RESUMEN
A synthetic approach towards the core of a structurally unique cytotoxic indole alkaloid eleganine A has been accomplished for the first time. The synthesis features a stereoselective Ireland-Claisen rearrangement as the key step, enabling the installation of 2 stereogenic centers and a stereodefined double bond in a single step. Furthermore, a SnCl4 promoted acylation of the indole C-2 position allows the coupling of a highly functionalized 4-ethylidene proline fragment with the indole part.
RESUMEN
The metabotropic glutamate receptor subtype 5 has evolved into a promising target for the treatment of various diseases of the central nervous system, such as Fragile X and L-DOPA induced dyskinesia. One of the most advanced clinical compound is Novartis' AFQ-056 (Mavoglurant), which served us as a template for a scaffold hopping approach, generating a structurally diverse set of potent analogs. Both the limited aqueous solubility and the relatively poor metabolic stability of AFQ-056 were improved with hexahydrocyclopenta[c]pyrrole derivative 54a, which proved to be a valuable candidate for further development.
Asunto(s)
Indoles/química , Indoles/farmacología , Receptor del Glutamato Metabotropico 5/metabolismo , Regulación Alostérica , Animales , Células CHO , Cricetulus , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Receptor del Glutamato Metabotropico 5/química , Relación Estructura-ActividadRESUMEN
Stereoselective total syntheses of Limazepine E and Barmumycin, potent, naturally occurring antitumor agents, are described. The total syntheses control the olefin geometry via a highly selective chelation-controlled Ireland-Claisen rearrangement of a seven-membered lactone-derived boron enolate for the synthesis of (E)-4-ethylidene proline, a crucial building block for a number of natural products.
Asunto(s)
Alquenos/química , Antineoplásicos/síntesis química , Azepinas/síntesis química , Pirrolidinas/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Azepinas/química , Azepinas/farmacología , Estructura Molecular , Pirrolidinas/química , Pirrolidinas/farmacología , EstereoisomerismoRESUMEN
A virtual screening approach using various in silico methodologies led to the discovery of 2-(m-tolylamino)-7,8-dihydroquinazolin-5(6H)-one (1) as a moderately active negative allosteric modulator (NAM) of the metabotropic glutamate receptor subtype 5 (mGluR5) showing high selectivity against the subtype mGluR1. Modifications of the parent compound by rational design yielded a series of highly potent derivatives which will serve as valuable starting points for further hit-to-lead optimization efforts toward a suitable drug candidate for the treatment of L-DOPA induced dyskinesia.