Complejos de ligandos azamacrocíclicos como miméticos de enzimas con actividad antioxidante

The imbalance between the generation and clearance of reactive oxygen species (ROS) causes oxidative stress, which is related to a variety of health issues that include neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease. In order to remove ROS, living organisms have developed a battery of protective enzymes, such as superoxide dismutases (SODs). Although SOD enzymes have shown therapeutic efficacy, their use has severe drawbacks such as the absence of oral activity, immunogenicity, short half-life and low cell permeability. Therefore, low-molecular weight mimetics may offer better outcomes regarding properties such as lack of antigenicity, good tissue penetrance, high stability, longer half-life in solution, and low production cost. A number of these low molecular SOD mimetics are complexes of polyamine ligands of either cyclic or open-chain topology. In this respect, it has been reported that several mononuclear or binuclear copper complexes of aza- macrocyclic ligands have SOD activities in vitro which rank among the highest ones so far reported for synthetic systems. A step forward to improve the activity, the likely-cell uptake and bio-distribution of these low molecular weight mimetics might be their incorporation in non-toxic nanoparticles (NPs). The grafting of the molecules to the surface of the nanoparticles may yield pre-concentration and amplification of the signal. The work here we present deals with the design, synthesis and study of seven new aza-macrocyclic ligands. The design of the ligands is based on the modification of the fundamental tetraazamacrocycle through three main ways: alkylation of the secondary amines, introduction of new functional groups in the pyridine derivative and elongation of the aza-macrocyclic moiety. In this thesis, we report the synthesis and characterization of the aforementioned seven new compounds, as well as the functionalization of four of them onto the surface of boehmite and silica NPs. Additionally, here we discuss on the acid base behavior of the ligands, and on their capability to coordinate Cu(II), Zn(II) and/or Fe(II), particularly at physiological pH. Finally, we present the SOD and catalase activity results of the studied complexes, both free in solution and grafted onto the surface of the NPs. Regarding the results, we should notice that all the studied ligands are capable to coordinate Cu(II), Zn(II) and/or Fe(II) in a quantitative way at physiological pH. Furthermore, the Cu(II) complexes present SOD activity, which is improved with the alkylation of the secondary amines, the addition of electron-withdrawing groups in para to the pyridinic moiety and the increase of the amount of coordinating amines in the macrocyclic chain. In addition, functionalization of the complexes onto the surface of boehmite NPs impressively enhance their SOD activity, what may be related with its positively charged surface, as we show in the last chapter of the thesis

Synchronous occurrence of IgG4-related sialadenitis and ductal carcinoma of the parotid gland a case report

Immunoglobulin G4-related disease (IgG4-RD) is a rare chronic systemic inflammatory pathology that poses a diagnostic challenge since it can simulate malignancy when it affects a salivary gland as a mass-like lesion. Here, the authors report an unusual clinical case of a 42-year-old man who presented with a painless, slow-growing swelling located in the right parotid gland with a 12-month evolution. Based on imaging tests and open biopsy, a diagnosis of chronic parotitis was presumed and oral methylprednisolone was prescribed. Due to poor response to medication, a total parotidectomy preserving the facial nerve was performed. The final pathology described a unilateral IgG4-related sialadenitis (IgG4-RS) in the parotid gland in combination with a poorly differentiated multifocal ductal carcinoma. The postoperative course was uneventful except for a temporary facial paresis (grade III according to the House-Brackmann classification system) that resolved completely within 5 months. There were no systemic manifestations on the whole-body 18F-FDG PET/CT. Adjuvant radiotherapy was administered without complications. Twenty-four months follow-up after surgery showed no recurrence or evidence of systemic involvement. This clinical report highlights the importance of considering the synchronous occurrence of a carcinoma underlying an isolated parotid gland mass in the context of IgG4-RS, especially if there is no response to prior steroid medication

Assembly of Polyiodide Networks with Cu(II) Complexes of Pyridinol-Based Tetraaza Macrocycles

