RESUMEN
Autophagy is postulated to be required by cancer cells to survive periods of metabolic and/or hypoxic stress. ATG7 is the E1 enzyme that is required for activation of Ubl conjugation pathways involved in autophagosome formation. This article describes the design and optimization of pyrazolopyrimidine sulfamate compounds as potent and selective inhibitors of ATG7. Cellular levels of the autophagy markers, LC3B and NBR1, are regulated following treatment with these compounds.
Asunto(s)
Proteína 7 Relacionada con la Autofagia/antagonistas & inhibidores , Descubrimiento de Drogas , Pirazoles/farmacología , Pirimidinas/farmacología , Ácidos Sulfónicos/farmacología , Autofagia/efectos de los fármacos , Proteína 7 Relacionada con la Autofagia/metabolismo , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad , Ácidos Sulfónicos/síntesis química , Ácidos Sulfónicos/químicaRESUMEN
Investigations of a biaryl ether scaffold identified tetrahydronaphthalene Raf inhibitors with good in vivo activity; however these compounds had affinity toward the hERG potassium channel. Herein we describe our work to eliminate this hERG activity via alteration of the substituents on the benzoic amide functionality. The resulting compounds have improved selectivity against the hERG channel, good pharmacokinetic properties and potently inhibit the Raf pathway in vivo.
Asunto(s)
Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Tetrahidronaftalenos/química , Animales , Línea Celular Tumoral , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Mutagénesis , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tetrahidronaftalenos/farmacocinética , Tetrahidronaftalenos/uso terapéutico , Trasplante HeterólogoRESUMEN
Tandem carbonyl ylide formation-1,3-dipolar cycloaddition of alpha-diazo N-acetyl-tetrahydro-beta-carbolin-1-one derivatives occur efficiently in the presence of a dirhodium catalyst to afford bimolecular cycloadducts in high yield. The Rh(II)-catalyzed reaction also takes place intramolecularly to give products derived from trapping of the carbonyl ylide dipole with a tethered alkene. The power of the intramolecular cascade sequence is that it rapidly assembles a pentacyclic ring system containing three new stereocenters and two adjacent quaternary centers stereospecifically in a single step and in high yield.
RESUMEN
The quasi-antiaromatic 2H-indol-2-one ring system is readily generated by treating a 3-hydroxy-substituted 1,3-dihydroindol-2-one with a Lewis acid. Stepwise addition of various pi-nucleophiles to the highly reactive 2H-indol-2-one system occurs smoothly to afford substituted oxindoles. The cyclization was also carried out in an intramolecular fashion to give spiro-substituted oxindoles in good yield.
Asunto(s)
Indoles/química , Compuestos Macrocíclicos/síntesis química , Ciclización , Indoles/síntesis química , Compuestos Macrocíclicos/química , Estructura MolecularRESUMEN
A synthesis of (+/-)-3H-epivincamine is reported. Important steps include (1) a Rh(II)-catalyzed intramolecular [3+2]-cycloaddition of an alpha-diazo indolo amide, (2) a reductive ring opening of the cycloadduct, (3) a decarboethoxylation reaction, and (4) a base-induced keto-amide ring contraction.
Asunto(s)
Rodio/química , Vincamina/síntesis química , Antihipertensivos/síntesis química , Ciclización , Vasodilatadores/síntesis químicaRESUMEN
[reaction: see text] The synthesis of the highly substituted indole portion of the complex tremorgenic natural products lolicine A and B is presented. The Diels-Alder reaction of a quinone monoimine enables the synthesis of an appropriately substituted indole. The key step in the synthesis is a tandem isopropenyl cuprate addition/aldol cyclocondensation which provides the necessary functionality for elaboration to the 2,2,5,5-tetramethyltetrahydrofuran.
Asunto(s)
Indoles/síntesis química , Micotoxinas/síntesis química , Terpenos/síntesis química , Cristalografía por Rayos X , Ciclización , Indoles/química , Hongos Mitospóricos/química , Conformación Molecular , Estructura Molecular , Micotoxinas/química , Terpenos/químicaRESUMEN
Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.
Asunto(s)
Antineoplásicos/síntesis química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Tetrahidronaftalenos/síntesis química , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Disponibilidad Biológica , Cristalografía por Rayos X , Diseño de Fármacos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/enzimología , Melanoma Experimental/patología , Ratones , Ratones Desnudos , Modelos Moleculares , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Estereoisomerismo , Relación Estructura-Actividad , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The total synthesis of several members of the vinca and tacaman classes of indole alkaloids has been accomplished. The central step in the synthesis consists of an intramolecular [3+2]-cycloaddition reaction of an alpha-diazo indoloamide which delivers the pentacyclic skeleton of the natural product in excellent yield. The acid lability of the oxabicyclic structure was exploited to establish the trans-D/E ring fusion of (+/-)-3H-epivincamine (3). Finally, a base induced keto-amide ring contraction was utilized to generate the E-ring of the natural product. A variation of the cascade sequence of reactions used to synthesize (+/-)-3H-epivincamine was also employed for the synthesis of the tacaman alkaloids (+/-)-tacamonine and (+/-)-apotacamine.
Asunto(s)
Alcaloides Indólicos/síntesis química , Indoles/química , Rodio/química , Alcaloides de la Vinca/síntesis química , Vinca/química , Catálisis , Ciclización , Alcaloides Indólicos/química , Estructura Molecular , Estereoisomerismo , Alcaloides de la Vinca/químicaRESUMEN
A series of N-propargylindole-2-carboxamides were found to undergo a AuCl 3-catalyzed cycloisomerization to give beta-carbolinones in high yield. The corresponding beta-chlorocarboline derivative was prepared and used for Pd(0)-catalyzed cross-coupling chemistry directed toward the synthesis of lavendamycin analogues.
Asunto(s)
Alquinos/química , Compuestos de Oro/química , Indoles/química , Estreptonigrina/análogos & derivados , Carbolinas/síntesis química , Carbolinas/química , Catálisis , Ciclización , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Paladio/química , Estereoisomerismo , Estreptonigrina/síntesis química , Estreptonigrina/químicaRESUMEN
N-arylsulfonyl quinone monoimines undergo smooth cycloadditions in a [4+2] sense to yield the expected cycloadducts. The crude cycloadducts, when subjected to a short series of simple transformations, produce synthetically useful quantities of 5-triflyloxyindoles in excellent overall yields. Such compounds are excellent participants in cross-coupling chemistry.