Category Archives: Publicación

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.

2020, Au, Publicación

Milián et al. Org Lett. 2020;22(21):8464-8469. Selective Synthesis of Phenanthrenes and Dihydrophenanthrenes via Gold-Catalyzed Cycloisomerization of Biphenyl Embedded Trienynes.

Publications > Milián et al

Org Lett. 2020, 22, 8464

Selective Synthesis of Phenanthrenes and Dihydrophenanthrenes via Gold-Catalyzed Cycloisomerization of Biphenyl Embedded Trienynes.

Ana Milián1, Patricia García-García1, Adrián Pérez-Redondo1, Roberto Sanz2, Juan J Vaquero1, Manuel A Fernández-Rodríguez1

1. Departamento de Quı́mica Orgánica y Quı́mica Inorgánica, Instituto de Investigación Quı́mica "Andrés M. del Rı́o" (IQAR). Universidad de Alcalá (IRYCIS). Campus Cientı́fico-Tecnológico, Facultad de Farmacia, Autovía A-II, Km 33.1, 28805 Alcalá de Henares, Madrid, Spain.  2. Área de Quı́mica Orgánica, Departamento de Quı́mica, Facultad de Ciencias, Universidad de Burgos, Pza. Misael Bañuelos s/n, 09001 Burgos, Spain.

Abstract

Readily available o'-alkenyl-o-alkynylbiaryls, a particular type of 1,7-enynes, undergo a selective cycloisomerization reaction in the presence of a gold(I) catalyst to give interesting phenanthrene and dihydrophenanthrene derivatives in high yields. The solvent used provokes a switch in the evolution of the gold intermediate and plays a key role in the reaction outcome.

2020, Au, Publicación

Otarola et al. Catalysts. 2020;22(21):1178. Gold-Catalyzed Synthetic Strategies towards Four-Carbon Ring Systems.

Publications > Otarola et al

Catalysts 2020, 22, 1178

Gold-Catalyzed Synthetic Strategies towards Four-Carbon Ring Systems.

Guillermo G Otarola, Juan J Vaquero, Estíbaliz Merino, Manuel A Fernández-Rodríguez

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

Abstract

Four carbon ring systems are frequently present in natural products with remarkable biological activities such as terpenoids, alkaloids, and steroids. The development of new strategies for the assembly of these structures in a rapid and efficient manner has attracted the interest of synthetic chemists for a long time. The current research is focused mainly on the development of synthetic methods that can be performed under mild reaction conditions with a high tolerance to functional groups. In recent years, gold complexes have turned into excellent candidates for this aim, owing to their high reactivity, and are thus capable of promoting a wide range of transformations under mild conditions. Their remarkable efficiency has been thoroughly demonstrated in the synthesis of complex organic molecules from simple starting materials. This review summarizes the main synthetic strategies described for gold-catalyzed four-carbon ring formation, as well as their application in the synthesis of natural products.

2020, Publicación

García-Marín et al. ChemMedChem. 2020;15(19):1788-1801. Pyrrolo[1,2-a]quinoxalines: Insulin Mimetics that Exhibit Potent and Selective Inhibition against Protein Tyrosine Phosphatase 1B

Publications > García-Marín et al

ChemMedChem 2020, 15, 1788 PubMed 32909701

Pyrrolo%@5B1,2-a%@5Dquinoxalines: Insulin Mimetics that Exhibit Potent and Selective Inhibition against Protein Tyrosine Phosphatase 1B.

Javier García-Marín1, Mercedes Griera2, Patricia Sánchez-Alonso3, Bruno Di Geronimo2, Francisco Mendicuti4, Manuel Rodríguez-Puyol1, Ramón Alajarín5, Beatriz de Pascual-Teresa6, Juan J Vaquero3, Diego Rodríguez-Puyol2

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 M. del Río, Facultad de Farmacia, Universidad de Alcalá, 28805, Alcalá de Henares, Spain.  4. Departamento de Biología de Sistemas, Universidad de Alcalá, 28805, Alcalá de Henares, Spain.  5. Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo CEU, 28925, Alcorcón, Spain.  6. Departamento de Química Analítica, Química Física e Ingeniería Química, Universidad de Alcalá, 28805, Alcalá de Henares, Spain.

Keywords: PTP1B; biological activity; inhibitors; insulin mimetics; pyrrolo%@5B1,2-a%@5Dquinoxaline

Abstract

PTP1B dephosphorylates insulin receptor and substrates to modulate glucose metabolism. This enzyme is a validated therapeutic target for type 2 diabetes, but no current drug candidates have completed clinical trials. Pyrrolo%@5B1,2-a%@5Dquinoxalines substituted at positions C1-C4 and/or C7-C8 were found to be nontoxic to cells and good inhibitors in the low- to sub-micromolar range, with the 4-benzyl derivative being the most potent inhibitor (0.24 μm). Some analogues bearing chlorine atoms at C7 and/or C8 kept potency and showed good selectivity compared to TCPTP (selectivity index >40). The most potent inhibitors behaved as insulin mimetics by increasing glucose uptake. The 4-benzyl derivative inhibited insulin receptor substrate 1 and AKT phosphorylation. Molecular docking and molecular dynamics simulations supported a putative binding mode for these compounds to the allosteric α3/α6/α7 pocket, but inconsistent results in enzyme inhibition kinetics were obtained due to the high tendency of these inhibitors to form stable aggregates. Computational calculations supported the druggability of inhibitors.

