Category Archives: Noticias

Noticias

Eur. J. Med. Chem. 10.21

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.
Noticias

Commun. Chem. 10.21

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*

Commun Chem 2021, 4, 142
DOI: 10.1038/s42004-021-00581-4

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.
Noticias

RSEQ Symposium 2021

Participación RSEQ Symposium 2021

 

RSEQ Symposium 2021, September 27-30th:

– 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

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.