RESUMEN
Myeloid cell leukemia-1 (MCL-1) is a member of the antiapoptotic BCL-2 proteins family and a key regulator of mitochondrial homeostasis. Overexpression of MCL-1 is found in many cancer cells and contributes to tumor progression, which makes it an attractive therapeutic target. Pursuing our previous study of macrocyclic indoles for the inhibition of MCL-1, we report herein the impact of both pyrazole and indole isomerism on the potency and overall properties of this family of compounds. We demonstrated that the incorporation of a fluorine atom on the naphthalene moiety was a necessary step to improve cellular potency and that, combined with the introduction of various side chains on the pyrazole, it enhanced solubility significantly. This exploration culminated in the discovery of compounds (Ra)-10 and (Ra)-15, possessing remarkable cellular potency and properties.
RESUMEN
Nitriles are recurring motifs in bioactive molecules and versatile functional groups in synthetic chemistry. Despite recent progress, direct introduction of a nitrile moiety in heteroarenes remains challenging. Recent developments in electrochemical reactions pave the way to more practical cyanation protocols. However, currently available methods typically require hazardous cyanide sources, expensive mediators, and often suffer from narrow substrate scope and laborious reaction set-up. To address the limitations of current synthetic methods, herein, an effective, sustainable, and scalable procedure for the direct C(sp2 )-H cyanation of aromatic N-heterocycles with a user-friendly flow-electrochemical set-up is reported. Furthermore, high substrate and functional-group tolerance is demonstrated, allowing late-stage functionalization of drug-like scaffolds, such as natural products and pharmaceuticals.
Asunto(s)
Productos Biológicos , Nitrilos , CianurosRESUMEN
Respiratory syncytial virus (RSV) is a seasonal virus that infects the lungs and airways of 64 million children and adults every year. It is a major cause of acute lower respiratory tract infection and is associated with significant morbidity and mortality. Despite the large medical and economic burden, treatment options for RSV-associated bronchiolitis and pneumonia are limited and mainly consist of supportive care. This publication covers the medicinal chemistry efforts resulting in the identification of JNJ-53718678, an orally bioavailable RSV inhibitor that was shown to be efficacious in a phase 2a challenge study in healthy adult subjects and that is currently being evaluated in hospitalized infants and adults. Cocrystal structures of several new derivatives helped in rationalizing some of the structure-activity relationship (SAR) trends observed.
Asunto(s)
Antivirales/química , Descubrimiento de Drogas/métodos , Imidazolidinas/química , Indoles/química , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Inhibidores de Proteínas Virales de Fusión/química , Administración Oral , Antivirales/administración & dosificación , Cristalografía por Rayos X/métodos , Células HeLa , Humanos , Imidazolidinas/administración & dosificación , Indoles/administración & dosificación , Estructura Secundaria de Proteína , Virus Sincitial Respiratorio Humano/fisiología , Inhibidores de Proteínas Virales de Fusión/administración & dosificaciónRESUMEN
Toll-like receptor (TLR) 7 and 8 agonists can potentially be used in the treatment of viral infections and are particularly promising for chronic hepatitis B virus (HBV) infection. An internal screening effort identified a pyrimidine Toll-like receptor 7 and 8 dual agonist. This provided a novel alternative over the previously reported adenine and pteridone type of agonists. Structure-activity relationship, lead optimization, in silico docking, pharmacokinetics, and demonstration of ex vivo and in vivo cytokine production of the lead compound are presented.
Asunto(s)
Antivirales/química , Virus de la Hepatitis B/efectos de los fármacos , Pirimidinas/química , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 8/agonistas , Animales , Antivirales/síntesis química , Antivirales/farmacocinética , Antivirales/farmacología , Simulación por Computador , Citocinas/biosíntesis , Perros , Hepatitis B/tratamiento farmacológico , Hepatitis B/virología , Virus de la Hepatitis B/fisiología , Ensayos Analíticos de Alto Rendimiento , Humanos , Macaca fascicularis , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
The enantioselective synthesis of the title compound, using Meyers' bicyclic lactam methodology, is described. This compound and a few of its derivatives are useful intermediates in natural product synthesis.
Asunto(s)
Indenos/síntesis química , Cetonas/síntesis química , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/química , Indenos/química , Cetonas/química , Lactamas/química , EstereoisomerismoRESUMEN
The synthesis and biological activity of novel CD-ring modified analogues of 22-oxa-1alpha,25-dihydroxyvitamin D(3), lacking the D-ring and featuring a connection between C-12 and C-21 (cis-perhydrindane CE-ring analogues), is described. The synthesis of the CE-ring system follows Meyers' methodology for the preparation of enantiomerically pure hydrinden-2-ones. The analogues show a complete lack of binding affinity for the vitamin D receptor (pig nVDR) and of antiproliferative activity (MCF-7 cells), as compared to calcitriol.