Synthesis and characterization of targeted 17ß-hydroxysteroid dehydrogenase type 7 inhibitors.
J Steroid Biochem Mol Biol
; 242: 106544, 2024 09.
Article
in En
| MEDLINE
| ID: mdl-38754521
ABSTRACT
Sex steroid hormones such as estrogen estradiol (E2) and androgen dihydrotestosterone (DHT) are involved in the development of hormone-dependent cancers. Blockade of 17ß-hydroxysteroid dehydrogenase type 7 (17ß-HSD7), a member of the short chain dehydrogenase/reductase superfamily, is thought to decrease E2 levels while increasing those of DHT. Therefore, its unique double action makes this enzyme as an interesting drug target for treatment of breast cancer. The chemical synthesis, molecular characterization, and preliminary biological evaluation as 17ß-HSD7 inhibitors of novel carbamate derivatives 3 and 4 are described. Like previous 17ß-HSD7 inhibitors 1 and 2, compounds 3 and 4 bear a hydrophobic nonyl side chain at the C-17ß position of a 4-aza-5α-androstane nucleus, but compound 3 has an oxygen atom replacing the CH2 in the steroid A-ring C-2 position, while compound 4 has a C17-spiranic E-ring containing a carbamate function. They both inhibited the in vitro transformation of estrone (E1) into E2 by 17ß-HSD7, but the introduction of a (17â¯R)-spirocarbamate is preferable to replacing C-2 methylene with an oxygen atom since compound 4 (IC50 = 63â¯nM) is an inhibitor 14 times more powerful than compound 3 (IC50 = 900â¯nM). Furthermore, when compared to the reference inhibitor 1 (IC50 = 111â¯nM), the use of a C17-spiranic E-ring made it possible to introduce differently the hydrophobic nonyl side chain, without reducing the inhibitory activity.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Enzyme Inhibitors
/
17-Hydroxysteroid Dehydrogenases
Limits:
Humans
Language:
En
Journal:
J Steroid Biochem Mol Biol
/
J. steroid biochem. mol. biol
/
Journal of steroid biochemistry and molecular biology
Journal subject:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
Year:
2024
Document type:
Article
Country of publication: