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1.
Front Pharmacol ; 14: 1193282, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37426813

RESUMEN

Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence. Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy -performed in a large and diverse chemolibrary- complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (in silico) and prospective (experimentally confirmed) screening. Results: The first generation of ligand-based models were fed by data, which to a great extent, had not been published in peer-reviewed articles. The first screening campaign performed with 188 compounds (46 in silico hits and 100 analogues, and 40 unrelated compounds: flavonols and pyrazoles) yielded three hits against MPro (IC50 ≤ 25 µM): two analogues of in silico hits (one glycoside and one benzo-thiazol) and one flavonol. A second generation of ligand-based models was developed based on this negative information and newly published peer-reviewed data for MPro inhibitors. This led to 43 new hit candidates belonging to different chemical families. From 45 compounds (28 in silico hits and 17 related analogues) tested in the second screening campaign, eight inhibited MPro with IC50 = 0.12-20 µM and five of them also impaired the proliferation of SARS-CoV-2 in Vero cells (EC50 7-45 µM). Discussion: Our study provides an example of a virtuous loop between computational and experimental approaches applied to target-focused drug discovery against a major and global pathogen, reaffirming the well-known "garbage in, garbage out" machine learning principle.

2.
Biomedicines ; 11(1)2023 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-36672707

RESUMEN

Bladder cancer is a worldwide problem and improved therapies are urgently needed. In the search for newer strong antitumor compounds, herein, we present the study of three nitric oxide-releasing compounds and evaluate them as possible therapies for this malignancy. Bladder cancer cell lines T24 and 253J were used to evaluate the antiproliferative, antimigratory, and genotoxic effects of compounds. Moreover, we determined the NF-κB pathway inhibition, and finally, the survivin downregulation exerted by our molecules. The results revealed that compounds 1 and 3 exerted a high antiproliferative activity against bladder cancer cells through DNA damage and survivin downregulation. In addition, compound 3 reduced bladder cancer cell migration. We found that nitric oxide donors are promising molecules for the development of a new therapeutic targeting the underlying mechanisms of tumorigenesis and progression of bladder cancer.

3.
Molecules ; 27(6)2022 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-35335119

RESUMEN

Prostate and bladder cancers are commonly diagnosed malignancies in men. Several nitric oxide donor compounds with strong antitumor activity have been reported. Thus, continuing with our efforts to explore the chemical space around bioactive furoxan moiety, multicomponent reactions were employed for the rapid generation of molecular diversity and complexity. We herein report the use of Ugi and Groebke-Blackburn-Bienaymé multicomponent reactions under efficient, safe, and environmentally friendly conditions to synthesize a small collection of nitric-oxide-releasing molecules. The in vitro antiproliferative activity of the synthesized compounds was measured against two different human cancer cell lines, LNCaP (prostate) and T24 (bladder). Almost all compounds displayed antiproliferative activity against both cancer cell lines, providing lead compounds with nanomolar GI50 values against the cancer bladder cell line with selectivity indices higher than 10.


Asunto(s)
Neoplasias , Donantes de Óxido Nítrico , Humanos , Óxido Nítrico/metabolismo , Oxadiazoles
4.
Neurotherapeutics ; 18(1): 309-325, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33118131

