RESUMEN
γ-Aminobutyric acid (GABA) and GABA derivatives have attracted increased attention over the years in the fields of medicinal chemistry and chemical biology due to their interesting biological properties and synthetic relevance. Here, we report a short synthetic route to γ-(het)aryl- and γ-alkenyl-γ-aminobutyric acids, including the antiepileptic drug vigabatrin, from readily available donor-acceptor cyclopropanes and ammonia or methylamine. This protocol includes a facile synthesis of 2-oxopyrrolidine-3-carboxamides and their acid hydrolysis to γ-aryl- or γ-alkenyl-substituted GABAs, which can serve as perspective building blocks for the synthesis of various GABA-based N-heterocycles and bioactive compounds.
Asunto(s)
Vigabatrin , Ácido gamma-Aminobutírico , Anticonvulsivantes/farmacología , Vigabatrin/farmacología , Pirrolidinas/química , Pirrolidinas/farmacologíaRESUMEN
A Lewis-acid-promoted domino ring-opening cyclization of readily available donor-acceptor cyclopropanes with a preinstalled electrophilic center, embedded in a donor group, to functionalized 1,2-dihydronaphthalenes is reported herein. The obtained compounds are transformed to pharmacologically attractive bridged tricyclic esters in a diastereospecific manner.
RESUMEN
Lewis acid-catalysed reactions of donor-acceptor cyclopropanes with 1,3-disubstituted 5-aminopyrazoles were investigated. Under catalysis with gallium(III) chloride, products of the three-membered ring opening via a nucleophilic attack of the exocyclic amino group were obtained in a chemoselective manner. Oppositely, in the presence of scandium(III) triflate, products of either N-alkylation or C(4)-alkylation, or a mixture of both were formed. The products of the C(4) alkylation were transformed in one step into tetrahydropyrazolo[3,4-b]azepines that are attractive for medicinal chemistry and pharmacology.
Asunto(s)
Ciclopropanos , Galio , Azepinas , Cloruros , Ácidos de Lewis , Estructura Molecular , Pirazoles , EscandioRESUMEN
The importance of intramolecular constraints in cyclic transition-state geometries is especially pronounced in n-endo-tet cyclizations, where the usual backside approach of a nucleophile to the breaking bond is impossible for the rings containing less than eight atoms. Herein, we expand the limits of endo-tet cyclizations and show that donor-acceptor cyclopropanes can provide a seven-membered ring via a genuine 6-endo-tet process. Substrates containing a N-alkyl-N-arylcarbamoyl moiety as an acceptor group undergo Lewis acid-induced cyclization to form tetrahydrobenz[b]azepin-2-ones in high yields. The reaction proceeds with the inversion of the configuration at the electrophilic carbon. In this process, a formally six-membered transition state yields a seven-membered ring as the pre-existing cycle is merged into the forming ring. The stereochemistry of the products can be controlled by the reaction time and by the nature of Lewis acid, opening access to both diastereomers by tuning of the reaction conditions.
RESUMEN
We propose a new concept of the triple role of protic ionic liquids with nucleophilic anions: a) a regenerable solvent, b) a Brønsted acid inducing diverse transformations via general acid catalysis, and c) a source of a nucleophile. The efficiency of this strategy was demonstrated using thiocyanate-based protic ionic liquids for the ring-opening of donor-acceptor cyclopropanes. A wide variety of activated cyclopropanes were found to react with 1-methylimidazolium thiocyanate under mild metal-free conditions via unusual nitrogen attack of the ambident thiocyanate ion on the electrophilic center of the three-membered ring affording pyrrolidine-2-thiones bearing donor and acceptor substituents at the C(5) and C(3) atoms, respectively, in a single time-efficient step. The ability of 1-methylimidazolium thiocyanate to serve as a triplex reagent was exemplarily illustrated by (4+2)-annulation with 1-acyl-2-(2-hydroxyphenyl)cyclopropane, epoxide ring-opening and other organic transformations.