Polyiodide networks are currently of great practical interest for the preparation of new electronic materials. The participation of metals in the formation of these networks is believed to improve their mechanical performance and thermal stability. Here we report the results on the construction of polyiodide networks obtained using Cu(II) complexes of a series of pyridinol-based tetraazacyclophanes as countercations. The assembly of these crystalline polyiodides takes place from aqueous solutions on the basis of similar structural elements, the [CuL]2+ and [Cu(H-1L)]+ (L = L2, L2-Me, L2-Me3) complex cations, so that the peculiarities induced by the increase of N-methylation of ligands, the structural variable of ligands, can be highlighted. First, solution equilibria involving ligands and complexes were analyzed (potentiometry, NMR, UV-vis, ITC). Then, the appropriate conditions could be selected to prepare polyiodides based on the above complex cations. Single-crystal XRD analysis showed that the coordination of pyridinol units to two metal ions is a prime feature of these ligands, leading to polymeric coordination chains of general formula {[Cu(H-1L)]}nn+ (L = L2-Me, L2-Me3). In the presence of the I-/I2 couple, the polymerization tendency stops with the formation of [(CuL)(CuH-1L)]3+ (L = L2-Me, L2-Me3) dimers which are surrounded by polyiodide networks. Moreover, coordination of the pyridinol group to two metal ions transforms the surface charge of the ring from negative to markedly positive, generating a suitable environment for the assembly of polyiodide anions, while N-methylation shifts the directional control of the assembly from H-bonds to I···I interactions. In fact, an extended concatenation of iodine atoms occurs around the complex dimeric cations, the supramolecular I···I interactions become shorter and shorter, fading into stronger forces dominated by the orbital overlap, which is promising for effective electronic materials

Enhancement of SOD activity in boehmite supported nanoreceptors

The binuclear Cu2+ complex of a pyridinophane polyamine ligand ranking amongst the fastest SOD mimetics so far reported displays a remarkable SOD activity enhancement when grafted to the surface of boehmite (γ-AlO(OH)) nanoparticles (BNPs)

Ditopic Aza-Scorpiand Ligands Interact Selectively with ds-RNA and Modulate the Interaction upon Formation of Zn2+ Complexes

Nucleic acids are essential biomolecules in living systems and represent one of the main targets of chemists, biophysics, biologists, and nanotechnologists. New small molecules are continuously developed to target the duplex (ds) structure of DNA and, most recently, RNA to be used as therapeutics and/or biological tools. Stimuli-triggered systems can promote and hamper the interaction to biomolecules through external stimuli such as light and metal coordination. In this work, we report on the interaction with ds-DNA and ds-RNA of two aza-macrocycles able to coordinate Zn2+ metal ions and form binuclear complexes. The interaction of the aza-macrocycles and the Zn2+ metal complexes with duplex DNA and RNA was studied using UV thermal and fluorescence indicator displacement assays in combination with theoretical studies. Both ligands show a high affinity for ds-DNA/RNA and selectivity for ds-RNA. The ability to interact with these duplexes is blocked upon Zn2+ coordination, which was confirmed by the low variation in the melting temperature and poor displacement of the fluorescent dye from the ds-DNA/RNA. Cell viability assays show a decrease in the cytotoxicity of the metal complexes in comparison with the free ligands, which can be associated with the observed binding to the nucleic acids

Inhibitory Effect of Azamacrocyclic Ligands on Polyphenol Oxidase in Model and Food Systems