RESUMEN

Motor neuron degeneration and neuroinflammation are the most striking pathological features of amyotrophic lateral sclerosis (ALS). ALS currently has no cure and approved drugs have only a modest clinically therapeutic effect in patients. Drugs targeting different deleterious inflammatory pathways in ALS appear as promising therapeutic alternatives. Here, we have assessed the potential therapeutic effect of an electrophilic nitroalkene benzoic acid derivative, (E)-4-(2-nitrovinyl) benzoic acid (BANA), to slow down paralysis progression when administered after overt disease onset in SOD1G93A rats. BANA exerted a significant inhibition of NF-κB activation in NF-κB reporter transgenic mice and microglial cell cultures. Systemic daily oral administration of BANA to SOD1G93A rats after paralysis onset significantly decreased microgliosis and astrocytosis, and significantly reduced the number of NF-κB-p65-positive microglial nuclei surrounding spinal motor neurons. Numerous microglia bearing nuclear NF-κB-p65 were observed in the surrounding of motor neurons in autopsy spinal cords from ALS patients but not in controls, suggesting ALS-associated microglia could be targeted by BANA. In addition, BANA-treated SOD1G93A rats after paralysis onset showed significantly ameliorated spinal motor neuron pathology as well as conserved neuromuscular junction innervation in the skeletal muscle, as compared to controls. Notably, BANA prolonged post-paralysis survival by ~30%, compared to vehicle-treated littermates. These data provide a rationale to therapeutically slow paralysis progression in ALS using small electrophilic compounds such as BANA, through a mechanism involving microglial NF-κB inhibition.


Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Nitrobenzoatos/uso terapéutico , Esclerosis Amiotrófica Lateral/mortalidad , Esclerosis Amiotrófica Lateral/patología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Células HT29/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/efectos de los fármacos , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/patología , Ratas , Médula Espinal/efectos de los fármacos , Médula Espinal/patología
5.
Redox Biol ; 39: 101833, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33352465

RESUMEN

Chronic metabolic diseases, like obesity, type II diabetes and atherosclerosis often involve a low-grade and sterile systemic inflammatory state, in which activation of the pro-inflammatory transcription factor NF-kB and the NLRP3 inflammasome play a major role. It is well established that genetic inhibition of the NLRP3 inflammasome ameliorates acute and chronic inflammation. Indeed, accumulating experimental evidences in murine models and also in humans suggest that inhibition of the NLRP3 inflammasome might be a suitable approach to tackle the deleterious effects of chronic metabolic diseases. In this work, we explored our previously synthesized nitroalkene-Trolox™ derivative named NATx0, as a non-conventional anti-inflammatory strategy to treat chronic inflammatory diseases, such as obesity-induced glucose intolerance. We found that NATx0 inhibited NF-kB nuclear translocation and pro-inflammatory gene expression in macrophages in vitro. In addition, treatment with NATx0 prevented NLRP3 inflammasome activation after LPS/ATP stimulation in macrophages in vitro. When tested acutely in vivo, NATx0 inhibited neutrophil recruitment in zebrafish larvae, and also diminished IL-1ß production after LPS challenge in mice. Finally, when NATx0 was administered chronically to diet-induced obese mice, it decreased muscle tissue inflammation and glucose intolerance, leading to improved glucose homeostasis. In conclusion, we propose that this novel nitroalkene-Trolox derivative is a suitable tool to tackle acute and chronic inflammation in vitro and in vivo mainly due to inhibition of NF-kB/NLRP3 activation.


Asunto(s)
Diabetes Mellitus Tipo 2 , Intolerancia a la Glucosa , Animales , Intolerancia a la Glucosa/tratamiento farmacológico , Inflamasomas , Inflamación/tratamiento farmacológico , Interleucina-1beta , Lipopolisacáridos , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR , Obesidad/tratamiento farmacológico , Vitamina E , Pez Cebra
6.
ChemMedChem ; 14(18): 1669-1683, 2019 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-31356736

RESUMEN

Cancer is the second leading cause of death worldwide. Herein, a strategy to quickly and efficiently identify novel lead compounds to develop anticancer agents, using green multicomponent reactions followed by antiproliferative activity and structure-activity relationship studies, is described. A second-generation focused library of nitric oxide-releasing compounds was prepared by microwave-assisted Passerini and Ugi reactions. Nearly all compounds displayed potent antiproliferative activities against a panel of human solid tumor cell lines, with 1-phenyl-1-[(tert-butylamino)carbonyl]methyl 3-[(3-phenylsulfonyl-[1,2,5]oxadiazol-4-yl N2 -oxide)oxy]benzoate (4 k) and N-[1-(tert-butylaminocarbonyl)-1-phenylmethyl]-N-(4-methylphenyl)-3-(3-phenylsulfonyl-[1,2,5]oxadiazol-4-yl N2 -oxide)oxyphenyl carboxamide (6 d) exhibiting the strongest activity on SW1573 lung cell line (GI50 =110 and 21 nm) with selectivity indices of 70 and 470, respectively. Preliminary mechanistic studies suggest a relationship between NO release and antiproliferative activity. Our strategy allowed the rapid identification of at least two molecules as future candidates for the development of potent antitumor drugs.


