'-tetrakis(carboxymethyl)cystaminate(4-) ion (TCC) and adenine (Hade), 2,6-diaminopurine (Hdap), 2,2'-bipyridine (bpy) or 1,10-phenanthroline (phen) as co-ligand were synthesized and characterized by X-ray diffraction and other physical methods: [Cu2(BCBC)2(µ2-N3,N7-H(N9)ade)(H2O)2]·H2O (1), [Cu2(BCBC)2(µ2-N7,N9-H(N3)dap)(H2O)2]·4H2O (2), [Cu2(µ2-TCC)(H(N9)ade)2(H2O)2]·10H2O (3), [Cu2(µ2-TCC)(bpy)2]·15H2O (4) and [Cu2(µ2-TCC)(phen)2]·14H2O (5). The crystal structure of H4TCC·3H2O was also determined. All ternary Cu(II) complexes have molecular structures. The N-(2-mercaptoethyl)-iminodiacetate moieties of BCBC or TCC ligands play a NO2+S-tripodal tetradentate role, with the S-(thioether or disulfide) atom as the apical/distal donor of the copper(II) center. In 1-3, the iminodiacetate moiety exhibits a mer-NO2 conformation (two nearly coplanar chelate rings) while in 4 and 5 (with bpy or phen as coligand) it displays a fac-NO+O (apical/distal) conformation. We conclude that the formation of the Cu-S(thioether or disulfide) bonds is strongly favored by the N-branched topology of the S-ligands in the reported compounds.
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2-Aminopurina/análogos & derivados , Adenina/metabolismo , Quelantes/química , Cobre/metabolismo , Disulfuros/química , Sulfuros/química , 2-Aminopurina/química , 2-Aminopurina/metabolismo , Adenina/química , Cobre/química , Cristalografía por Rayos X , Estructura Molecular , Nitrógeno/química , Oxígeno/química , Azufre/químicaRESUMEN
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.
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Aluminio/química , Quelantes/química , Quelantes/farmacología , Animales , Quelantes/síntesis química , Quelantes/farmacocinética , Técnicas de Química Sintética , Femenino , Radioisótopos de Galio/farmacocinética , Ligandos , Espectroscopía de Resonancia Magnética , Ratones , Estructura Molecular , Pironas/química , Espectrometría de Masa por Ionización de Electrospray , Distribución TisularRESUMEN
This work reports the synthesis, characterization and study of complex formation equilibria of the new ligand 6,6'-(2-(diethylamino)ethylazanediyl)bis(methylene)bis(5-hydroxy-2-hydroxymethyl-4H-pyran-4-one) with Fe(III), Al(III), Cu(II) and Zn(II). On the basis of previous encouraging results with tetradentate bis-kojic acid chelators, this ligand was designed to improve the pharmacokinetic properties: increase the solubility, neutral at physiological pH7.4, and enhancement of membrane crossing ability. Fe(III) and Al(III) complexation gave evidence of high metal-sequestering capacity of L9. Cellular assays showed that the ligand is capable of crossing cellular membranes and it does not present toxic effects. Complex formation equilibria with the essential metal ions Cu(II) and Zn(II) have been furthermore studied to evaluate disturbances of this chelator on the homeostatic equilibria of these essential metal ions. A variety of techniques (potentiometry, UV-visible spectrophotometry, 1D and 2D NMR spectroscopy, ESI-MS (electrospray ionization-mass spectrometry), quantum mechanical calculations and X-ray diffraction) have facilitated the characterization of the ligand, and the corresponding iron and zinc complexes, together with an exhaustive analysis of the protonation and complex equilibria.