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Mushrooms have been used for millennia as cancer remedies. Our goal was to screen several mushroom species from the rainforests of Costa Rica, looking for new antitumor molecules. Mushroom extracts were screened using two human cell lines: A549 (lung adenocarcinoma) and NL20 (immortalized normal lung epithelium). Extracts able to kill tumor cells while preserving non-tumor cells were considered "anticancer". The mushroom with better properties was Macrocybe titans. Positive extracts were fractionated further and tested for biological activity on the cell lines. The chemical structure of the active compound was partially elucidated through nuclear magnetic resonance, mass spectrometry, and other ancillary techniques. Chemical analysis showed that the active molecule was a triglyceride containing oleic acid, palmitic acid, and a more complex fatty acid with two double bonds. The synthesis of all possible triglycerides and biological testing identified the natural compound, which was named Macrocybin. A xenograft study showed that Macrocybin significantly reduces A549 tumor growth. In addition, Macrocybin treatment resulted in the upregulation of Caveolin-1 expression and the disassembly of the actin cytoskeleton in tumor cells (but not in normal cells). In conclusion, we have shown that Macrocybin constitutes a new biologically active compound that may be taken into consideration for cancer treatment.
Asunto(s)
Agaricales/química , Antineoplásicos/farmacología , Productos Biológicos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Línea Celular , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patologíaRESUMEN
A new synthesis of treprostinil is described using a plug flow reactor in two of the key steps. First, a Claisen rearrangement reaction is described in scaled flow at multigram amounts. Yields and selectivity of this step are sharply improved compared to those from previous syntheses. Second, the key Pauson-Khand reaction in flow is described under catalytic conditions with 5 mol% of cobalt carbonyl and only 3 equiv. of CO. Scaling up of this reaction safely ensures a good yield of an advanced intermediate which is transformed into treprostinil in three steps. Other improvements are the introduction of the carboxymethyl chain into the phenol from the beginning to reduce the protection-deprotection steps. The synthesis is completed in 14% global yield after 12 linear steps from (S)-epichlorhydrin.
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SCOPE: To identify the age-dependent effect of diets containing elevated amounts of either saturated or unsaturated fatty acids on cardiac steatosis in mice. METHODS AND RESULTS: Five- and eight-week-old C57BL/6J mice cohorts are given free access to either a saturated or an unsaturated fatty-acid-enriched diet during 8 weeks. Body weight (BW) and food intake are monitored during this period. Cardiac lipid content, carnitine palmitoyltransferase-I (CPT-I) activity, and the amount of uncoupling proteins 2 and 3 (UCP2 and UCP3) are analyzed and correlated with blood leptin concentration. Leptin and PPARγ gene expression is quantified in white adipose tissue (WAT). Both diets have a similar effect on food intake, BW, and adiposity, independently of the age. Nevertheless, cardiac steatosis is specifically identified in adolescent mice consuming the saturated diet. These animals also display lower activity of cardiac CPT-I, a down-regulation of cardiac UCP2, together with lower concentration of plasma leptin. Accordingly, leptin gene expression is reduced in the visceral WAT. CONCLUSION: Consumption of diets containing elevated amounts of saturated fat during adolescence and early adult life promotes cardiac steatosis in mice. An insufficient endocrine activity of WAT, in terms of leptin production, may account for such an effect.
Asunto(s)
Envejecimiento , Enfermedades Cardiovasculares/etiología , Grasas de la Dieta/efectos adversos , Leptina/fisiología , Tejido Adiposo Blanco/química , Tejido Adiposo Blanco/metabolismo , Factores de Edad , Animales , Enfermedades Cardiovasculares/fisiopatología , Carnitina O-Palmitoiltransferasa/metabolismo , Grasas de la Dieta/administración & dosificación , Grasas Insaturadas en la Dieta/administración & dosificación , Regulación hacia Abajo/efectos de los fármacos , Ácidos Grasos/análisis , Leptina/genética , Lípidos/análisis , Masculino , Ratones , Ratones Endogámicos C57BL , Miocardio/química , Miocardio/metabolismo , PPAR gamma/genética , Aceite de Palma/administración & dosificación , Aceite de Palma/química , Proteína Desacopladora 2/genéticaRESUMEN
Cobalt-catalyzed alkyne cyclotrimerization and crossed [2 + 2 + 2] cycloadditions are developed in a plug flow reactor. The protocol generally uses 5 mol % of Co2(CO)8 and is scalable at least at multigram scale. Efficient and scalable use of Co2(CO)8 for crossed reactions of diynes and alkynes has hardly any precedent.
