Chemical synthesis, characterisation and biological evaluation of furanic-estradiol derivatives as inhibitors of 17ß-hydroxysteroid dehydrogenase type 1.
Med Chem
; 7(2): 80-91, 2011 Mar.
Article
en En
| MEDLINE
| ID: mdl-21222612
ABSTRACT
Local biosynthesis of estrogens, especially estradiol (E2), is thought to be important for the maintenance and growth of estrogen-sensitive diseases. To control E2 formation, we have investigated a series of epoxide and furanic E2 derivatives as inhibitors of 17ß-hydroxysteroid dehydrogenase type 1 (17ß-HSD1), the enzyme responsible for the conversion of estrone (E1) into E2. We report here a strategy to synthesize a series of E2-furanic derivatives from E1. An intermediate epoxide was first obtained and then reduced to give a furanic steroid, which allowed us to introduce a molecular diversity like alcohol, bromide, ester, acid and amide. The inhibition of the transformation of [(14)C]-E1 (100 nM) into [(14)C]-E2 by these compounds was first evaluated with homogenated HEK-293 cells overexpressing 17ß-HSD1. The epoxide and butylamide derivatives showed the best inhibitions with 72% and 66%, respectively, at 10 µM. All furanic compounds showed a lower 17ß-HSD1 inhibitory potency in intact T47-D breast cancer cells than in homogenated cells, but a great improvement of the inhibitory activity was observed for the epoxide, which gave 62% and 90% of inhibition of the [(14)C]-E1 (60 nM) into [(14)C]-E2 transformation at 1 and 10 µM, respectively.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Inhibidores Enzimáticos
/
Estradiol
/
Estradiol Deshidrogenasas
/
Furanos
Límite:
Humans
Idioma:
En
Revista:
Med Chem
Asunto de la revista:
QUIMICA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Canadá