RESUMEN
A novel series of potent agonists of the bile acid receptor TGR5 bearing a dihydropyridone scaffold was developed from a high-throughput screen. Starting from a micromolar hit compound, we implemented an extensive structure-activity-relationship (SAR) study with the synthesis and biological evaluation of 83 analogues. The project culminated with the identification of the potent nanomolar TGR5 agonist 77A. We report the GLP-1 secretagogue effect of our lead compound ex vivo in mouse colonoids and in vivo. In addition, to identify specific features favorable for TGR5 activation, we generated and optimized a three-dimensional quantitative SAR model that contributed to our understanding of our activity profile and could guide further development of this dihydropyridone series.
Asunto(s)
Relación Estructura-Actividad Cuantitativa , Factores de Transcripción , Animales , Ratones , Péptido 1 Similar al Glucagón , Ácidos y Sales BiliaresRESUMEN
Cyclopropyl malonoyl peroxide (1), which can be prepared in a single step from the commercially available diacid, is an effective reagent for the dihydroxylation of alkenes. Reaction of 1 with an alkene in the presence of 1 equiv of water at 40 °C followed by alkaline hydrolysis leads to the corresponding diol (40-93%). With 1,2-disubstituted alkenes, the reaction proceeds with syn selectivity (3:1 to >50:1). A mechanism consistent with the experimental findings that is supported by oxygen-labeling studies is proposed.
Asunto(s)
Alquenos/química , Peróxidos/química , HidroxilaciónRESUMEN
The effect of fluorinated alcohols on the dihydroxylation of alkenes using cyclopropyl malonoyl peroxide is described. Addition of perfluoro-tert-butyl alcohol to a toluene solution of alkene and peroxide increases the rate of product formation and the stereoselectivity observed, providing a simple and effective method for acceleration of this important class of reaction. Basic hydrolysis of the crude reaction mixture provides access to syn-diols in high yield and stereoselectivity.
Asunto(s)
Alcoholes/síntesis química , Alquenos/química , Hidrocarburos Fluorados/química , Peróxidos/química , Alcoholes/química , Catálisis , Hidrólisis , Hidroxilación , Estructura MolecularRESUMEN
A six-step synthesis of the tetracyclic core of the natural compound (+/-)-dibromoagelaspongin, isolated from Agelas sp. Sponge, was achieved from the commercially available 5-aminopentan-1-ol, 2-trichloroacetylpyrrole, and 2-aminopyrimidine. Following a biomimetic inspired approach, successive oxidative reactions including the final DMDO biomimetic oxidation gave the interesting triaminomethane-fused core.