RESUMEN
A straightforward method for ring opening of donor-acceptor cyclopropanes with trimethylsilyl cyanide as a surrogate of cyanide ion in the presence of B(C6F5)3 or trifluoromethanesulfonic acid as a catalyst has been developed. The methodology provides a short route to γ-cyanoesters that can be useful synthetic intermediates for the synthesis of diverse bioactive molecules such as glutaric and δ-aminovaleric acid derivatives, 3-arylpiperidines, or other substituted phenethylamines. Oppositely, the attempts to synthesize these γ-cyanoesters by direct reaction of cyclopropanes with sodium cyanide under typical SN2 conditions led to the formation of 2-arylsuccinonitriles.
RESUMEN
Into the fold: Prion diseases are neurodegenerative disorders characterized by the accumulation in the brain of a self-replicating, misfolded isoform (PrPSc ) of the cellular prion protein (PrPC ). No therapies are available for these pathologies. We capitalized on previously described cell-based assays to screen a library of small molecules, and identified 55, a compound capable of counteracting both prion replication and toxicity. Compound 55 may represent the starting point for the development of a completely new class of therapeutics for prion diseases.
Asunto(s)
Proteínas Priónicas/metabolismo , Bibliotecas de Moléculas Pequeñas/metabolismo , Animales , Encéfalo/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células HEK293 , Humanos , Concentración 50 Inhibidora , Mutagénesis , Proteínas PrPSc/antagonistas & inhibidores , Proteínas PrPSc/genética , Proteínas PrPSc/metabolismo , Enfermedades por Prión/metabolismo , Enfermedades por Prión/patología , Proteínas Priónicas/antagonistas & inhibidores , Proteínas Priónicas/genética , Unión Proteica , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/toxicidadRESUMEN
We report the discovery of the bicyclic octahydrocyclohepta[b]pyrrol-4(1H)-one scaffold as a new chemotype with anti-HCV activity on genotype 1b and 2a subgenomic replicons. The most potent compound 34 displayed EC50 values of 1.8 µM and 4.5 µM in genotype 1b and 2a, respectively, coupled with the absence of any antimetabolic effect (gt 1b SI = 112.4; gt 2a SI = 44.2) in a cell-based assay. Compound 34 did not target HCV NS5B, IRES, NS3 helicase, or selected host factors, and thus future work will involve the unique mechanism of action of these new antiviral compounds.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Hepacivirus/efectos de los fármacos , Línea Celular , Genotipo , Hepacivirus/genética , Hepacivirus/fisiología , Humanos , Replicación Viral/efectos de los fármacosRESUMEN
Matrix metalloproteinases (MMPs) are well-established targets for several pathologies. In particular, MMP-2 and MMP-13 play a prominent role in cancer progression. In this study, a structure-based screening campaign was applied to prioritize metalloproteinase-oriented fragments. This computational model was applied to a representative fragment set from the publically available EDASA Scientific compound library. These fragments were prioritized, and the top-ranking hits were tested in a biological assay to validate the model. Two scaffolds showed consistent activity in the assay, and the isatin-based compounds were the most interesting. These latter fragments have significant potential as tools for the design and realization of novel MMP inhibitors. In addition to their micromolar activity, the chemical synthesis affords flexible and creative access to their analogues.
Asunto(s)
Descubrimiento de Drogas , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A facile one-pot approach based on a thermally induced metal- and solvent-free 5-endo-dig cyclization reaction of the amino propargylic alcohols in combination with Dess-Martin periodinane-promoted oxidative dearomatization of 4,5,6,7-tetrahydroindole intermediates provides an efficient and robust access to 5,6-dihydro-1H-indol-2(4H)ones. Green, relatively mild and operationally simple characteristics of the synthetic sequence are the major advantages, which greatly amplify the developed methodology. The utility of obtained indolones as unified key precursors is demonstrated by the application of these products to the formal total syntheses of a whole pleiad of Erythrina- and Lycorine-type alkaloids, namely (±)-erysotramidine, (±)-erysotrine, (±)-erythravine, (±)-γ-lycorane, and abnormal erythrinanes (±)-coccoline and (±)-coccuvinine.