2020, Publicación, Renal

Miguel et al. Nefrologia. 2020;:. The pHLIP system as a vehicle for microRNAs in the kidney.

Publications > Miguel et al

Nefrologia. 2020, 40, 491

The pHLIP system as a vehicle for microRNAs in the kidney.

Verónica Miguel1, a, Carlos Rey2, José Luis Aceña3, Francisco Maqueda3, Carlos Fernández-Hernando4, Diego Rodríguez-Puyol5, Juan J Vaquero3, Santiago Lamas2

1. Programa de Procesos Fisiológicos y Patológicos, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, España. Electronic address:.  2. Programa de Procesos Fisiológicos y Patológicos, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, España.  3. Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química Andrés M. del Río (IQAR), Universidad de Alcalá, IRYCIS, Alcalá de Henares, Madrid, España.  4. Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, Estados Unidos.  5. Department of Medicine and Medical Specialties, Research Foundation of the University Hospital Príncipe de Asturias, IRYCIS, Alcalá University, Alcalá de Henares, Madrid, España.

a. vmiguel@cbm.csic.es

Palabras clave: Fibrosis renal; PNA; PNAs; Renal fibrosis; miRNA; miRNAs; pHLIP

Resumen

MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene expression through post-transcriptional repression of their target messenger RNAs. A study of changes in expression of certain miRNAs in the kidney has supplied evidence on their pathogenic role and therapeutic potential in nephrology. This review proposes a nanotechnology approach based on the binding of analogs or inhibitors of miRNAs formed by peptide nucleic acids (PNAs) to peptides with a transmembrane structure sensitive to a low pH, called pHLIPs (pH %@5Blow%@5D insertion peptides). The review draws on the concept that an acidic pH in the microenvironment of the renal tubule may facilitate concentration and distribution of the pHLIP-PNA complex in this organ. In this context, we have demonstrated for the first time that targeted administration of miR-33 inhibitors with the pHLIP system effectively prevents the development of renal fibrosis, thus opening up this technology to new strategies for diagnosis and treatment of kidney diseases.

2020, Publicación

Altarejos et al. Eur J Org Chem. 2020:3024-3029. Practical Solvent-Free Microwave-Assisted Hydroboration of Alkynes

Publications > Altarejos et al

Eur. J. Org. Chem. 2020, 3024

Practical Solvent-Free Microwave-Assisted Hydroboration of Alkynes.

Julia Altarejos, David Sucunza, Juan J Vaquero, Javier Carreras

Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química “Andrés M. del Río” (IQAR), Universidad de Alcalá, IRYCIS, 28805 Madrid, Alcalá de Henares, Spain.

. javier.carreras@uah.es

Abstract

A simple and rapid protocol for the anti-Markovnikov hydroboration of alkynes assisted by microwave irradiation has been developed. Pinacolborane smoothly reacts with terminal alkynes to obtain (E)-alkenyl boronates in good yields and short reactions times in the absence of solvent. Further transformations on the carbon-boron bond of the adducts can be sequentially achieved without the need of purifying the alkenyl boronates.

2020, AzaBN, Publicación

Abengozar et al. Chem Commun (Camb). 2020;56(25):3669-3672. Expanding the BN-embedded PAH family: 4a-aza-12a-borachrysene.

Publications > Abengozar et al

Chem Commun 2020, 56, 3669 PubMed 32115593

Expanding the BN-embedded PAH family: 4a-aza-12a-borachrysene.

Alberto Abengozara, Isabel Valencia, Guillermo G Otarola, David Sucunza, Patricia Garcia-Garcia, Adrian Perez-Redondo, Francisco Mendicuti, Juan J Vaquero

Departamento de Quimica Organica y Quimica Inorganica, Instituto de Investigacion Quimica "Andres M. del Rio" (IQAR), Universidad de Alcala, IRYCIS, 28805 Alcala de Henares, Spain.

a. david.sucunza@uah.es, juanjose.vaquero@uah.es

Abstract

Previously unknown 4a-aza-12a-borachrysene has been synthesized in only four steps. The reactions of this BN-embedded PAH with bromine and organolithium compounds proceed with complete regioselectivity, resulting in the formation of nine derivatives. One of these, a phenylalkynyl-substituted derivative, exhibits a remarkably high fluorescence quantum yield (PhiF = 0.68).