RESUMEN
Following our interest in new diterpene glycosides with better taste profiles than that of Rebaudioside M, we have recently isolated and characterized Rebaudioside IX-a novel steviol glycoside-from a commercially-supplied extract of Stevia rebaudiana Bertoni. This molecule contains a hexasaccharide group attached at C-13 of the central diterpene core, and contains three additional glucose units when compared with Rebaudioside M. Here we report the complete structure elucidation-based on extensive Nuclear Magnetic Resonance (NMR) analysis (1H, 13C, Correlation Spectroscopy (COSY), Heteronuclear Single Quantum Coherence-Distortionless Enhancement Polarization Transfer (HSQC-DEPT), Heteronuclear Multiple Bond Correlation (HMBC), 1D Total Correlation Spectroscopy (TOCSY), Nuclear Overhauser Effect Spectroscopy (NOESY)) and mass spectral data-of this novel diterpene glycoside with nine sugar moieties and containing a relatively rare 1ï 6 α-linked glycoside. A steviol glycoside bearing nine glucose units is unprecedented in the literature, and could have an impact on the natural sweetener catalog.
Asunto(s)
Diterpenos/química , Glicósidos/química , Stevia/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Extractos Vegetales/químicaRESUMEN
In a continued search for novel diterpenoid glycosides, we recently isolated and characterized a Rebaudioside M derivative with a hydroxyl group at position 15 in the central diterpene core from an extract of Stevia rebaudiana Bertoni. Here we report the complete structure elucidation of 15α-hydroxy-Rebaudioside M (2) on the basis of NMR (1H, 13C, COSY, HSQC-DEPT, HMBC, 1D TOCSY, NOESY) and mass spectral data. Steviol glycoside with a hydroxyl group at C-15 in the central diterpene core has not been previously reported.
Asunto(s)
Stevia/química , Diterpenos/química , Diterpenos/aislamiento & purificación , Glicósidos/química , Glicósidos/aislamiento & purificaciónRESUMEN
A series of potent indolyl azetidine rMCHR1 antagonists were found to show poor CNS penetration due to Pgp efflux. We envisioned a strategy which included: lowering basicity; changing the conformational flexibility motif; and removal of a hydrogen bond donor, in an attempt to optimize this property while maintaining target receptor efficacy. This work resulted in mitigation of Pgp efflux, and led us to identify 1-dihydroindolyl azetidine derivatives with CNS penetration and excellent rMCHR1 binding affinity.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Azetidinas/farmacología , Indoles/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/deficiencia , Animales , Azetidinas/síntesis química , Azetidinas/química , Enlace de Hidrógeno , Indoles/síntesis química , Indoles/química , Ratones , Ratones Noqueados , Estructura Molecular , Ratas , Receptores de Somatostatina/metabolismo , EstereoisomerismoRESUMEN
There is an increasing amount of evidence to support that activation of the metabotropic glutamate receptor 4 (mGlu4 receptor), either with an orthosteric agonist or a positive allosteric modulator (PAM), provides impactful interventions in diseases such as Parkinson's disease, anxiety, and pain. mGlu4 PAMs may have several advantages over mGlu4 agonists for a number of reasons. As part of our efforts in identifying therapeutics for central nervous system (CNS) diseases such as Parkinson's disease, we have been focusing on metabotropic glutamate receptors. Herein we report our studies with a series of tricyclic thiazolopyrazoles as mGlu4 PAMs.
Asunto(s)
Fármacos del Sistema Nervioso Central/síntesis química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Pirazoles/síntesis química , Receptores de Glutamato Metabotrópico/fisiología , Regulación Alostérica , Animales , Compuestos Aza/síntesis química , Compuestos Aza/química , Compuestos Aza/farmacología , Azulenos/síntesis química , Azulenos/química , Azulenos/farmacología , Encéfalo/metabolismo , Línea Celular , Fármacos del Sistema Nervioso Central/química , Fármacos del Sistema Nervioso Central/farmacología , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Técnicas In Vitro , Indazoles/síntesis química , Indazoles/química , Indazoles/farmacología , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Permeabilidad , Pirazoles/química , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A full account of concise, enantioselective syntheses of the anticancer agent (-)-salinosporamide A and derivatives, including (-)-homosalinosporamide, that was inspired by biosynthetic considerations is described. The brevity of the synthetic strategy stems from a key bis-cyclization of a ß-keto tertiary amide, which retains optical purity enabled by A(1,3)-strain rendering slow epimerization relative to the rate of bis-cyclization. Optimization studies of the key bis-cyclization, enabled through byproduct isolation and characterization, are described that ultimately allowed for a gram scale synthesis of a versatile bicyclic core structure with a high degree of stereoretention. An optimized procedure for zincate generation by the method of Knochel, generally useful for the synthesis of salino A derivatives, led to dramatic improvements in side-chain attachment and a novel diastereomer of salino A. The versatility of the described strategy is demonstrated by the synthesis of designed derivatives including (-)-homosalinosporamide A. Inhibition of the human 20S and 26S proteasome by these derivatives using an enzymatic assay are also reported. The described total synthesis of salino A raises interesting questions regarding how biosynthetic enzymes leading to the salinosporamides proceeding via optically active ß-keto secondary amides, are able to maintain the stereochemical integrity at the labile C2 stereocenter or if a dynamic kinetic resolution is operative.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Lactonas/síntesis química , Lactonas/farmacología , Inhibidores de Proteasoma , Pirroles/síntesis química , Pirroles/farmacología , Antineoplásicos/química , Catálisis , Cristalografía por Rayos X , Ciclización , Humanos , Lactonas/química , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura Molecular , Complejo de la Endopetidasa Proteasomal/química , Complejo de la Endopetidasa Proteasomal/metabolismo , Pirroles/química , EstereoisomerismoRESUMEN
A concise, enantioselective synthesis of the Phase I anticancer agent, (-)-salinosporamide A, is described. The brevity of the described strategy stems from a key bis-cyclization of a beta-keto tertiary amide, accomplished on gram scale, which retains optical purity enabled by A(1,3)-strain rendering epimerization slow relative to the rate of bis-cyclization. The versatility of the strategy for derivative synthesis is demonstrated by the synthesis of (-)-homosalinosporamide A.