This document is the unedited Author's version of a Submitted Work that was subsequently accepted for publication in Journal of Agricultural and Food Chemistry, copyright © American Chemical Society after peer review. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jafc.0c02407[EN] Enzymatic browning is one of the main problems faced by the food industry due to the enzyme polyphenol oxidase (PPO) provoking an undesirable color change in the presence of oxygen. Here, we report the evaluation of 10 different azamacrocyclic compounds with diverse morphologies as potential inhibitors against the activity of PPO, both in model and real systems. An initial screening of 10 ligands shows that all azamacrocyclic compounds inhibit to some extent the enzymatic browning, but the molecular structure plays a crucial role on the power of inhibition. Kinetic studies of the most active ligand (L2) reveal a S-parabolic I-parabolic noncompetitive inhibition mechanism and a remarkable inhibition at micromolar concentration (IC50 = 10 mu M). Furthermore, L2 action has been proven on apple juice to significantly reduce the enzymatic browning.Financial support by the Spanish Ministerio de Ciencia, Innovacion y Universidades (project RTI2018-100910-B-C44), Ministerio de Economia y Competitividad (projects CTQ2016-78499-C6-1-R, Unidad de Excelencia MDM 2015-0038 and CTQ2017-90852-REDC), and Generalitat Valenciana (Project PROMETEOII2015-002) is gratefully acknowledged.Muñoz-Pina, S.; Ros-Lis, JV.; Delgado-Pinar, E.; Martínez-Camarena, Á.; Verdejo, B.; García-España, E.; Argüelles Foix, AL.... (2020). Inhibitory Effect of Azamacrocyclic Ligands on Polyphenol Oxidase in Model and Food Systems. Journal of Agricultural and Food Chemistry. 68(30):7964-7973. https://doi.org/10.1021/acs.jafc.0c02407796479736830Simpson, B. K. (Ed.). (2012). Food Biochemistry and Food Processing. doi:10.1002/9781118308035İyidoǧan, N. F., & Bayındırlı, A. (2004). Effect of l-cysteine, kojic acid and 4-hexylresorcinol combination on inhibition of enzymatic browning in Amasya apple juice. Journal of Food Engineering, 62(3), 299-304. doi:10.1016/s0260-8774(03)00243-7Croguennec, T. (2016). Enzymatic Browning. Handbook of Food Science and Technology 1, 159-181. doi:10.1002/9781119268659.ch6Brütsch, L., Rugiero, S., Serrano, S. S., Städeli, C., Windhab, E. J., Fischer, P., & Kuster, S. (2018). Targeted Inhibition of Enzymatic Browning in Wheat Pastry Dough. Journal of Agricultural and Food Chemistry, 66(46), 12353-12360. doi:10.1021/acs.jafc.8b04477Ma, L., Zhang, M., Bhandari, B., & Gao, Z. (2017). Recent developments in novel shelf life extension technologies of fresh-cut fruits and vegetables. Trends in Food Science & Technology, 64, 23-38. doi:10.1016/j.tifs.2017.03.005Queiroz, C., Mendes Lopes, M. L., Fialho, E., & Valente-Mesquita, V. L. (2008). Polyphenol Oxidase: Characteristics and Mechanisms of Browning Control. Food Reviews International, 24(4), 361-375. doi:10.1080/87559120802089332Seo, S.-Y., Sharma, V. K., & Sharma, N. (2003). Mushroom Tyrosinase:  Recent Prospects. Journal of Agricultural and Food Chemistry, 51(10), 2837-2853. doi:10.1021/jf020826fTRONC, J.-S., LAMARCHE, F., & MAKHLOUF, J. (1997). Enzymatic Browning Inhibition in Cloudy Apple Juice by Electrodialysis. Journal of Food Science, 62(1), 75-78. doi:10.1111/j.1365-2621.1997.tb04371.xJiang, S., & Penner, M. H. (2019). The nature of β-cyclodextrin inhibition of potato polyphenol oxidase-catalyzed reactions. Food Chemistry, 298, 125004. doi:10.1016/j.foodchem.2019.125004Buckow, R., Kastell, A., Terefe, N. S., & Versteeg, C. (2010). Pressure and Temperature Effects on Degradation Kinetics and Storage Stability of Total Anthocyanins in Blueberry Juice. Journal of Agricultural and Food Chemistry, 58(18), 10076-10084. doi:10.1021/jf1015347Massini, L., Rico, D., & Martin-Diana, A. B. (2018). Quality Attributes of Apple Juice. Fruit Juices, 45-57. doi:10.1016/b978-0-12-802230-6.00004-7McEvily, A. J., Iyengar, R., & Otwell, W. S. (1992). Inhibition of enzymatic browning in foods and beverages. Critical Reviews in Food Science and Nutrition, 32(3), 253-273. doi:10.1080/10408399209527599Iyengar, R., & McEvily, A. J. (1992). Anti-browning agents: alternatives to the use of sulfites in foods. Trends in Food Science & Technology, 3, 60-64. doi:10.1016/0924-2244(92)90131-fMuñoz-Pina, S., Ros-Lis, J. V., Argüelles, Á., Coll, C., Martínez-Máñez, R., & Andrés, A. (2018). Full inhibition of enzymatic browning in the presence of thiol-functionalised silica nanomaterial. Food Chemistry, 241, 199-205. doi:10.1016/j.foodchem.2017.08.059Muñoz-Pina, S., Ros-Lis, J. V., Argüelles, Á., Martínez-Máñez, R., & Andrés, A. (2020). Influence of the functionalisation of mesoporous silica material UVM-7 on polyphenol oxidase enzyme capture and enzymatic browning. Food Chemistry, 310, 125741. doi:10.1016/j.foodchem.2019.125741Castillo, C. E., Máñez, M. A., Basallote, M. G., Clares, M. P., Blasco, S., & García-España, E. (2012). Copper(ii) complexes of quinoline polyazamacrocyclic scorpiand-type ligands: X-ray, equilibrium and kinetic studies. Dalton Transactions, 41(18), 5617. doi:10.1039/c2dt30223cSantra, S., Mukherjee, S., Bej, S., Saha, S., & Ghosh, P. (2015). Amino-ether macrocycle that forms CuII templated threaded heteroleptic complexes: a detailed selectivity, structural and theoretical investigations. Dalton Transactions, 44(34), 15198-15211. doi:10.1039/c5dt00596eFan, R., Serrano-Plana, J., Oloo, W. N., Draksharapu, A., Delgado-Pinar, E., Company, A., … Münck, E. (2018). Spectroscopic