Publications > García-Marín et al

J Comput Aided Mol Des. 2022, 36, 575 PubMed 35869378

Insight into the mechanism of molecular recognition between human Integrin-Linked Kinase and Cpd22 and its implication at atomic level.

Javier García-Marín^1, a, Diego Rodríguez-Puyol^2, b, Juan J Vaquero^3, c

1. Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química Andrés M. del Río (IQAR), Universidad de Alcalá (IRYCIS), Alcalá de Henares, 28805, Madrid, Spain.  2. Departamento de Química Biológica y Estructural, Centro de Investigaciones Biológicas, CIB-CSIC, C/Ramiro de Maeztu 9, 28040, Madrid, Spain.  3. Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AX, UK.

a. javier.garciamarin@uah.es  b. javier.garciamarin@uah.es  c. javier.garciamarin@uah.es

Keywords: Cpd22; ILK; Integrin-linked kinase; Molecular dynamics; PELE; Pseudokinase

Abstract

Pseudokinases have received increasing attention over the past decade because of their role in different physiological phenomena. Although pseudokinases lack several active-site residues, thereby hindering their catalytic activity, recent discoveries have shown that these proteins can play a role in intracellular signaling thanks to their non-catalytic functions. Integrin-linked kinase (ILK) was discovered more than two decades ago and was subsequently validated as a promising target for neoplastic diseases. Since then, only a few small-molecule inhibitors have been described, with the V-shaped pyrazole Cpd22 being the most interesting and characterized. However, little is known about its detailed mechanism of action at atomic level. In this study, using a combination of computational chemistry methods including PELE calculations, docking, molecular dynamics and experimental surface plasmon resonance, we were able to prove the direct binding of this molecule to ILK, thus providing the basis of its molecular recognition by the protein and the effect over its architecture. Our breakthroughs show that Cpd22 binding stabilizes the ILK domain by binding to the pseudo-active site in a similar way to the ATP, possibly modulating its scaffolding properties as pseudokinase. Moreover, our results explain the experimental observations obtained during Cpd22 development, thus paving the way to the development of new chemical probes and potential drugs.

Publications > Milián et al

Angew Chem Int Ed Engl. 2022, e202205651 PubMed 35510716

Metal-Free Temperature-Controlled Regiodivergent Borylative Cyclizations of Enynes: BCl(3) -Promoted Skeletal Rearrangement.

Ana Milián, Manuel A Fernández-Rodríguez, Estíbaliz Merino, Juan J Vaquero, Patricia García-García

Universidad de Alcalá (IRYCIS). Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química "Andrés M. del Río" (IQAR). Campus Científico-Tecnológico, Facultad de Farmacia, Autovía A-II, Km 33.1, 28805-Alcalá de Henares, Madrid, Spain.

Keywords: Boron; Cyclization; Enynes; Phenanthrenes; Rearrangement

Abstract

Metal-free borylative cyclization of biphenyl-embedded 1,3,5-trien-7-ynes in the presence of simple and inexpensive BCl(3) provided synthetically useful borylated building blocks. The outcome of the process depends on the reaction temperature, with borylated phenanthrenes obtained at 60 °C and phenanthrene-fused borylated cyclobutanes formed at 0 °C. Based on DFT calculations, a mechanism for these novel transformations has been proposed, which involves an uncommon skeletal rearrangement, including migration of a methyl group and alkyne fragmentation, unprecedented in BCl(3) -promoted cyclization reactions.

Publications > Salardón et al

J. Environ. Chem. Eng. 2022, 10, 107486

Electrochemically driven one-pot oxidative conversion of arylhydrazines into aromatic iodides.

Noemi Salardón, Guillermo Otárola, Clara Mañas, Estíbaliz Merino, Belen Batanero

Palabras clave: Environmentally friendly transformation; Aryl iodides; Iodide redox mediator; Arylhydrazines; Anodic oxidation; C-N bond cleavage; Electrografting

Resumen

The efficient metal-free electrosynthesis of 2,4-dinitrophenyl iodide is here reported starting from 2,4-dinitrophenylhydrazine. Surprisingly this dinitrated arylhydrazine minimizes, under the applied experimental conditions, any anodic multilayered film formation. This sustainable iodide-mediated oxidative dehydrazination enables coupling reaction of electrogenerated iodine with aryl radicals from electron-deficient arylhydrazines employing electricity as the driving force and an inexpensive halogen source. A mechanistic proposal explaining the formation of aryl iodides is presented and discussed.

Publications > Ortiz

Clin Kidney J. 2021, 15, 372 PubMed 35211298

RICORS2040: the need for collaborative research in chronic kidney disease.

Alberto Ortiz

Keywords: COVID-19; accelerated ageing; burden of disease; chronic kidney disease; decade of the kidney; kidney failure; kidney transplantation; research funding

Abstract

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true.

Publications > article

Nefrologia. 2022, 42, 65 PubMed 34803202

CKD: The burden of disease invisible to research funders.

Alberto Ortiz

Keywords: Accelerated aging; Burden of disease; COVID-19; Chronic kidney disease; Decade of the kidney; Kidney failure; Kidney transplantation; Research funding

Abstract

The uptake of the current concept of chronic kidney disease (CKD) by the public, physicians and health authorities is low. Physicians still mix up CKD with chronic kidney insufficiency or failure. In a recent manuscript, only 23% of participants in a cohort of persons with CKD had been diagnosed by their physicians as having CKD while 29% has a diagnosis of cancer and 82% had a diagnosis of hypertension. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. A prevalent view is that for those in whom kidneys fail, the problem is "solved" by dialysis or kidney transplantation. However, the main burden of CKD is accelerated aging and all-cause and cardiovascular premature death. CKD is the most prevalent risk factor for lethal COVID-19 and the factor that most increases the risk of death in COVID-19, after old age. Moreover, men and women undergoing KRT still have an annual mortality which is 10-100-fold higher than similar age peers, and life expectancy is shortened by around 40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth global cause of death by 2040 and the second cause of death in Spain before the end of the century, a time when 1 in 4 Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded CIBER network research structure in Spain. Leading Spanish kidney researchers grouped in the kidney collaborative research network REDINREN have now applied for the RICORS call of collaborative research in Spain with the support of the Spanish Society of Nephrology, ALCER and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true. However, only the highest level of research funding through the CIBER will allow to adequately address the issue before it is too late.

Publications > de-Lucio et al

Eur J Med Chem. 2022, 227, 113915 PubMed 34695777

Pyridazino-pyrrolo-quinoxalinium salts as highly potent and selective leishmanicidal agents targeting trypanothione reductase.

Héctor de Lucio^1, a, Javier García-Marín^{2, 3, 4, b}, Patricia Sánchez-Alonso^5, c, Juan Carlos García-Soriano^1, d, Miguel Ángel Toro^1, e, Juan J Vaquero^{2, 3, 4, f}, Federico Gago^6, g, Ramón Alajarín^{2, 3, 4, h}, Antonio Jiménez-Ruiz^1, i

1. Departamento de Biología de Sistemas, Universidad de Alcalá, E-28805, Alcalá de Henares, Madrid, Spain. Electronic address:.  2. Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, 28805, Alcalá de Henares, Madrid, Spain.  3. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) Ctra, Colmenar Viejo, km. 9100, 28034, Madrid, Spain.  4. Instituto de Investigación Química Andrés Manuel del Río (IQAR), Universidad de Alcalá, 28805, Alcalá de Henares, Madrid, Spain. Electronic address:.  5. Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, 28805, Alcalá de Henares, Madrid, Spain. Electronic address:.  6. Área de Farmacología, Departamento de Ciencias Biomédicas, Unidad Asociada al IQM-CSIC, Universidad de Alcalá, E-28805, Alcalá de Henares, Madrid, Spain. Electronic address:.

a. hector.lucio@edu.uah.es  b. javier.garciamarin@uah.es  c. sanchezalonsopatricia@gmail.com  d. jcarlos.garcias@uah.es  e. migueltoro83@gmail.com  f. juanjose.vaquero@uah.es  g. federico.gago@uah.es  h. ramon.alajarin@uah.es  i. antonio.jimenez@uah.es

Keywords: Enzyme inhibitor; Leishmania; Pyridazino%@5B2,3-a%@5Dpyrrolo%@5B2,1-c%@5Dquinoxalinium; Trypanothione disulfide reductase

Abstract

Fifteen pyridazino-pyrrolo-quinoxalinium salts were synthesized and tested for their antiprotozoal activity against Leishmania infantum amastigotes. Eleven of them turned out to be leishmanicidal, with EC(50) values in the nanomolar range, and displayed low toxicity against the human THP-1 cell line. Selectivity indices for these compounds range from 10 to more than 1000. Compounds 3b and 3f behave as potent inhibitors of the oxidoreductase activity of the essential enzyme trypanothione disulfide reductase (TryR). Interestingly, binding of 3f is not affected by high trypanothione concentrations, as revealed by the noncompetitive pattern of inhibition observed when tested in the presence of increasing concentrations of this substrate. Furthermore, when analyzed at varying NADPH concentrations, the characteristic pattern of hyperbolic uncompetitive inhibition supports the view that binding of NADPH to TryR is a prerequisite for inhibitor-protein association. Similar to other TryR uncompetitive inhibitors for NADPH, 3f is responsible for TryR-dependent reduction of cytochrome c in a reaction that is typically inhibited by superoxide dismutase.

Publications > Risco et al

J Anal Appl Pyrolysis 2021, 159, 105323

Chemical recovery of waste electrical and electronic equipment by microwave-assisted pyrolysis: A review.

Álvaro Risco, David Sucunza, Sergio González-Egido

Palabras clave: Electronic waste; Chemical recycling; Microwave pyrolysis; Catalytic pyrolysis; Brominated flame-retardants

Resumen

Over the past few decades, electrical and electronic equipment has become more accessible to people of different social status. Currently, however, only a small fraction of the resulting waste is treated properly, even though it has the potential to become a major source of raw materials. Waste electrical and electronic equipment (WEEE), or e-waste, is mainly composed of plastics and metals that can be recovered with a lower environmental impact and more efficiently in comparison with conventional processes, even when similar technologies are used. Pyrolysis is a thermochemical processing technique that is able to exploit the polymers in WEEE as well as concentrate the metals into a solid residue. Furthermore, this process can be adapted or combined with other technologies to minimize the content of organic halides that stem from the hazardous brominated flame-retardants (BFRs), which are common additives used in these products. Microwave-assisted pyrolysis (MAP) uses a heating mechanism that differs significantly but has advantages over conventional pyrolysis, such as a rapid volumetric heating or a higher energy efficiency. Despite the increasing interest in the application of MAP over the last years, research to date in this field remains scarce. As such, this article reviews current studies into the treatment of WEEE by MAP, thereby shedding light on the different variables that have an impact on its effectiveness and efficiency, to provide a comprehensive understanding of this technology. In addition, this review offers an overview of the characteristics of pyrolysis products and possible routes for their subsequent refining.