Asunto(s)
Antineoplásicos/farmacología , Benzoatos/farmacología , Óxido Nítrico/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Benzoatos/síntesis química , Benzoatos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Microondas , Estructura Molecular , Óxido Nítrico/química , Relación Estructura-Actividad , Células Tumorales Cultivadas
7.
Br J Pharmacol ; 176(6): 757-772, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30588602

RESUMEN

BACKGROUND AND PURPOSE: Atherosclerosis is characterized by chronic low-grade inflammation with concomitant lipid accumulation in the arterial wall. Anti-inflammatory and anti-atherogenic properties have been described for a novel class of endogenous nitroalkenes (nitrated-unsaturated fatty acids), formed during inflammation and digestion/absorption processes. The lipid-associated antioxidant α-tocopherol is transported systemically by LDL particles including to the atheroma lesions. To capitalize on the overlapping and complementary salutary properties of endogenous nitroalkenes and α-tocopherol, we designed and synthesized a novel nitroalkene-α-tocopherol analogue (NATOH) to address chronic inflammation and atherosclerosis, particularly at the lesion sites. EXPERIMENTAL APPROACH: We synthesized NATOH, determined its electrophilicity and antioxidant capacity and studied its effects over pro-inflammatory and cytoprotective pathways in macrophages in vitro. Moreover, we demonstrated its incorporation into lipoproteins and tissue both in vitro and in vivo, and determined its effect on atherosclerosis and inflammatory responses in vivo using the Apo E knockout mice model. KEY RESULTS: NATOH exhibited similar antioxidant capacity to α-tocopherol and, due to the presence of the nitroalkenyl group, like endogenous nitroalkenes, it exerted electrophilic reactivity. NATOH was incorporated in vivo into the VLDL/LDL lipoproteins particles to reach the atheroma lesions. Furthermore, oral administration of NATOH down-regulated NF-κB-dependent expression of pro-inflammatory markers (including IL-1ß and adhesion molecules) and ameliorated atherosclerosis in Apo E knockout mice. CONCLUSIONS AND IMPLICATIONS: In toto, the data demonstrate a novel pharmacological strategy for the prevention of atherosclerosis based on a creative, natural and safe drug delivery system of a non-conventional anti-inflammatory compound (NATOH) with significant potential for clinical application.


Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/farmacología , Aterosclerosis/tratamiento farmacológico , Ciclopentanos/farmacología , Inflamación/tratamiento farmacológico , Nitrocompuestos/farmacología , alfa-Tocoferol/análogos & derivados , alfa-Tocoferol/farmacología , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antioxidantes/síntesis química , Antioxidantes/química , Aterosclerosis/metabolismo , Citocinas/antagonistas & inhibidores , Citocinas/metabolismo , Femenino , Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Estructura Molecular , Células RAW 264.7
8.
Sci Rep ; 8(1): 12784, 2018 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-30143727

