All posts by administrador

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.

Noticias

Advances in Heterocyclic Chemistry 03.21

Recent developments in the chemistry of BN-aromatic hydrocarbons

Alberto Abengózar, Patricia García-García, Manuel A. Fernández-Rodríguez, David Sucunza*, Juan J. Vaquero*

Advances in Heterocyclic Chemistry, 2021, In Press, Corrected Proof
DOI: 10.1016/bs.aihch.2021.01.001

50 days’ free access, clicking on next link before April 21, 2021
https://authors.elsevier.com/a/1cgCsErrnROHF

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.
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Covers 2020

This year the group has contributed with two cover:

· Chem Med Chem
Pyrrolo[1,2‐a]quinoxalines: Insulin Mimetics that Exhibit Potent and Selective Inhibition against Protein Tyrosine Phosphatase 1B
Javier García‐Marín, Mercedes Griera, Patricia Sánchez‐Alonso, Bruno Di Geronimo, Francisco Mendicuti, Manuel Rodríguez‐Puyol*, Ramón Alajarín*, Beatriz de Pascual‐Teresa, Juan J. Vaquero*, Diego Rodríguez‐Puyol*

The Front Cover shows a C2C12 cell with the inhibitor 4‐benzylpyrrolo[1,2‐a]quinoxaline targeting the α3/α6/α7 tunnel in the Protein Tyrosine Phosphatase 1B (PTP1B) represented as a ribbon diagram. The insulin receptor (clear green) and the glucose transporter (clear yellow) shown at the cell membrane are involved in the glucose uptake by the cell. The inhibition of PTP1B by this molecule and their analogues produces an insulin mimetic effect. This is indicated by red arrows for the glucose molecules (in sticks) crossing the cell membrane to the cytosol.

· Org Lett
Selective Synthesis of Phenanthrenes and Dihydrophenanthrenes via Gold-Catalyzed Cycloisomerization of Biphenyl Embedded Trienynes
Ana Milián, Patricia García-García*, Adrián Pérez-Redondo, Roberto Sanz, Juan J. Vaquero, and Manuel A. Fernández-Rodríguez*

The cover art illustrates the solvent-controlled gold(I)-catalyzed selective synthesis of phenanthrenes and dihydrophenanthrenes from easily available biphenyl-embedded trienynes. Notably, the phenanthrene synthesis developed is complementary to the well-studied strategy that produces regioisomeric phenanthrenes, resulting from the competitive nucleophilic addition of biphenyl to the activated alkyne. In addition, the isolation of the cyclobutenyl derivative depicted in the figure accounts for the participation of cyclobutene species in the catalytic cycle.
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.

Noticias

Catalysts 10.20

Gold-Catalyzed Synthetic Strategies towards Four-Carbon Ring Systems

Guillermo Otárola, Juan J. Vaquero, Estíbaliz Merino*, Manuel A. Fernández-Rodríguez*

Catalysts, 2020, Early View
DOI: 10.3390/catal10101178

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.

Noticias

Nefrología 10.20

The pHLIP system as a vehicle for microRNAs in the kidney

Verónica Miguel, Carlos Rey, José Luis Aceña, Francisco Maqueda, Carlos Fernández-Hernando, Diego Rodríguez-Puyol, Juan J. Vaquero, Santiago Lamas

Nefrología, 2020
DOI: 10.1016/j.nefro.2020.05.007

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 [low] 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, 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.