Category Archives: Noticias

Noticias

Org. Lett. 07.21

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.
Noticias

ACS Med. Chem. Lett. 07.21

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

Bioorg. Med. Chem. 07.21

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

ChemMedChem 06.21

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.
Noticias

Dyes Pigm. 05.21

A new family of fluorescent pyridazinobenzimidazolium cations with DNA binding properties

Pedro Bosch, Gema Marcelo, Alejandra Matamoros-Recio, David Sucunza*, Francisco Mendicuti, Alberto Domingo, Juan J. Vaquero*

Dyes Pigm., 2021, In Press
DOI: 10.1016/j.dyepig.2021.109443

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.
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.
Noticias

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.
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.
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.