RESUMEN

Inflammation plays a major role in the onset and development of chronic non-communicable diseases like obesity, cardiovascular diseases and cancer. Combined, these diseases represent the most common causes of death worldwide, thus development of novel pharmacological approaches is crucial. Electrophilic nitroalkenes derived from fatty acids are formed endogenously and exert anti-inflammatory actions by the modification of proteins involved in inflammation signaling cascades. We have developed novel nitroalkenes derived from α-tocopherol aiming to increase its salutary actions by adding anti-inflammatory properties to a well-known nutraceutical. We synthesized and characterized an α-tocopherol-nitroalkene (NATOH) and two hydrosoluble analogues derived from Trolox (NATxME and NATx0). We analyzed the kinetics of the Michael addition reaction of these compounds with thiols in micellar systems aiming to understand the effect of hydrophobic partition on the reactivity of nitroalkenes. We studied NATxME in vitro showing it exerts non-conventional anti-inflammatory responses by inducing Nrf2-Keap1-dependent gene expression and inhibiting the secretion of NF-κB dependent pro-inflammatory cytokines. NATxME was also effective in vivo, inhibiting neutrophil recruitment in a zebrafish model of inflammation. This work lays the foundation for the rational design of a new therapeutic strategy for the prevention and treatment of metabolic and inflammation-related diseases.


Asunto(s)
Alquenos/síntesis química , Alquenos/farmacología , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Transducción de Señal , Tocoferoles/síntesis química , Tocoferoles/farmacología , Alquenos/química , Animales , Antiinflamatorios/química , Cromanos/síntesis química , Cromanos/química , Cromanos/farmacología , Cinética , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Micelas , Infiltración Neutrófila/efectos de los fármacos , Células RAW 264.7 , Tocoferoles/química , Pez Cebra
9.
Eur J Med Chem ; 143: 1888-1902, 2018 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-29129514

RESUMEN

A one-pot efficient, practical and eco-friendly synthesis of tocopherol analogues has been developed using water or solvent free conditions via Passerini and Ugi multicomponent reactions. These reactions can be optimized using microwave irradiation or ultrasound as the energy source. Accordingly, a small library of 30 compounds was prepared for biological tests. The evaluation of the antiproliferative activity in the human solid tumor cell lines A549 (lung), HBL-100 (breast), HeLa (cervix), SW1573 (lung), T-47D (breast), and WiDr (colon) provided lead compounds with GI50 values between 1 and 5 µM. A structure-activity relationship is also discussed. One of the studied compounds comes up as a future candidate for the development of potent tocopherol-mimetic therapeutic agents for cancer.


Asunto(s)
Antineoplásicos/farmacología , Tocoferoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tocoferoles/síntesis química , Tocoferoles/química
10.
Molecules ; 20(7): 11793-807, 2015 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-26132905

RESUMEN

Parasitic flatworms cause serious infectious diseases that affect humans and livestock in vast regions of the world, yet there are few effective drugs to treat them. Thioredoxin glutathione reductase (TGR) is an essential enzyme for redox homeostasis in flatworm parasites and a promising pharmacological target. We purified to homogeneity and characterized the TGR from the tapeworm Mesocestoides vogae (syn. M. corti). This purification revealed absence of conventional TR and GR. The glutathione reductase activity of the purified TGR exhibits a hysteretic behavior typical of flatworm TGRs. Consistently, M. vogae genome analysis revealed the presence of a selenocysteine-containing TGR and absence of conventional TR and GR. M. vogae thioredoxin and glutathione reductase activities were inhibited by 3,4-bis(phenylsulfonyl)-1,2,5-oxadiazole N2-oxide (VL16E), an oxadiazole N-oxide previously identified as an inhibitor of fluke and tapeworm TGRs. Finally, we show that mice experimentally infected with M. vogae tetrathyridia and treated with either praziquantel, the reference drug for flatworm infections, or VL16E exhibited a 28% reduction of intraperitoneal larvae numbers compared to vehicle treated mice. Our results show that oxadiazole N-oxide is a promising chemotype in vivo and highlights the convenience of M. vogae as a model for rapid assessment of tapeworm infections in vivo.


