Archivo de la categoría: Publicación

2019, Publicación, Renal

Valino-Rivas et al. Trends Mol Med. 2019;25(4):341-360. NIK as a Druggable Mediator of Tissue Injury.

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Publicaciones > Valino-Rivas et al

Trends Mol Med. 2019 Apr;25(4):341-360. doi: 10.1016/j.molmed.2019.02.005. Epub 2019 Mar 26. PubMed 30926358

NIK as a Druggable Mediator of Tissue Injury.

Lara Valino-Rivas1, Juan Jose Vaquero2, David Sucunza2, Sara Gutierrez2, Ana B Sanz1, Manuel Fresno3, Alberto Ortiz1, 4, a, Maria Dolores Sanchez-Nino1, 4, b

1. Department of Nephrology and Hypertension, Instituto de Investigacion Sanitaria (IIS) Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid (UAM), Red de Investigacion Renal (REDINREN), and Fundacion Renal Inigo Alvarez de Toledo (FRIAT), Madrid, Spain.  2. Departamento de Quimica Organica y Quimica Inorganica, Universidad de Alcala and REDINREN, Madrid, Spain.  3. Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas de la UAM, Madrid, Spain.  4. These authors contributed equally. Electronic address:.

a. aortiz@fjd.es  b. mdsanchez@fjd.es

Keywords: *MAP3K14; *NIK; *TWEAK; *acute kidney injury; *apoptosis; *autoimmunity; *cell death; *chronic kidney disease; *cirrhosis; *diabetes; *epigenetic; *esteatohepatitis; *hepatitis; *inflammation; *mantle lymphoma; *myeloid leukemia; *osteoporosis; *sarcopenia; *verteporfin

Abstract

NF-kappaB-inducing kinase (NIK, MAP3K14) is best known as the apical kinase that triggers non-canonical NF-kappaB activation and by its role in the immune system. Recent data indicate a role for NIK expressed by non-lymphoid cells in cancer, kidney disease, liver injury, glucose homeostasis, osteosarcopenia, vascular calcification, hematopoiesis, and endothelial function. The spectrum of NIK-associated disease now ranges from immunodeficiency (when NIK is defective) to autoimmunity, cancer, sterile inflammation, fibrosis, and metabolic disease when NIK is overactive. The development of novel small-molecule NIK inhibitors has paved the way to test NIK targeting to treat disease in vivo, and may eventually lead to NIK targeting in the clinic. In addition, NIK activators are being explored for specific conditions such as myeloid leukemia.

2019, AzaBN, Publicación

Abengozar et al. Org Lett. 2019;21(8):2550-2554. Synthesis, Functionalization, and Optical Properties of 1,2-Dihydro-1-aza-2-boraphenanthrene and Several Highly Fluorescent Derivatives.

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Publicaciones > Abengozar et al

Org Lett. 2019 Apr 19;21(8):2550-2554. doi: 10.1021/acs.orglett.9b00448. Epub 2019 Apr 5. PubMed 30951317

Synthesis, Functionalization, and Optical Properties of 1,2-Dihydro-1-aza-2-boraphenanthrene and Several Highly Fluorescent Derivatives.

Alberto Abengozar1, Patricia Garcia-Garcia1, David Sucunza1, Diego Sampedro2, Adrian Perez-Redondo1, Juan J Vaquero1

1. Departamento de Quimica Organica y Quimica Inorganica, Instituto de Investigacion Quimica "Andres M. del Rio" (IQAR) , Universidad de Alcala , 28805 Alcala de Henares , Spain.  2. Departamento de Quimica, Centro de Investigacion en Sintesis Quimica (CISQ) , Universidad de La Rioja , Madre de Dios 53 , 26006 Logrono , Spain.

Abstract

Previously unknown 1,2-dihydro-1-aza-2-boraphenanthrene has been synthesized in only three steps from 2-bromo-1-vinylnaphthalene. The reactivity of this new BN-phenanthrene, and of several substituted derivatives, has been tested against bromine and organolithium compounds. Bromination proceeded with complete regioselectivity, affording bromo-substituted compounds suitable for further functionalization via cross-coupling reactions. This new family of BN-phenanthrenes exhibits a substantial increase in the quantum yield (up to varphiF = 0.93) with respect to phenanthrene.

2019, Au, Publicación

Garre et al. J Org Chem. 2019;:. Regiodivergent Electrophilic Cyclizations of Alkynylcyclobutanes for the Synthesis of Cyclobutane-Fused O-Heterocycles.

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Publicaciones > Garre et al

J Org Chem. 2019 Apr 18. doi: 10.1021/acs.joc.9b00618. PubMed 30896164

Regiodivergent Electrophilic Cyclizations of Alkynylcyclobutanes for the Synthesis of Cyclobutane-Fused O-Heterocycles.

