Todas las entradas de: Javier Carreras Pérez Aradros

Noticias

Nuevo artículo, Eur. J. Med. Chem. 10.21

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

Héctor de Lucio, Javier García-Marín, Patricia Sánchez-Alonso, Juan Carlos García-Soriano, Miguel Ángel Toro, Juan J Vaquero, Federico Gago, Ramón Alajarín, Antonio Jiménez-Ruiz

Eur. J. Med. Chem. , 2021
DOI: 10.1016/j.ejmech.2021.113915

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.
Miembros

Antonio Valero

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Antonio Valero

  • Contrato predoctoral proyecto CM/JIN/2019-025 (2021)
  • Máster Universitario en Química Orgánica, Universidad de Valencia (2020/2021)
  • Grado en Química por la Universidad de Valencia (2020)

Publicaciones en el grupo

Synthesis of Tri- and Tetrasubstituted Alkenyl Boronates from Alkynes /
Julia Altarejos, Antonio Valero, Rubén Manzano, Javier Carreras
Eur. J. Org. Chem. 2022; e202200521. doi:10.1002/ejoc.202200521
Noticias

Participación RSEQ Symposium 2021

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Participación RSEQ Symposium 2021

 

El grupo ha contribuido en el primer RSEQ Symposium 2021, organizado entre el 27-30 de septiembre, con diversas contribuciones:

– Oral:
· Enantioselective synthesis of 2,3-substituted cyclopropylboronates
Julia Altarejos, David Sucunza, Juan J. Vaquero, Javier Carreras

– Póster:
· Visible light-mediated enantioselective aminoarylation of alkenes: streamlined access to ?,?-diarylethylamines
Estíbaliz Merino, Cedric Hervieu, Mariia Kirillova,Yawen Hu, Cristina Nevado

· Metal-Free Temperature-controlled Regiodivergent Borylative Cyclization of enynes: a Boron-migration Promoted Skeletal Rearrangement
Ana Milián, Manuel A. Fernández-Rodriguez, Patricia García-García, Estíbaliz Merino, Juan J. Vaquero

· Functionalization of 4a,8a-Dihydro-4a-Aza-8a-Boranaphthalene via Regioselective Iridium-Catalyzed C−H Borylation
Patricia García-García, David Sucunza, Juan J. Vaquero, Isabel Valencia

2021, Publicación, Renal

García-Marín et al. ChemMedChem. 2021;16(18):2895-2906. A Computer-Driven Scaffold-Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2-a]quinoxaline Core.

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Publicaciones > García-Marín et al

ChemMedChem. 2021 Sep 16;16(18):2895-2906. doi: 10.1002/cmdc.202100338. Epub 2021 Jul 19. PubMed 34137509

A Computer-Driven Scaffold-Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2-a]quinoxaline Core.

Javier García-Marín1, Mercedes Griera2, Ramón Alajarín3, Manuel Rodríguez-Puyol4, Diego Rodríguez-Puyol5, Juan J Vaquero6

1. Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, 28805, Alcalá de Henares, Spain.  2. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra. Colmenar Viejo, km. 9100, 28034, Madrid, Spain.  3. Instituto de Investigación Química Andrés Manuel del Río (IQAR), Universidad de Alcalá, Alcalá de Henares, Spain.  4. Departamento de Química Biológica y Estructural, Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), Calle Ramiro de Maeztu 9, 28040, Madrid, Spain.  5. Graphenano Medical Care, S.L., C/Pablo Casals, no. 13, Yecla, Murcia, Spain.  6. Departamento de Biología de Sistemas, Universidad de Alcalá, 28805, Alcalá de Henares, Spain.

Keywords: MM-ISMSA; PTP1B, phosphatase; glucose uptake; molecular dynamics; molecular modelling; pyrrolo[1,2-a]quinoxaline; scaffold hopping

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is a very promising target for the treatment of metabolic disorders such as type II diabetes mellitus. Although it was validated as a promising target for this disease more than 30 years ago, as yet there is no drug in advanced clinical trials, and its biochemical mechanism and functions are still being studied. In the present study, based on our experience generating PTP1B inhibitors, we have developed and implemented a scaffold-hopping approach to vary the pyrrole ring of the pyrrolo[1,2-a]quinoxaline core, supported by extensive computational techniques aimed to explain the molecular interaction with PTP1B. Using a combination of docking, molecular dynamics and end-point free-energy calculations, we have rationally designed a hypothesis for new PTP1B inhibitors, supporting their recognition mechanism at a molecular level. After the design phase, we were able to easily synthesize proposed candidates and their evaluation against PTP1B was found to be in good concordance with our predictions. Moreover, the best candidates exhibited glucose uptake increments in cellulo model, thus confirming their utility for PTP1B inhibition and validating this approach for inhibitors design and molecules thus obtained.

