Identification of steroidal derivatives inhibiting the transformations of allopregnanolone and estradiol by 17ß-hydroxysteroid dehydrogenase type 10.
Bioorg Med Chem Lett
; 28(22): 3554-3559, 2018 12 01.
Article
em En
| MEDLINE
| ID: mdl-30297283
ABSTRACT
17ß-Hydroxysteroid dehydrogenase type 10 (17ß-HSD10) is a mitochondrial enzyme known for its potential role in Alzheimer's Disease (AD). 17ß-HSD10, by its oxidative activity, could decrease the concentration of two important neurosteroids, allopregnanolone (ALLOP) and 17ß-estradiol (E2), respectively preventing their neurogenesis and neuroprotective effects. Since the inhibition of 17ß-HSD10 could lead to a new treatment for AD, we developed two biological assays using labeled ALLOP or E2 as substrates to measure the inhibitory activity of compounds against pure 17ß-HSD10 protein. After the optimization of different parameters (time, concentration of enzyme, substrate and cofactor), analogs of the first reported steroidal inhibitor of 17ß-HSD10 in intact cells were screened to determine their inhibitory potency for the ALLOP or the E2 oxidation. One compound, androstane derivative 5, possesses the best dual inhibition against both transformations (ALLOP, IC50â¯=â¯235⯵M and E2, IC50â¯=â¯610⯵M). Some compounds are dual inhibitors to a lesser extent, and others seem selective for one of the transformations in particular. By developing two reliable assays and by identifying a first generation of steroidal inhibitors of pure 17ß-HSD10, this preliminary study opens the door to new and more potent inhibitors.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pregnanolona
/
Esteroides
/
Inibidores Enzimáticos
/
Estradiol
/
17-Hidroxiesteroide Desidrogenases
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Canadá