M Soledad Garre1, David Sucunza1, Enrique Aguilar2, Patricia Garcia-Garcia1, Juan J Vaquero1

1. Departamento de Quimica Organica y Quimica Inorganica, Campus Cientifico-Tecnologico, Facultad de Farmacia , Universidad de Alcala (IRYCIS) , Autovia A-II, Km 33.1 , 28805 Alcala de Henares , Madrid , Spain.  2. Departamento de Quimica Organica e Inorganica, Instituto Universitario de Quimica Organometalica "Enrique Moles" , Universidad de Oviedo , C/Julian Claveria, 8 , 33006 Oviedo , Spain.

Abstract

Cyclobutane-fused dihydropyrans and methylenetetrahydrofurans are highly interesting cores found in numerous natural products. Both these cores are selectively prepared from a common alkynylcyclobutane precursor bearing an appended hydroxyl group herein. Thus, cyclobutane-fused dihydropyrans can be obtained by a selective 6-endo-dig iodocyclization, whereas gold-catalyzed 5-exo-dig cycloisomerization provides a bicyclic core containing a methylenetetrahydrofuran moiety as major product. Several cyclobutane-fused O-heterocycles with diverse substituents are synthesized following the reported methodology.

2019, Publicación, Renal

Cuarental et al. Nefrologia. 2019;39(6):568-580. MAP3K kinases and kidney injury.

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Publicaciones > Cuarental et al

Nefrologia. 2019 Nov - Dec;39(6):568-580. doi: 10.1016/j.nefro.2019.03.004. PubMed 31196660

MAP3K kinases and kidney injury.

Leticia Cuarental1, 2, David Sucunza-Saenz2, 3, 4, Lara Valino-Rivas1, 2, Beatriz Fernandez-Fernandez1, 2, Ana Belen Sanz1, 2, Alberto Ortiz1, 2, Juan Jose Vaquero2, 3, 4, Maria Dolores Sanchez-Nino1, 5, a

1. IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain.  2. REDINREN, Spain.  3. Departamento de Quimica Organica y Quimica Inorganica, Universidad de Alcala, 28871, Alcala de Henares, Madrid, Spain.  4. Instituto Ramon y Cajal de Investigacion Sanitaria, (IRYCIS), Madrid, Spain.  5. REDINREN, Spain. Electronic address:.

a. mdsanchez@fjd.es

Palabras clave: *ASK1; *Acute kidney injury; *Diabetic kidney disease; *Enfermedad renal cronica; *Enfermedad renal diabetica; *Kidney; *MAP3K kinases; *MAP3K quinasas; *MAP3K14; *NF-kappaB; *NIK; *Rinon; *Selonsertib; *TWEAK

Resumen

Mitogen-activated protein kinases (MAP kinases) are functionally connected kinases that regulate key cellular process involved in kidney disease such as all survival, death, differentiation and proliferation. The typical MAP kinase module is composed by a cascade of three kinases: a MAP kinase kinase kinase (MAP3K) that phosphorylates and activates a MAP kinase kinase (MAP2K) which phosphorylates a MAP kinase (MAPK). While the role of MAPKs such as ERK, p38 and JNK has been well characterized in experimental kidney injury, much less is known about the apical kinases in the cascade, the MAP3Ks. There are 24 characterized MAP3K (MAP3K1 to MAP3K21 plus RAF1, BRAF and ARAF). We now review current knowledge on the involvement of MAP3K in non-malignant kidney disease and the therapeutic tools available. There is in vivo interventional evidence clearly supporting a role for MAP3K5 (ASK1) and MAP3K14 (NIK) in the pathogenesis of experimental kidney disease. Indeed, the ASK1 inhibitor Selonsertib has undergone clinical trials for diabetic kidney disease. Additionally, although MAP3K7 (MEKK7, TAK1) is required for kidney development, acutely targeting MAP3K7 protected from acute and chronic kidney injury; and targeting MAP3K8 (TPL2/Cot) protected from acute kidney injury. By contrast MAP3K15 (ASK3) may protect from hypertension and BRAF inhibitors in clinical use may induced acute kidney injury and nephrotic syndrome. Given their role as upstream regulators of intracellular signaling, MAP3K are potential therapeutic targets in kidney injury, as demonstrated for some of them. However, the role of most MAP3K in kidney disease remains unexplored.

2018, Publicación, Renal

Gutierrez et al. Eur J Med Chem. 2018;157:946-959. Discovery of potent calpain inhibitors based on the azolo-imidazolidenone.

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Publicaciones > Gutierrez et al

Eur J Med Chem. 2018 Sep 5;157:946-959. doi: 10.1016/j.ejmech.2018.08.045. PubMed 30165342

Discovery of potent calpain inhibitors based on the azolo-imidazolidenone.

