Category Archives: 2021

2021, AzaBN, Publicación

Valencia et al. J Org Chem. 2021;:. 1,10a-Dihydro-1-aza-10a-boraphenanthrene and 6a,7-Dihydro-7-aza-6a-boratetraphene: Two New Fluorescent BN-PAHs.

Publications > Valencia et al

J Org Chem. 2021 Nov 22. doi: 10.1021/acs.joc.1c01095. PubMed 34806882

1,10a-Dihydro-1-aza-10a-boraphenanthrene and 6a,7-Dihydro-7-aza-6a-boratetraphene: Two New Fluorescent BN-PAHs.

Isabel Valencia1, Patricia García-García1, David Sucunza1, Francisco Mendicuti2, Juan J Vaquero1

1. Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química "Andrés M. del Río" (IQAR), Universidad de Alcalá, IRYCIS, Campus Científico-Tecnológico, 28805 Alcalá de Henares, Spain.  2. Departamento de Química Analítica, Química Física e Ingeniería Química, Instituto de Investigación Química "Andrés M. del Río" (IQAR), Universidad de Alcalá, Campus Científico-Tecnológico, 28805 Alcalá de Henares, Spain.

Abstract

Previously unknown 1,10a-dihydro-1-aza-10a-boraphenanthrene and 6a,7-dihydro-7-aza-6a-boratetraphene have been efficiently synthesized. Bromination of these BN-PAHs proceeds with complete regioselectivity, resulting in the formation of different substituted derivatives via cross-coupling reactions. These compounds exhibit rather high fluorescence quantum yields (up to ϕ(F) = 0.80).

2021, BioImag, Publicación

Mariz et al. Journal. 2021;4(1):142. Two-photon activated precision molecular photosensitizer targeting mitochondria.

Publications > Mariz et al

2021; 4(1):142.

Two-photon activated precision molecular photosensitizer targeting mitochondria.

Inês F. A. Mariz, Sandra N. Pinto, Ana M. Santiago, José M. G. Martinho, Javier Recio, Juan J. Vaquero, Ana M. Cuadro, Ermelinda Maçôas

Resumen

Mitochondria metabolism is an emergent target for the development of novel anticancer agents. It is amply recognized that strategies that allow for modulation of mitochondrial function in specific cell populations need to be developed for the therapeutic potential of mitochondria-targeting agents to become a reality in the clinic. In this work, we report dipolar and quadrupolar quinolizinium and benzimidazolium cations that show mitochondria targeting ability and localized light-induced mitochondria damage in live animal cells. Some of the dyes induce a very efficient disruption of mitochondrial potential and subsequent cell death under two-photon excitation in the Near-infrared (NIR) opening up possible applications of azonia/azolium aromatic heterocycles as precision photosensitizers. The dipolar compounds could be excited in the NIR due to a high two-photon brightness while exhibiting emission in the red part of the visible spectra (600–700 nm). Interaction with the mitochondria leads to an unexpected blue-shift of the emission of the far-red emitting compounds, which we assign to emission from the locally excited state. Interaction and possibly aggregation at the mitochondria prevents access to the intramolecular charge transfer state responsible for far-red emission.

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.

Publications > García-Marín et al

ChemMedChem. 2021 Sep 16;16(18):2895-2906. doi: 10.1002/cmdc.202100338. 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.

Publications > Risco et al

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.

2021, Publicación

Altarejos et al. Org Lett. 2021;23(15):6174-6178. Enantioselective Copper-Catalyzed Synthesis of Trifluoromethyl-Cyclopropylboronates.

Publications > 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.

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.

Publications > 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.

2021, Publicación

Garcia-Marin et al. ACS Med Chem Lett. 2021;12(11):1656-1662. Tripeptides as Integrin-Linked Kinase Modulating Agents Based on a Protein-Protein Interaction with α-Parvin.

Publications > 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.

2021, AzaBN, Publicación

Abengozar et al. Adv. Heterocycl. Chem.. 2021;:197-259. Recent developments in the chemistry of BN-aromatic hydrocarbons.

Publications > Abengozar et al

Adv. Heterocycl. Chem. 2021 Mar 28; :197-259.

Recent developments in the chemistry of BN-aromatic hydrocarbons.

