RESUMEN
In order to identify structural features of pyrimethamine (5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine) that contribute to its inhibitory activity (IC50 value) and chaperoning efficacy toward ß-N-acetylhexosaminidase, derivatives of the compound were synthesized that differ at the positions bearing the amino, ethyl, and chloro groups. Whereas the amino groups proved to be critical to its inhibitory activity, a variety of substitutions at the chloro position only increased its IC50 by 2-3-fold. Replacing the ethyl group at the 6-position with butyl or methyl groups increased IC50 more than 10-fold. Surprisingly, despite its higher IC50, a derivative lacking the chlorine atom in the para-position was found to enhance enzyme activity in live patient cells a further 25% at concentrations >100 µM, while showing less toxicity. These findings demonstrate the importance of the phenyl group in modulating the chaperoning efficacy and toxicity profile of the derivatives.
Asunto(s)
Proteínas Mutantes/metabolismo , Mutación/genética , Pirimetamina/química , Pirimetamina/metabolismo , beta-N-Acetilhexosaminidasas/metabolismo , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/genética , Células Cultivadas , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Fibroblastos/patología , Humanos , Modelos Moleculares , Estructura Molecular , Proteínas Mutantes/genética , Relación Estructura-ActividadRESUMEN
The total synthesis of the thiopeptide antibiotic, thiocillin I, is described. This work unequivocally defines the full structure (constitution and configuration) of the natural product as 1.
Asunto(s)
Antibacterianos/síntesis química , Péptidos/síntesis química , Antibacterianos/química , Estructura Molecular , Péptidos/químicaRESUMEN
The oxidation of 2-methylthiazoles to 2-formylthiazoles simplifies the implementation of the Bagley variant of the Bohlmann-Rahtz reaction as a key step in a concise new route to pyridine cores of thiopeptide antibiotics.
Asunto(s)
Antibacterianos/síntesis química , Péptidos/síntesis química , Piridinas/química , Tiazoles/química , Antibacterianos/química , Estructura Molecular , Oxidación-Reducción , Péptidos/química , EstereoisomerismoRESUMEN
Iodobenzene diacetate in MeOH containing a catalytic amount of TFA efficiently oxidizes aldoximes to nitrile oxides. The latter may be trapped in situ with olefins in a bimolecular or an intramolecular mode. The new method enables the execution of tandem oxidative dearomatization of phenols/intramolecular nitrile oxide cycloaddition sequences leading to useful synthetic intermediates.