2021, Publicación

Risco et al. Journal. 2021;159:105323. Chemical recovery of waste electrical and electronic equipment by microwave-assisted pyrolysis: A review.

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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.

Noticias

Nuevo artículo, Org. Lett. 07.21

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Enantioselective Copper-Catalyzed Synthesis of Trifluoromethyl-Cyclopropylboronates

Julia Altarejos, David Sucunza, Juan J. Vaquero, and Javier Carreras*

Org. Lett., 2021, ASAP
DOI: 10.1021/acs.orglett.1c02420

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.
2021, Publicación, Renal

Sánchez-Alonso et al. Bioorg Med Chem. 2021;44:116295. Pyrrolo[1,2-a]quinoxal-5-inium salts and 4,5-dihydropyrrolo[1,2-a]quinoxalines: Synthesis, activity and computational docking for protein tyrosine phosphatase 1B.

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Publicaciones > Sánchez-Alonso et al

Bioorg Med Chem. 2021 Jul 3; 44:116295.

Pyrrolo[1,2-a]quinoxal-5-inium salts and 4,5-dihydropyrrolo[1,2-a]quinoxalines: Synthesis, activity and computational docking for protein tyrosine phosphatase 1B.

Patricia Sánchez-Alonso1, Mercedes Griera2, Javier García-Marín1, 3, 4, Manuel Rodríguez-Puyol5, 6, 7, Ramón Alajarín1, 3, 8, a, Juan J Vaquero1, 3, 4, Diego Rodríguez-Puyol5, 6, 7

1. Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, 28805 Alcalá de Henares, Madrid, Spain.  2. Graphenano Medical Care, SL, Spain.  3. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra. Colmenar Viejo, km. 9100, 28034 Madrid, Spain.  4. Instituto de Investigación Química Andrés M. del Río (IQAR), Facultad de Farmacia, Universidad de Alcalá, 28805 Alcalá de Henares, Madrid, Spain.  5. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra. Colmenar Viejo, km. 9100, 28034 Madrid, Spain.  6. Departamento de Biología de Sistemas, Universidad de Alcalá, 28805 Alcalá de Henares, Madrid, Spain.  7. Fundación Renal Iñigo Álvarez de Toledo (FRIAT) y REDinREN del Instituto de Salud Carlos III, Madrid, Spain.  8. Instituto de Investigación Química Andrés M. del Río (IQAR), Facultad de Farmacia, Universidad de Alcalá, 28805 Alcalá de Henares, Madrid, Spain. Electronic address:.

a. ramon.alajarin@uah.es

Keywords: 4,5-Dihydropyrrolo[1,2-a]quinoxaline, pyrrolo[1,2-a]quinoxal-5-inium; Diabetes mellitus; Inhibitor; PTP1B; Phosphatase; Selectivity; TC-PTP

Abstract

Protein tyrosine phosphatase (PTP1B) is an interesting therapeutical target for diabetes, obesity, heart disease and cancer. As such, inhibition of PTP1B using orally administered drugs is still being pursued by academia and pharmaceutical companies. The failure of catalytic-site inhibitors led to the focus in this field being switched to allosteric inhibitors. To date, the non-competitive inhibitors that have reached clinical trials target the site formed by the α3/α6/α7 tunnel or the site found in a disordered C-terminal non-catalytic segment. Herein, pyrrolo[1,2-a]quinoxal-5-inium salts and 4,5-dihydropyrrolo[1,2-a]quinoxalines are synthesized from pyrrolo[1,2-a]quinoxalines by alkylation and reduction, respectively. These compounds showed no toxicity in HepG2 cells and exhibited inhibitory activity against PTP1B, with inhibition percentages of between 37% and 53% at 1 μM and activities (IC(50)) of between 0.25 and 1.90 μM. The inhibitory activity against T-cell protein tyrosine phosphatase (TC-TPT) was also assayed, with 4,5-dihydropyrrolo[1,2-a]quinoxalines being found to be slightly more active and selective. Compounds from the two series behave as insulin mimetics since they exhibit enhancement of glucose uptake in C2C12 cells. Computational docking studies provide information about the putative binding mode for both series and the preference for the α3/α6/α7 allosteric tunnel.