Alberto Abengozar, Patricia Garcia-Garcia, Manuel A. Fernández-Rodríguez, David Sucunza, Juan J Vaquero

Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química “Andrés M. del Río” (IQAR), Universidad de Alcalá (IRYCIS), Campus Científico-Tecnológico, Facultad de Farmacia, Alcalá de Henares, Madrid, Spain.

Abstract

Heterocycles containing both N and B heteroatoms in their structure were first reported by Dewar in the middle of the last century. However, they received little attention until the early years of this century, when several groups revisited these compounds due to their interest in BN/CC isosterism. As a result of these systematic studies, very significant advances have been made in our understanding of the chemistry of these BN-heterocycles. The purpose of this review is to summarize the most significant advances in the last two decades as regards the development of synthetic strategies and studies of their reactivity, as well as to provide an overview of their general properties and main applications.

2021, BioImag, Publicación

Bosch et al. Dyes and Pigments. 2021;:109443. A new family of fluorescent pyridazinobenzimidazolium cations with DNA binding properties.

Publications > Bosch et al

Dyes and Pigments. 2021 Aug 1; :109443.

A new family of fluorescent pyridazinobenzimidazolium cations with DNA binding properties.

Pedro Bosch1, Gema Marcelo2, Alejandra Matamoros-Recio3, David Sucunza4, Francisco Mendicuti2, Alberto Domingo3, Juan J Vaquero4

1. Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, 28871, Alcalá de Henares, Madrid, Spain.  2. Departamento de Química Analítica, Química Física e Ingeniería Química, 28805, Alcalá de Henares, Madrid, Spain.  3. Departamento de Biología de Sistemas, Instituto de Investigación Química “Andrés M. Del Río” (IQAR), Universidad de Alcalá, IRYCIS, 28805, Alcalá de Henares, Madrid, Spain.  4. Departamento de Química Orgánica y Química Inorgánica, 28805, Alcalá de Henares, Madrid, Spain.

Abstract

A series of novel azonia aromatic heterocycles formed by a pyridazinobenzimidazolium system has been synthesized. Spectrofluorimetric and circular dichroism measurements, as well as theoretical simulations for these materials, have shown their interesting fluorescence properties and DNA-binding ability. Stoichiometries and binding constants were obtained by fluorescence and the induced circular dichroism spectra analysis. Moreover, the potential of these compounds for cell staining has been investigated in living HeLa cells by confocal microscopy imaging.

2021, Publicación

Hervieu et al. Nat Chem. 2021;13(4):327-334. Asymmetric, visible light-mediated radical sulfinyl-Smiles rearrangement to access all-carbon quaternary stereocentres.

Publications > Hervieu et al

Nat Chem. 2021 Apr;13(4):327-334. doi: 10.1038/s41557-021-00668-4. PubMed 33833448

Asymmetric, visible light-mediated radical sulfinyl-Smiles rearrangement to access all-carbon quaternary stereocentres.

Cédric Hervieu1, Mariia S Kirillova1, Tatiana Suárez1, Marco Müller1, Estíbaliz Merino1, a, Cristina Nevado2, b

1. Department of Chemistry, University of Zurich, Zurich, Switzerland.  2. Department of Organic and Inorganic Chemistry, Chemical Research Institute Andrés M. del Río (IQAR), University of Alcala, Madrid, Spain.

a. estibaliz.merino@uah.es  b. estibaliz.merino@uah.es

Abstract

The asymmetric construction of all-carbon quaternary centres within acyclic settings represents a long-standing challenge for synthetic chemists. Alongside polar and radical methods, rearrangement reactions represent an attractive platform, but still broadly applicable methods are in high demand. Here we report an asymmetric, radical sulfinyl-Smiles rearrangement to access acyclic amides that bear an α-all-carbon quaternary centre. Our strategy uses enantioenriched N-arylsulfinyl acrylamides as acceptors for a variety of radicals produced in situ under mild photoredox conditions. The sulfinamido group not only directs the 1,4-migration of the aryl moiety onto the α-carbon of the amide, which thus governs its absolute configuration, but also functions as a traceless chiral auxiliary. The amides obtained in this multicomponent process are prevalent in pharmaceuticals, agrochemicals and bioactive natural products, and can be transformed into valuable chiral α,α-disubstituted acids, oxindoles as well as into β,β-disubstituted amines, highlighting the synthetic potential of this transformation.