Asunto(s)
Cestodos/efectos de los fármacos , Infecciones por Cestodos/parasitología , Complejos Multienzimáticos/metabolismo , NADH NADPH Oxidorreductasas/metabolismo , Oxadiazoles/farmacología , Secuencia de Aminoácidos , Animales , Cestodos/metabolismo , Mesocestoides , Ratones , Datos de Secuencia Molecular , Complejos Multienzimáticos/química , NADH NADPH Oxidorreductasas/química , Homología de Secuencia de Aminoácido
11.
PLoS One ; 7(4): e35033, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22536349

RESUMEN

Parasitic flatworms are responsible for serious infectious diseases that affect humans as well as livestock animals in vast regions of the world. Yet, the drug armamentarium available for treatment of these infections is limited: praziquantel is the single drug currently available for 200 million people infected with Schistosoma spp. and there is justified concern about emergence of drug resistance. Thioredoxin glutathione reductase (TGR) is an essential core enzyme for redox homeostasis in flatworm parasites. In this work, we searched for flatworm TGR inhibitors testing compounds belonging to various families known to inhibit thioredoxin reductase or TGR and also additional electrophilic compounds. Several furoxans and one thiadiazole potently inhibited TGRs from both classes of parasitic flatworms: cestoda (tapeworms) and trematoda (flukes), while several benzofuroxans and a quinoxaline moderately inhibited TGRs. Remarkably, five active compounds from diverse families possessed a phenylsulfonyl group, strongly suggesting that this moiety is a new pharmacophore. The most active inhibitors were further characterized and displayed slow and nearly irreversible binding to TGR. These compounds efficiently killed Echinococcus granulosus larval worms and Fasciola hepatica newly excysted juveniles in vitro at a 20 µM concentration. Our results support the concept that the redox metabolism of flatworm parasites is precarious and particularly susceptible to destabilization, show that furoxans can be used to target both flukes and tapeworms, and identified phenylsulfonyl as a new drug-hit moiety for both classes of flatworm parasites.


Asunto(s)
Anticestodos/farmacología , Antiplatelmínticos/farmacología , Echinococcus granulosus/efectos de los fármacos , Fasciola hepatica/efectos de los fármacos , Proteínas del Helminto/antagonistas & inhibidores , Complejos Multienzimáticos/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , Animales , Anticestodos/química , Anticestodos/toxicidad , Antiplatelmínticos/química , Antiplatelmínticos/toxicidad , Línea Celular , Evaluación Preclínica de Medicamentos , Echinococcus granulosus/enzimología , Fasciola hepatica/enzimología , Fibroblastos/efectos de los fármacos , Proteínas del Helminto/química , Humanos , Larva/efectos de los fármacos , Larva/enzimología , Linfocitos/efectos de los fármacos , Ratones , Modelos Moleculares , Complejos Multienzimáticos/química , NADH NADPH Oxidorreductasas/química , Oxadiazoles/química , Oxadiazoles/farmacología , Oxadiazoles/toxicidad , Teoría Cuántica , Quinoxalinas/química , Quinoxalinas/farmacología , Quinoxalinas/toxicidad , Relación Estructura-Actividad , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/toxicidad
13.
Drug Chem Toxicol ; 34(3): 285-93, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21649483

RESUMEN

Nitric oxide donor tocopherol analogs were found to be incorporated in low-density lipoprotein to release nitric oxide into the hydrophobic core of the lipoprotein, thus inhibiting lipid oxidation processes associated with atheroma plaque formation. Previously, we studied their cytotoxicity against human and murine macrophages as first selection for in vivo studies. Herein, we examined both the in vitro mutagenic and DNA-damage effects of selected compounds to further evaluate drug potential. While the compounds of interest were nongenotoxics in both experimental tests (Ames and alkaline comet), one of the potential blood metabolites exhibited genotoxicity (alkaline comet test), and the furazan derivative was mutagenic (Ames test). Two selected (nitrooxy and furoxan) compounds were studied in long- and short-term in vivo treatment, and in these conditions, animal toxicity was not evidenced, suggesting the possibility of these compounds as potential antiatherogenic drugs.