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A catalytic, scalable intra- and intermolecular Pauson-Khand reaction protocol using generally 5 mol% of Co2(CO)8 as the catalyst in a plug flow reactor (PFR) is shown.
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Herein we report investigations into the p38alpha MAP kinase activity of trisubstituted imidazoles that led to the identification of compounds possessing highly potent in vivo activity. The SAR of a novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation.
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Antiinflamatorios/farmacología , Imidazoles/farmacología , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Piridinas/farmacología , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/metabolismo , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacocinética , Bencimidazoles/química , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Edema/tratamiento farmacológico , Receptores ErbB/metabolismo , Humanos , Imidazoles/química , Imidazoles/farmacocinética , Ratones , Ratones Endogámicos BALB C , Fragmentos de Péptidos/metabolismo , Piridinas/química , Piridinas/farmacocinética , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The synthesis of a series of C3'-cis-substituted carboxycyclopropyl glycines bearing a wide variety of functional groups is described, and the structure-activity relationship for this series as agonists of group II metabotropic glutamate receptors is reported.
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Glicina/química , Glicina/farmacología , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Cristalografía por Rayos X , Ciclización , Glicina/síntesis química , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38alphainhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNFalpha release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other p38 reference compounds. A SAR strategy to address CyP3A4 liability is also described.
Asunto(s)
Antiinflamatorios/síntesis química , Bencimidazoles/síntesis química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Administración Oral , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Bencimidazoles/química , Bencimidazoles/farmacología , Sitios de Unión , Disponibilidad Biológica , Colágeno , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Lipopolisacáridos/farmacología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Endogámicos BALB C , Proteína Quinasa 14 Activada por Mitógenos/química , Modelos Moleculares , Ratas , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
The asymmetric synthesis and biological activity of (2S,1'S,2'R,3'R)-2-(2'-carboxy-3'-hydroxymethylcyclopropyl) glycine ((+)-3) is described. This novel C-3' substituted carboxy cyclopropyl glycine is a highly potent group 2 and group 3 mGluR agonist that has proven to be orally active in both fear potentiated startle (animal model for anxiety) and PCP-induced motor activation (animal model for psychosis) assays in rats.
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Glicina/síntesis química , Receptores de Glutamato Metabotrópico/agonistas , Administración Oral , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , AMP Cíclico/biosíntesis , Miedo , Glicina/análogos & derivados , Glicina/química , Glicina/farmacología , Técnicas In Vitro , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
There are still some synthetic chemists who hesitate to use metal-mediated or -catalysed reactions. The Pauson-Khand reaction (PKR) is a powerful transformation that has now been sufficiently well developed to be routinely considered when planning a synthesis, especially of polycyclic complex molecules. This tutorial review aims to encourage the use of this process explaining the best ways of performing a PKR both in the stoichiometric and the catalytic version, showing the scope of the process and its limitations. Additionally, asymmetry can be introduced in the reaction using several strategies, which will be discussed. The most recent examples of the synthetic applications of the PKR in natural product synthesis will give the reader an idea of the great usefulness of this reaction.
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Hidrocarburos Policíclicos Aromáticos/síntesis química , Compuestos Bicíclicos con Puentes/síntesis química , Catálisis , Cobalto/química , Ciclización , Modelos Químicos , Estructura Molecular , Compuestos Organometálicos/síntesis químicaRESUMEN
The asymmetric synthesis and biological activity of (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-methylcyclopropyl) glycine 7 and its epimer at the C3' center 6 are described. Compound 7 is a highly potent and selective agonist for group 2 metabotropric glutamate receptors (mGluRs). It is also systemically 4 orders of magnitude more active in the fear-potentiated startle model of anxiety in rats than the rigid constrained bicyclic system LY354740. Therefore, we have shown that high molecular complexity of conformationally constrained bicyclic systems is not a requirement to achieve highly selective and potent group 2 mGluRs agonists.