All posts by administrador

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.

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.
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.

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.
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.

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.
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.

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.