Sara Gutierrez1, Maria Moron1, Mercedes Griera2, David Sucunza1, Laura Calleros2, Andrea Garcia-Jerez2, Claire Coderch3, Francisco J Hermoso3, Carolina Burgos1, Manuel Rodriguez-Puyol2, Beatriz de Pascual-Teresa3, Maria L Diez-Marques2, Antonio Jimenez2, Miguel Toro-Londono2, Diego Rodriguez-Puyol4, Juan J Vaquero1

1. Departamento de Quimica Organica y Quimica Inorganica, Universidad de Alcala.  2. Departamento de Biologia de Sistemas, Universidad de Alcala, 28871, Alcala de.  3. Departamento de Quimica y Bioquimica, Facultad de Farmacia, Universidad San.  4. Research Unit and Nephrology Section, Hospital Principe de Asturias and.

Keywords: Azolo-imidazolidenone; Blockade of apoptosis; Calpain inhibitors; SAR; Uncompetitive inhibition

Abstract

A series of new azolopyrimidine-peptide hybrids and indolomethylideneimidazolones

2018, AzaBN, Publicación

Abengozar et al. Org Lett. 2018;20(16):4902-4906. C-H Functionalization of BN-Aromatics Promoted by Addition of Organolithium Compounds to the Boron Atom.

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Publicaciones > Abengozar et al

Org Lett. 2018 Aug 17;20(16):4902-4906. doi: 10.1021/acs.orglett.8b02040. PubMed 30070487

C-H Functionalization of BN-Aromatics Promoted by Addition of Organolithium Compounds to the Boron Atom.

Alberto Abengozar1, Miguel Angel Fernandez-Gonzalez2, David Sucunza1, Luis Manuel Frutos2, Antonio Salgado3, Patricia Garcia-Garcia1, Juan J Vaquero1

1. Departamento de Quimica Organica y Quimica Inorganica, Instituto de Investigacion Quimica "Andres M. del Rio" (IQAR) , Universidad de Alcala , 28805 Alcala de Henares , Madrid , Spain.  2. Departamento de Quimica Analitica, Quimica Fisica e Ingenieria Quimica, Instituto de Investigacion Quimica "Andres M. del Rio" (IQAR) , Universidad de Alcala , 28805 Alcala de Henares , Madrid , Spain.  3. Centro de Espectroscopia de Resonancia Magnetica Nuclear (CERMN), CAI Quimicas , Universidad de Alcala , 28805 Alcala de Henares , Madrid , Spain.

Abstract

Addition of an organolithium compound to a BN-phenanthrene with embedded B and N atoms is proposed to result in coordination of RLi to the boron atom. This coordination, supported by NMR spectroscopy and DFT calculations, increases the nucleophilicity of the system in the beta position to the N atom and is therefore a useful tool for promoting regioselective C-H functionalization of BN aromatics.

2018, Publicación, TosMIC

Gutierrez et al. J Org Chem. 2018;83(12):6623-6632. gamma-Carboline Synthesis by Heterocyclization of TosMIC Derivatives.

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Publicaciones > Gutierrez et al

J Org Chem. 2018 Jun 15;83(12):6623-6632. doi: 10.1021/acs.joc.8b00906. Epub 2018 May 24. PubMed 29756452

gamma-Carboline Synthesis by Heterocyclization of TosMIC Derivatives.

Sara Gutierrez, David Sucunza, Juan J Vaquero

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

Abstract

A new method for the synthesis of gamma-carbolines by a heterocyclization that involves alpha-indol-2-ylmethyl TosMIC derivatives and different electrophiles has been developed. This methodology has been successfully applied to the synthesis of several highly substituted gamma-carbolines.

2018, Publicación

Malvicini et al. Mol Cancer Ther. 2018;17(5):966-976. A Tricin Derivative from Deschampsia antarctica Desv. Inhibits Colorectal Carcinoma Growth and Liver Metastasis through the Induction of a Specific Immune Response.

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Publicaciones > Malvicini et al

Mol Cancer Ther. 2018 May;17(5):966-976. doi: 10.1158/1535-7163.MCT-17-0193. PubMed 29483221

A Tricin Derivative from Deschampsia antarctica Desv. Inhibits Colorectal Carcinoma Growth and Liver Metastasis through the Induction of a Specific Immune Response.