and DFT Characterization of a Highly Reactive Nonheme FeV–Oxo Intermediate. Journal of the American Chemical Society, 140(11), 3916-3928. doi:10.1021/jacs.7b11400Martínez-Camarena, Á., Liberato, A., Delgado-Pinar, E., Algarra, A. G., Pitarch-Jarque, J., Llinares, J. M., … García-España, E. (2018). Coordination Chemistry of Cu2+ Complexes of Small N-Alkylated Tetra-azacyclophanes with SOD Activity. Inorganic Chemistry, 57(17), 10961-10973. doi:10.1021/acs.inorgchem.8b01492Algarra, A. G., Basallote, M. G., Belda, R., Blasco, S., Castillo, C. E., Llinares, J. M., … Verdejo, B. (2009). Synthesis, Protonation and CuIIComplexes of Two Novel Isomeric Pentaazacyclophane Ligands: Potentiometric, DFT, Kinetic and AMP Recognition Studies. European Journal of Inorganic Chemistry, 2009(1), 62-75. doi:10.1002/ejic.200800576Díaz, P., Basallote, M. G., Máñez, M. A., García-España, E., Gil, L., Latorre, J., … Luis, S. V. (2003). Thermodynamic and kinetic studies on the Cu2+ coordination chemistry of a novel binucleating pyridinophane ligandElectronic supplementary information (ESI) available: Table S1: observed rate constants for the acid-promoted decomposition of Cu2+ complexes with ligand L. Table S2: observed rate constants for the acid-promoted decomposition of Cu2+ complexes with macrocycle L1. Fig. S1: Variation of some selected 13C chemical shifts as a function of pH. See http://www.rsc.org/suppdata/dt/b2/b209013a/. Dalton Transactions, (6), 1186-1193. doi:10.1039/b209013aBasallote, M. G., Doménech, A., Ferrer, A., García-España, E., Llinares, J. M., Máñez, M. A., … Verdejo, B. (2006). Synthesis and Cu(II) coordination of two new hexaamines containing alternated propylenic and ethylenic chains: Kinetic studies on pH-driven metal ion slippage movements. Inorganica Chimica Acta, 359(7), 2004-2014. doi:10.1016/j.ica.2006.01.030Acosta-Rueda, L., Delgado-Pinar, E., Pitarch-Jarque, J., Rodríguez, A., Blasco, S., González, J., … García-España, E. (2015). Correlation between the molecular structure and the kinetics of decomposition of azamacrocyclic copper(ii) complexes. Dalton Transactions, 44(17), 8255-8266. doi:10.1039/c5dt00408jAlarcón, J., Albelda, M. T., Belda, R., Clares, M. P., Delgado-Pinar, E., Frías, J. C., … Soriano, C. (2008). Synthesis and coordination properties of an azamacrocyclic Zn(II) chemosensor containing pendent methylnaphthyl groups. Dalton Transactions, (46), 6530. doi:10.1039/b808993kClares, M. P., Aguilar, J., Aucejo, R., Lodeiro, C., Albelda, M. T., Pina, F., … García-España, E. (2004). Synthesis and H+, Cu2+, and Zn2+Coordination Behavior of a Bis(fluorophoric) Bibrachial Lariat Aza-Crown. Inorganic Chemistry, 43(19), 6114-6122. doi:10.1021/ic049694tSiddiq, M., & Dolan, K. D. (2017). 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Recent Developments in the Stereoselective Synthesis of Nitrogen-Containing Heterocycles usingN-Acylimines as Reactive Substrates. Advanced Synthesis & Catalysis, 358(23), 3657-3682. doi:10.1002/adsc.201600644Liu, W., Zou, L., Liu, J., Zhang, Z., Liu, C., & Liang, R. (2013). The effect of citric acid on the activity, thermodynamics and conformation of mushroom polyphenoloxidase. Food Chemistry, 140(1-2), 289-295. doi:10.1016/j.foodchem.2013.02.028Son, S. M., Moon, K. D., & Lee, C. Y. (2000). Kinetic Study of Oxalic Acid Inhibition on Enzymatic Browning. Journal of Agricultural and Food Chemistry, 48(6), 2071-2074. doi:10.1021/jf991397xÖZ, F., COLAK, A., ÖZEL, A., SAĞLAM ERTUNGA, N., & SESLI, E. (2011). PURIFICATION AND CHARACTERIZATION OF A MUSHROOM POLYPHENOL OXIDASE AND ITS ACTIVITY IN ORGANIC SOLVENTS. Journal of Food Biochemistry, 37(1), 36-44. doi:10.1111/j.1745-4514.2011.00604.xAyaz, F. A., Demir, O., Torun, H., Kolcuoglu, Y., & Colak, A. (2008). Characterization of polyphenoloxidase (PPO) and total phenolic contents in medlar (Mespilus germanica L.) fruit during ripening and over ripening. Food Chemistry, 106(1), 291-298. doi:10.1016/j.foodchem.2007.05.096Qin, X.-Y., Lee, J., Zheng, L., Yang, J.-M., Gong, Y., & Park, Y.-D. (2018). Inhibition of α-glucosidase by 2-thiobarbituric acid: Molecular dynamics simulation integrating parabolic noncompetitive inhibition kinetics. Process Biochemistry, 65, 62-70. doi:10.1016/j.procbio.2017.10.016Chakrabarty, S. P., Ramapanicker, R., Mishra, R., Chandrasekaran, S., & Balaram, H. (2009). Development and characterization of lysine based tripeptide analogues as inhibitors of Sir2 activity. Bioorganic & Medicinal Chemistry, 17(23), 8060-8072. doi:10.1016/j.bmc.2009.10.003Gou, L., Lee, J., Yang, J.-M., Park, Y.-D., Zhou, H.-M., Zhan, Y., & Lü, Z.-R. (2017). Inhibition of tyrosinase by fumaric acid: Integration of inhibition kinetics with computational docking simulations. International Journal of Biological Macromolecules, 105, 1663-1669. doi:10.1016/j.ijbiomac.2016.12.013Tang, H., Cui, F., Li, H., Huang, Q., & Li, Y. (2018). Understanding the inhibitory mechanism of tea polyphenols against tyrosinase using fluorescence spectroscopy, cyclic voltammetry, oximetry, and molecular simulations. RSC Advances, 8(15), 8310-8318. doi:10.1039/c7ra12749aDewey, T. G. (Ed.). (1991). Biophysical and Biochemical Aspects of Fluorescence Spectroscopy. doi:10.1007/978-1-4757-9513-4Gou, L., Lee, J., Hao, H., Park, Y.-D., Zhan, Y., & Lü, Z.-R. (2017). The effect of oxaloacetic acid on tyrosinase activity and structure: Integration of inhibition kinetics with docking simulation. International Journal of Biological Macromolecules, 101, 59-66. doi:10.1016/j.ijbiomac.2017.03.07