Asunto(s)
Aterosclerosis/tratamiento farmacológico , Mutágenos/toxicidad , Donantes de Óxido Nítrico/toxicidad , Tocoferoles/toxicidad , Animales , Línea Celular , Ensayo Cometa , Relación Dosis-Respuesta a Droga , Humanos , Inyecciones Intramusculares , Masculino , Ratones , Ratones Endogámicos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Mutágenos/química , Donantes de Óxido Nítrico/química , Donantes de Óxido Nítrico/uso terapéutico , Ratas , Ratas Sprague-Dawley , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Relación Estructura-Actividad , Tocoferoles/química , Tocoferoles/uso terapéutico
14.
Free Radic Biol Med ; 50(3): 411-8, 2011 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-21145389

RESUMEN

Nitro-fatty acids represent endogenously occurring products of oxidant-induced nitration reactions. We have previously synthesized a mixture of four isomers of nitroarachidonic acid, a novel anti-inflammatory signaling mediator. In this study, we synthesized and chemically and biologically characterized for the first time an esterified nitroalkene derived from the nitration of methylarachidonate (AAMet): 6-methylnitroarachidonate (6-AAMetNO(2)). Synthesis was performed by reacting AAMet with sodium nitrite under acidic conditions. Analysis by mass spectrometry (positive-ion ESI-MS) showed an [M+H](+) ion of m/z 364, characteristic of AAMetNO(2). Fragmentation of this ion yielded a daughter ion at m/z 317, corresponding to the neutral loss of the nitro group ([M+H-HNO(2)](+)). Furthermore, IR signal at 1378 cm(-1) and NMR data confirmed the structure of a 6-nitro-positional isomer. This novel esterified nitroalkene was capable of promoting vascular protective actions including: (a) the induction of vasorelaxation via endothelium-independent mechanisms, associated with an increase in smooth muscle cell cGMP levels, and (b) a potent dose-dependent inhibition of human platelet aggregation. We postulate that 6-AAMetNO(2) could be a potential drug for the prevention of vascular and inflammatory diseases, and the presence of the methyl group may increase its pharmacological potential.


Asunto(s)
Ácidos Araquidónicos/síntesis química , Ácidos Araquidónicos/farmacología , GMP Cíclico/metabolismo , Inhibidores de Agregación Plaquetaria/síntesis química , Vasodilatadores/síntesis química , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Ácidos Araquidónicos/química , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Humanos , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/síntesis química , Donantes de Óxido Nítrico/química , Donantes de Óxido Nítrico/farmacología , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Ratas , Ratas Endogámicas WKY , Vasodilatación/efectos de los fármacos , Vasodilatadores/química , Vasodilatadores/farmacología
15.
Eur J Med Chem ; 45(12): 5767-72, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20889239

RESUMEN

Triosephosphate isomerase from Trypanosoma cruzi (TcTIM), an enzyme in the glycolytic pathway that exhibits high catalytic rates of glyceraldehyde-3-phosphate- and dihydroxyacetone-phosphate-isomerization only in its dimeric form, was screened against an in-house chemical library containing nearly 230 compounds belonging to different chemotypes. After secondary screening, twenty-six compounds from eight different chemotypes were identified as screening positives. Four compounds displayed selectivity for TcTIM over TIM from Homo sapiens and, concomitantly, in vitro activity against T. cruzi.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Triosa-Fosfato Isomerasa/antagonistas & inhibidores , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Dimerización , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Modelos Moleculares , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Estereoisomerismo , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/química , Trypanosoma cruzi/enzimología
16.
Bioorg Med Chem ; 17(24): 8143-8, 2009 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-19897374

RESUMEN

Nitric oxide-releasing alpha-tocopherol mimetics with LDL-protective activity were designed to maintain the tocopherol substructure necessary for its biochemical recognition by alpha-tocopherol transfer protein. In order to study the molecular interactions to alpha-TTP, theoretical binding studies by means of docking techniques and experimental binding assays, using a fluorescent probe, were performed. Furoxanyl-tocopherol-hybrid analogs 7 and 9 have the best ability to bind to alpha-TTP suggesting that they could be incorporated to LDL in vivo to further release nitric oxide and prevent oxidative modifications.