Noticias

Nuevo artículo, ACS Med. Chem. Lett. 07.21

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

Javier Garcia-Marin,* Mercedes Griera-Merino, Alejandra Matamoros-Recio, Sergio de Frutos, Manuel Rodríguez-Puyol, Ramón Alajarín, Juan J. Vaquero,* Diego Rodríguez-Puyol*

ACS Med. Chem. Lett. , 2021, In Press
DOI: 10.1021/acsmedchemlett.1c00183

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.
Noticias

Nuevo artículo, Bioorg. Med. Chem. 07.21

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Pyrrolo[1,2-a]quinoxal-5-inium Salts and 4,5-dihydropyrrolo[1,2-a]quinoxalines: Synthesis, Activity and Computational Docking for Protein Tyrosine Phosphatase 1B

Patricia Sánchez-Alonso, Mercedes Griera, Javier García-Marín, Manuel Rodríguez-Puyol,* Ramón Alajarín,* Juan J.Vaquero,* Diego Rodríguez-Puyol*

Bioorg. Med. Chem., 2021, In Press
DOI: 10.1016/j.bmc.2021.116295

Protein tyrosine phosphatase (PTP1B) is an interesting therapeutical target for diabetes, obesity, heart disease and cancer. As such, inhibition of PTP1B using orally administered drugs is still being pursued by academia and pharmaceutical companies. The failure of catalytic-site inhibitors led to the focus in this field being switched to allosteric inhibitors. To date, the non-competitive inhibitors that have reached clinical trials target the site formed by the <3/<6/<7 tunnel or the site found in a disordered C-terminal non-catalytic segment. Herein, pyrrolo[1,2-a]quinoxal-5-inium salts and 4,5-dihydropyrrolo[1,2-a]quinoxalines are synthesized from pyrrolo[1,2-a]quinoxalines by alkylation and reduction, respectively. These compounds showed no toxicity in HepG2 cells and exhibited inhibitory activity against PTP1B, with inhibition percentages of between 37% and 53% at 1 μM and activities (IC50) of between 0.25 and 1.90 μM. The inhibitory activity against T-cell protein tyrosine phosphatase (TC-TPT) was also assayed, with 4,5-dihydropyrrolo[1,2-a]quinoxalines being found to be slightly more active and selective. Compounds from the two series behave as insulin mimetics since they exhibit enhancement of glucose uptake in C2C12 cells. Computational docking studies provide information about the putative binding mode for both series and the preference for the <3/<6/<7 allosteric tunnel.
Noticias

Nuevo artículo, ChemMedChem 06.21

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A computer-driven scaffold-hopping approach generating new PTP1B inhibitors from the pyrrolo[1,2-a]quinoxaline core

Javier García-Marín,* Mercedes Griera, Ramón Alajarín, Manuel Rodríguez-Puyol, Diego Rodríguez-Puyol, Juan J. Vaquero*

ChemMedChem, 2021, Accepted Article
DOI: 10.1002/cmdc.202100338

Protein tyrosine phosphatase 1B is a very promising target for the treatment of metabolic disorders such as type II diabetes mellitus. Although it was validated as a promising target for this disease more than 30 years ago, as yet there is no drug in advanced clinical trials, and its biochemical mechanism and functions are still being studied. In the present study, based on our experience generating PTP1B inhibitors, we have developed and implemented a scaffold-hopping approach to vary the pyrrole ring of the pyrrolo[1,2- a ]quinoxaline core, supported by extensive computational techniques aimed to explain the molecular interaction with PTP1B. Using a combination of docking, molecular dynamics and end-point free-energy calculations, we have rationally designed a hypothesis for new PTP1B inhibitors, supporting their recognition mechanism at a molecular level. After the design phase, we were able to easily synthesize proposed candidates and their evaluation against PTP1B was found to be in good concordance with our predictions. Moreover, the best candidates exhibited glucose uptake increments in cellulo modell, thus confirming their utility for PTP1B inhibition and validating this approach for inhibitors design and molecules thus obtained.