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Characterization of a Ferryl Flip in Electronically Tuned Nonheme Complexes. Consequences in Hydrogen Atom Transfer Reactivity

Two oxoiron(IV) isomers (R2a and R2b) of general formula [FeIV(O)(RPyNMe3)(CH3CN)]2+ are obtained by reaction of their iron(II) precursor with NBu4IO4. The two isomers differ in the position of the oxo ligand, cis and trans to the pyridine donor. The mechanism of isomerization between R2a and R2b has been determined by kinetic and computational analyses uncovering an unprecedented path for interconversion of geometrical oxoiron(IV) isomers. The activity of the two oxoiron(IV) isomers in hydrogen atom transfer (HAT) reactions shows that R2a reacts one order of magnitude faster than R2b, which is explained by a repulsive noncovalent interaction between the ligand and the substrate in R2b. Interestingly, the electronic properties of the R substituent in the ligand pyridine ring do not have a significant effect on reaction rates. Overall, the intrinsic structural aspects of each isomer define their relative HAT reactivity, overcoming changes in electronic properties of the ligand.10 página

Characterization of a Ferryl Flip in Electronically Tuned Nonheme Complexes. Consequences in Hydrogen Atom Transfer Reactivity

Two oxoiron(IV) isomers (R2a and R2b) of general formula [FeIV(O)(RPyNMe3)(CH3CN)]2+ are obtained by reaction of their iron(II) precursor with NBu4IO4. The two isomers differ in the position of the oxo ligand, cis and trans to the pyridine donor. The mechanism of isomerization between R2a and R2b has been determined by kinetic and computational analyses uncovering an unprecedented path for interconversion of geometrical oxoiron(IV) isomers. The activity of the two oxoiron(IV) isomers in hydrogen atom transfer (HAT) reactions shows that R2a reacts one order of magnitude faster than R2b, which is explained by a repulsive noncovalent interaction between the ligand and the substrate in R2b. Interestingly, the electronic properties of the R substituent in the ligand pyridine ring do not have a significant effect on reaction rates. Overall, the intrinsic structural aspects of each isomer define their relative HAT reactivity, overcoming changes in electronic properties of the ligand

Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic