Publicaciones > de-Lucio et al

Eur J Med Chem. 2022 Jan 5;227:113915. doi: 10.1016/j.ejmech.2021.113915. 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[2,3-a]pyrrolo[2,1-c]quinoxalinium; 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.

Publicaciones > Risco et al

J Anal Appl Pyrolysis 2021; 159:105323. doi: 10.1016/j.jaap.2021.105323

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.

Publicaciones > Altarejos et al

Org Lett. 2021 Aug 6;23(15):6174-6178. doi: 10.1021/acs.orglett.1c02420. PubMed 34320310

Enantioselective Copper-Catalyzed Synthesis of Trifluoromethyl-Cyclopropylboronates.

Julia Altarejos¹, David Sucunza², Juan J Vaquero³, Javier Carreras¹

1. Universidad de Alcalá, Departamento de Química Orgánica y Química Inorgánica,, Alcalá de Henares 28805, Spain.  2. Instituto de Investigación Química Andrés Manuel del Río (IQAR), Universidad de Alcalá, Alcalá de Henares 28805, Spain.  3. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid 28034, Spain.

Abstract

A copper-catalyzed enantioselective cyclopropanation involving trifluorodiazoethane in the presence of alkenyl boronates has been developed. This transformation enables the preparation of 2-substituted-3-(trifluoromethyl)cyclopropylboronates with high levels of stereocontrol. The products are valuable synthetic intermediates by transformation of the boronate group. This methodology can be applied to the synthesis of novel trifluoromethylated analogues of trans-2-arylcyclopropylamines, which are prevalent motifs in biologically active compounds.

Publicaciones > Garcia-Marin et al

ACS Med Chem Lett. 2021 Jul 15;12(11):1656-1662. doi: 10.1021/acsmedchemlett.1c00183. PubMed 34790291

Tripeptides as Integrin-Linked Kinase Modulating Agents Based on a Protein-Protein Interaction with α-Parvin.

Javier Garcia-Marin¹, Mercedes Griera-Merino², Alejandra Matamoros-Recio³, Sergio de Frutos⁴, Manuel Rodríguez-Puyol⁵, Ramón Alajarín¹, Juan J Vaquero⁴, Diego Rodríguez-Puyol²

1. Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Alcalá de Henares 28805, Spain.  2. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra. Colmenar Viejo, km. 9100, Madrid 28034, Spain.  3. Instituto de Investigación Química Andrés Manuel del Río (IQAR), Universidad de Alcalá, Alcalá de Henares 28805, Spain.  4. Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares 28805, Spain.  5. Graphenano Medical Care, S.L, Yecla 30510, Spain.

Abstract

Integrin-linked kinase (ILK) has emerged as a controversial pseudokinase protein that plays a crucial role in the signaling process initiated by integrin-mediated signaling. However, ILK also exhibits a scaffolding protein function inside cells, controlling cytoskeletal dynamics, and has been related to non-neoplastic diseases such as chronic kidney disease (CKD). Although this protein always acts as a heterotrimeric complex bound to PINCH and parvin adaptor proteins, the role of parvin proteins is currently not well understood. Using in silico approaches for the design, we have generated and prepared a set of new tripeptides mimicking an α-parvin segment. These derivatives exhibit activity in phenotypic assays in an ILK-dependent manner without altering kinase activity, thus allowing the generation of new chemical probes and drug candidates with interesting ILK-modulating activities.