RESUMO
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.
Assuntos
Proteínas Mutantes/metabolismo , Mutação/genética , Pirimetamina/química , Pirimetamina/metabolismo , beta-N-Acetil-Hexosaminidases/metabolismo , Doença de Alzheimer/enzimologia , Doença de Alzheimer/genética , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Fibroblastos/patologia , Humanos , Modelos Moleculares , Estrutura Molecular , Proteínas Mutantes/genética , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antibacterianos/síntese química , Peptídeos/síntese química , Antibacterianos/química , Estrutura Molecular , Peptídeos/químicaRESUMO
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.
Assuntos
Antibacterianos/síntese química , Peptídeos/síntese química , Piridinas/química , Tiazóis/química , Antibacterianos/química , Estrutura Molecular , Oxirredução , Peptídeos/química , EstereoisomerismoRESUMO
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.