Asunto(s)
Antioxidantes/metabolismo , Donantes de Óxido Nítrico/metabolismo , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Tocoferoles/metabolismo , Vitamina E/metabolismo , alfa-Tocoferol , Sustitución de Aminoácidos , LDL-Colesterol/química , LDL-Colesterol/metabolismo , Humanos , Datos de Secuencia Molecular , Unión Proteica , Conformación Proteica , Relación Estructura-Actividad
17.
Biochem J ; 417(1): 223-34, 2009 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-18671672

RESUMEN

Nitroalkene derivatives of fatty acids act as adaptive, anti-inflammatory signalling mediators, based on their high-affinity PPARgamma (peroxisome-proliferator-activated receptor gamma) ligand activity and electrophilic reactivity with proteins, including transcription factors. Although free or esterified lipid nitroalkene derivatives have been detected in human plasma and urine, their generation by inflammatory stimuli has not been reported. In the present study, we show increased nitration of cholesteryl-linoleate by activated murine J774.1 macrophages, yielding the mononitrated nitroalkene CLNO2 (cholesteryl-nitrolinoleate). CLNO2 levels were found to increase approximately 20-fold 24 h after macrophage activation with Escherichia coli lipopolysaccharide plus interferon-gamma; this response was concurrent with an increase in the expression of NOS2 (inducible nitric oxide synthase) and was inhibited by the (*)NO (nitric oxide) inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester). Macrophage (J774.1 and bone-marrow-derived cells) inflammatory responses were suppressed when activated in the presence of CLNO2 or LNO2 (nitrolinoleate). This included: (i) inhibition of NOS2 expression and cytokine secretion through PPARgamma and *NO-independent mechanisms; (ii) induction of haem oxygenase-1 expression; and (iii) inhibition of NF-kappaB (nuclear factor kappaB) activation. Overall, these results suggest that lipid nitration occurs as part of the response of macrophages to inflammatory stimuli involving NOS2 induction and that these by-products of nitro-oxidative reactions may act as novel adaptive down-regulators of inflammatory responses.


Asunto(s)
Ésteres del Colesterol/metabolismo , Activación de Macrófagos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Animales , Antígenos CD36/metabolismo , Línea Celular , Ésteres del Colesterol/síntesis química , Ésteres del Colesterol/farmacología , Activación Enzimática/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Inflamación/inducido químicamente , Inflamación/metabolismo , Interferón gamma/farmacología , Interleucina-1beta/metabolismo , Lipopolisacáridos/farmacología , Macrófagos/citología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Factores de Necrosis Tumoral/metabolismo
18.
Bioorg Med Chem ; 15(18): 6262-72, 2007 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-17627828

RESUMEN

Synthesis, physicochemical, and biological characterization of a series of alpha-tocopherol mimetics with NO-releasing capacity are reported. The selected NO-donor moieties were nitrooxy and furoxan. All products were tested for their in vitro NO-releasing capacities, vasodilating properties and mammal cytotoxic activities. The lipophilic-hydrophilic balance of all products was also evaluated. A new hybrid furoxan, phenol derivative 17, possesses adequate profile of the studied properties.


Asunto(s)
Antioxidantes/farmacología , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico/metabolismo , Oxadiazoles/síntesis química , Vasodilatadores/farmacología , alfa-Tocoferol/síntesis química , Animales , Antioxidantes/síntesis química , Antioxidantes/química , Aorta Torácica/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Macrófagos/efectos de los fármacos , Ratones , Estructura Molecular , Donantes de Óxido Nítrico/síntesis química , Donantes de Óxido Nítrico/química , Oxadiazoles/química , Oxadiazoles/farmacología , Ratas , Ratas Endogámicas WKY , Vasodilatación/efectos de los fármacos , Vasodilatadores/síntesis química , Vasodilatadores/química , Difracción de Rayos X , alfa-Tocoferol/química , alfa-Tocoferol/farmacología
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