Asunto(s)
Hidrocarburos Aromáticos con Puentes/síntesis química , Limoninas/síntesis química , Hidrocarburos Aromáticos con Puentes/química , Insecticidas/síntesis química , Insecticidas/química , Limoninas/química , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Naftalenos/síntesis química , Naftalenos/químicaRESUMEN
The efficient regulation of cholesterol biosynthesis, metabolism, acquisition, and transport is an essential component of lipid homeostasis. The farnesoid X receptor (FXR) is a transcriptional sensor for bile acids, the primary product of cholesterol metabolism. Accordingly, the development of potent, selective, small molecule agonists, partial agonists, and antagonists of FXR would be an important step in further deconvoluting FXR physiology. Herein, we describe the development of four novel classes of potent FXR activators originating from natural product-like libraries. Initial screening of a 10,000-membered, diversity-orientated library of benzopyran containing small molecules for FXR activation utilizing a cell-based reporter assay led to the identification of several lead compounds possessing low micromolar activity (EC50's = 5-10 microM). These compounds were systematically optimized employing parallel solution-phase synthesis and solid-phase synthesis to provide four classes of compounds that potently activate FXR. Two series of compounds, bearing stilbene or biaryl moieties, contain members that are the most potent FXR agonists reported to date in cell-based assays. These compounds may find future utility as chemical tools in studies aimed at further defining the physiological role of FXR and discovering potential therapeutic agents for the treatment of diseases linked to cholesterol and bile acid metabolism and homeostasis.
Asunto(s)
Proteínas de Unión al ADN/agonistas , Factores de Transcripción/agonistas , Benzopiranos/síntesis química , Bilis/metabolismo , Ácidos y Sales Biliares/metabolismo , Factores Biológicos , Colesterol/metabolismo , Proteínas de Unión al ADN/síntesis química , Proteínas de Unión al ADN/fisiología , Evaluación Preclínica de Medicamentos/métodos , Ligandos , Estructura Molecular , Receptores Citoplasmáticos y Nucleares , Factores de Transcripción/síntesis química , Factores de Transcripción/fisiologíaRESUMEN
The farnesoid X receptor (FXR) functions as a bile acid (BA) sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins. However, BAs are poor reagents for characterizing FXR functions due to multiple receptor independent properties. Accordingly, using combinatorial chemistry we evolved a small molecule agonist termed fexaramine with 100-fold increased affinity relative to natural compounds. Gene-profiling experiments conducted in hepatocytes with FXR-specific fexaramine versus the primary BA chenodeoxycholic acid (CDCA) produced remarkably distinct genomic targets. Highly diffracting cocrystals (1.78 A) of fexaramine bound to the ligand binding domain of FXR revealed the agonist sequestered in a 726 A(3) hydrophobic cavity and suggest a mechanistic basis for the initial step in the BA signaling pathway. The discovery of fexaramine will allow us to unravel the FXR genetic network from the BA network and selectively manipulate components of the cholesterol pathway that may be useful in treating cholesterol-related human diseases.
Asunto(s)
Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/agonistas , Proteínas de Unión al ADN/química , Hepatocitos/metabolismo , Factores de Transcripción/química , Secuencia de Aminoácidos/genética , Animales , Derivados del Benceno/síntesis química , Derivados del Benceno/farmacología , Sitios de Unión/efectos de los fármacos , Sitios de Unión/fisiología , Ácido Quenodesoxicólico/metabolismo , Colon/metabolismo , Reacciones Cruzadas/genética , Proteínas de Unión al ADN/agonistas , Proteínas de Unión al ADN/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/genética , Marcación de Gen , Biblioteca Genómica , Hepatocitos/efectos de los fármacos , Humanos , Hígado/metabolismo , Conformación Molecular , Estructura Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos , Estructura Terciaria de Proteína/efectos de los fármacos , Estructura Terciaria de Proteína/genética , ARN Mensajero/genética , Receptores Citoplasmáticos y Nucleares , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factores de Transcripción/agonistas , Factores de Transcripción/genéticaRESUMEN
Using a polymer-bound selenenyl bromide resin, o-allyl and o-prenyl anilines were cycloaded to afford a series of solid-supported indoline and indole scaffolds. These scaffolds were then functionalized and cleaved via four distinct methods, namely traceless reduction, radical cyclization, radical rearrangement, and oxidative elimination, to afford 2-methyl indolines, polycyclic indolines, 2-methyl indoles, and 2-propenyl indolines, respectively. A number of small combinatorial libraries of compounds reminiscent of certain designed ligands of biological interest were constructed demonstrating the potential utility of the developed methodology to chemical biology studies and the drug discovery process.
Asunto(s)
Técnicas Químicas Combinatorias/métodos , Indoles/síntesis química , Compuestos de Anilina/química , Ciclización , Diseño de Fármacos , Radicales Libres/química , Oxidación-Reducción , Relación Estructura-ActividadRESUMEN
Psammaplin A is a symmetrical bromotyrosine-derived disulfide natural product isolated from the Psammaplysilla sponge, which exhibits in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Inspired by the structure of this marine natural product, a combinatorial scrambling strategy for the construction of heterodimeric disulfide analogues was developed and applied to the construction of a 3828-membered library starting from 88 homodimeric disulfides. These psammaplin A analogues were screened directly against various gram positive bacterial strains leading to the discovery of a series of potent antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA). Among the most active leads derived from these studies are compounds 104, 105, 113, 115, 123, and 128. The present, catalytically-induced, disulfide exchange strategy may be extendable to other types of building blocks bearing thiol groups facilitating the construction of diverse discovery-oriented combinatorial libraries.