Asunto(s)
Alcaloides/síntesis química , Alcaloides de Amaryllidaceae/síntesis química , Erythrina/química , Indoles/química , Fenantridinas/síntesis química , Alcaloides/química , Alcaloides de Amaryllidaceae/química , Ciclización , Tecnología Química Verde/métodos , Hidrocarburos Yodados/síntesis química , Hidrocarburos Yodados/química , Indoles/síntesis química , Oxidación-Reducción , Fenantridinas/química , Estereoisomerismo , TemperaturaRESUMEN
The 2-oxo-1, 2-dihydroquinoline Chemotype is well represented among screening compound collection. However, the chemical space of 2-oxo-1, 2-dihydroquinoline has not been thoroughly investigated. In this work we report the synthesis of a small but novel 2-oxo-1, 2-dihydroquinoline compound array for screening purposes, especially in drug discovery, possessing three convenient point of diversity.
RESUMEN
Earlier we reported the discovery and design of NBD-556 and their analogs which demonstrated their potential as HIV-1 entry inhibitors. However, progress in developing these inhibitors has been stymied by their CD4-agonist properties, an unfavorable trait for use as drug. Here, we demonstrate the successful conversion of a full CD4-agonist (NBD-556) through a partial CD4-agonist (NBD-09027), to a full CD4-antagonist (NBD-11021) by structure-based modification of the critical oxalamide midregion, previously thought to be intolerant of modification. NBD-11021 showed unprecedented neutralization breath for this class of inhibitors, with pan-neutralization against a panel of 56 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates (IC50 as low as 270 nM). The cocrystal structure of NBD-11021 complexed to a monomeric HIV-1 gp120 core revealed its detail binding characteristics. The study is expected to provide a framework for further development of NBD series as HIV-1 entry inhibitors for clinical application against AIDS.
Asunto(s)
Fármacos Anti-VIH/química , Antígenos CD4/metabolismo , VIH-1/efectos de los fármacos , Oxalatos/química , Piperidinas/química , Pirroles/química , Tiazoles/química , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Fusión Celular , Línea Celular , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/metabolismo , Transcriptasa Inversa del VIH/metabolismo , VIH-1/aislamiento & purificación , VIH-1/fisiología , Humanos , Enlace de Hidrógeno , Modelos Moleculares , Conformación Molecular , Oxalatos/síntesis química , Oxalatos/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Conformación Proteica , Pirroles/síntesis química , Pirroles/farmacología , Receptores CCR5/metabolismo , Receptores CXCR4/metabolismo , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacología , Internalización del Virus/efectos de los fármacosRESUMEN
Although all-oral direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) treatment is now a reality, today's HCV drugs are expensive, and more affordable drugs are still urgently needed. In this work, we report the identification of the 2-phenyl-4,5,6,7-Tetrahydro-1H-indole chemical scaffold that inhibits cellular replication of HCV genotype 1b and 2a subgenomic replicons. The anti-HCV genotype 1b and 2a profiling and effects on cell viability of a selected representative set of derivatives as well as their chemical synthesis are described herein. The most potent compound 39 displayed EC50 values of 7.9 and 2.6 µM in genotype 1b and 2a, respectively. Biochemical assays showed that derivative 39 had no effect on HCV NS5B polymerase, NS3 helicase, IRES mediated translation and selected host factors. Thus, future work will involve both the chemical optimization and target identification of 2-phenyl-4,5,6,7-Tetrahydro-1H-indoles as new anti-HCV agents.
Asunto(s)
Antivirales/farmacología , Descubrimiento de Drogas , Hepacivirus/efectos de los fármacos , Indoles/farmacología , Antivirales/síntesis química , Antivirales/química , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Indoles/síntesis química , Indoles/química , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
Herein we suggest an approach to oxygenated bicyclic amino acids based on an aza-Cope-Mannich rearrangement. Seven distinct amino acid scaffolds analogous to the natural products were prepared on a gram scale with precise control of stereochemistry. Successful implementation of our strategy resulted in the formal synthesis of acetylaranotin.