Asunto(s)
Amidas/química , Antineoplásicos/síntesis química , Lactonas/síntesis química , Pirroles/síntesis química , Antineoplásicos/química , Cristalografía por Rayos X , Ciclización , Lactonas/química , Conformación Molecular , Pirroles/química , EstereoisomerismoRESUMEN
Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report on the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a beta-lactone as the central pharmacophore, 28 novel congeners were synthesized and examined. Structural features such as the length of the alpha- and beta-alkyl chains, their chemical composition, and amino ester substitutions were altered and the resulting compounds explored for inhibitory activity toward the thioesterase domain of FAS. Nineteen congeners show improved potency for FAS in biochemical assays relative to orlistat. Three of that subset, including the natural product valilactone, also display an increased potency in inducing tumor cell death and improved solubility compared to orlistat. These findings support the idea that an orlistat congener can be optimized for use in a preclinical drug design and for clinical drug development.
Asunto(s)
Antineoplásicos/síntesis química , Ácido Graso Sintasas/antagonistas & inhibidores , Lactonas/síntesis química , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Fibroblastos , Humanos , Lactonas/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Orlistat , Solubilidad , Relación Estructura-ActividadRESUMEN
Natural products continue to demonstrate their utility both as therapeutics and as molecular probes for the discovery and mechanistic deconvolution of various cellular processes. However, this utility is dampened by the inherent difficulties involved in isolating and characterizing new bioactive natural products, in obtaining sufficient quantities of purified compound for further biological studies, and in developing bioactive probes. Key to characterizing the biological activity of natural products is the identification of the molecular target(s) within the cell. The marine sponge-derived natural product Pateamine A (PatA) has been found to be an inhibitor of eukaryotic translation initiation. Herein, we describe the methods utilized for identification of the eukaryotic translation initiation factor 4A (eIF4A) as one of the primary protein targets of PatA. We begin by describing the synthesis of an active biotin conjugate of PatA (B-PatA), made possible by total synthesis, followed by its use for affinity purification of PatA binding proteins from cellular lysates. We have attempted to present the methodology as a general technique for the identification of protein targets for small molecules including natural products.
Asunto(s)
Compuestos Epoxi/aislamiento & purificación , Compuestos Epoxi/farmacología , Factor 4A Eucariótico de Iniciación/antagonistas & inhibidores , Macrólidos/aislamiento & purificación , Macrólidos/farmacología , Tiazoles/aislamiento & purificación , Tiazoles/farmacología , Animales , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Biotina/química , Biotina/metabolismo , Cromatografía de Afinidad , Ciclohexilaminas/química , Diseño de Fármacos , Compuestos Epoxi/química , Compuestos Epoxi/metabolismo , Factor 4A Eucariótico de Iniciación/aislamiento & purificación , Humanos , Macrólidos/síntesis química , Macrólidos/química , Macrólidos/metabolismo , Modelos Biológicos , Unión Proteica , Sefarosa/análogos & derivados , Sefarosa/química , Sefarosa/metabolismo , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/metabolismoRESUMEN
4-Alkylidene-beta-lactones (hetero ketene dimers) and alpha-amino acids are useful precursors for total syntheses of the beta-lactone-containing proteasome inhibitors salinosporamide A, cinnabaramide A, and derivatives. A key step is a nucleophile-promoted, bis-cyclization of keto acids that simultaneously generates the gamma-lactam and beta-lactone of these natural products. This reaction sequence may have implications for the biosynthesis of these natural products.
Asunto(s)
Lactonas/síntesis química , Pirroles/síntesis química , Color , Estructura MolecularRESUMEN
Concise syntheses of orlistat (Xenical), a two-carbon transposed orlistat derivative, and valilactone are described that employ the tandem Mukaiyama aldol-lactonization (TMAL) process as a key step. This process allows facile modification of the alpha-side chain. Versatile strategies for modifying the delta-side chain are described, involving cuprate addition and olefin metathesis. Comparative antagonistic activity of these derivatives toward a recombinant form of the thioesterase domain of fatty acid synthase is reported along with comparative activity-based profiling.