Mariana Malvicini1, Ana Gutierrez-Moraga2, Marcelo M Rodriguez3, Sofia Gomez-Bustillo1, Lorena Salazar1, Carlos Sunkel2, Leonor Nozal2, Antonio Salgado4, Manuel Hidalgo4, Pedro P Lopez-Casas5, Jose Luis Novella6, Juan Jose Vaquero4, Julio Alvarez-Builla4, Adda Mora4, Manuel Gidekel7, Guillermo Mazzolini2, a

1. Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomedicas, CONICET- Universidad Austral, Buenos Aires, Argentina.  2. Universidad Autonoma de Chile, Providencia, Chile.  3. Universidad de La Frontera, Temuco, Chile.  4. Departamento de Quimica Organica, Universidad de Alcala, Madrid, Spain.  5. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.  6. Gastrointestinal Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Madrid, Spain.  7. Creative BioScience, Huechuraba, Santiago, Chile.

a. gmazzoli@cas.austral.edu.ar, mgidekel@creativebio-science.com

Abstract

In colorectal carcinoma patients, distant metastatic disease is present at initial diagnosis in nearly 25% of them. The majority of patients with metastatic colorectal carcinoma have incurable disease; therefore, new therapies are needed. Agents derived from medicinal plants have already demonstrated therapeutic activities in human cancer cells. Antartina is an antitumor agent isolated from Deschampsia antarctica Desv. This study aimed to evaluate the antitumor properties of Antartina in colorectal carcinoma models. We used human and murine colorectal carcinoma cell lines for investigating proliferation, apoptosis, and cell-cycle effects of Antartina therapy in vitro Avatar and immunocompetent colorectal carcinoma animal models were applied for evaluating the effects of Antartina in vivo Immune response against colorectal carcinoma model was investigated using CTL assay, analyzing dendritic cell activation and intratumor T-cell subpopulation, and by tumor rechallenge experiments. Antartina inhibits in vitro human colorectal carcinoma cell proliferation; however, in vivo experiments in Avatar colorectal carcinoma model Antartina display a limited antitumor effect. In an immunocompetent colorectal carcinoma mice model, Antartina potently inhibited tumor growth and liver metastases, leading to complete tumor regressions in >30% of mice and increased animal survival. In addition, Antartina induced a potent specific cytotoxic T-cell response against colorectal carcinoma and a long-lasting antitumor immunity. Interestingly, Antartina increased tumor immunogenicity and stimulated dendritic cell activation. No toxic effects were observed at the doses employed. Our findings showed that Antartina has the ability to induce antitumor immunity against colorectal carcinoma and can be used to develop new tools for the treatment of colorectal carcinoma. Mol Cancer Ther; 17(5); 966-76. (c)2018 AACR.

2018, BioImag, Publicación

Bosch et al. Org. Chem. Front.. 2018;5(12):1916-1927. Dibenzopyridoimidazocinnolinium cations: a new family of light-up fluorescent DNA probes.

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Publicaciones > Bosch et al

Org. Chem. Front. 2018 May 2; 5(12):1916-1927. doi: 10.1039/C8QO00236C

Dibenzopyridoimidazocinnolinium cations: a new family of light-up fluorescent DNA probes.

Pedro Bosch1, David Sucunza1, Francisco Mendicuti2, Alberto Domingo3, Juan J Vaquero1

1. Departamento de Quimica Organica y Quimica Inorganica, Instituto de Investigacion Quimica "Andres M. del Rio" (IQAR) , Universidad de Alcala , 28805 Alcala de Henares , Spain.  2. Departamento de Química Analítica, Química Física e Ingeniería Química, Universidad de Alcalá, Spain.  3. Departamento de Biología de Sistemas, Universidad de Alcalá, Spain.

Abstract

Steady-state and time-resolved fluorescence, circular dichroism and molecular modelling techniques have been applied to a new family of weakly fluorescent dibenzopyridoimidazocinnolinium derivatives whose fluorescence intensity increases significantly (larger than × 3.5) upon DNA addition. The synthesis of these azonia cations, which bind to DNA by intercalation, was carried out using a Westphal condensation and a Suzuki cross coupling reaction as key steps. A live-cell staining analysis by confocal microscopy imaging was also performed and showed the capacity of these new compounds for active uptake and accumulation by living cells, with complex patterns of intracellular distribution observed.

2018, AzaBN, Publicación

Abengozar et al. Chem Commun (Camb). 2018;54(20):2467-2470. Synthesis of functionalized helical BN-benzo[c]phenanthrenes.

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Publicaciones > Abengozar et al

Chem Commun (Camb). 2018 Mar 6;54(20):2467-2470. doi: 10.1039/c7cc09264d. PubMed 29319090

Synthesis of functionalized helical BN-benzo[c]phenanthrenes.

Alberto Abengozara, Patricia Garcia-Garcia, David Sucunza, Adrian Perez-Redondo, Juan J Vaquero

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

a. patricia.garciagarci@uah.es, juanjose.vaquero@uah.es

Abstract

A novel parent BN-benzo[c]phenanthrene, with helical chirality and remarkable structural features, has been easily obtained in three steps with a global yield of 55%. Moreover, Cl-substituted derivatives have been prepared and these have served as useful starting materials for the development of palladium-catalyzed cross-coupling reactions.