Synthesis and biological evaluation of (6- and 7-phenyl) coumarin derivatives as selective nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1.
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is an enzyme that catalyzes NADPH-dependent reduction of the weak estrogen, estrone, into the most potent estrogen, estradiol, which exerts proliferative effects via the estrogen receptors. Overexpression of 17β-HSD1 in estrogen-responsive tissues is related to the development of hormone-dependent diseases, such as breast cancer and endometriosis; thus, 17β-HSD1 represents an attractive target for the development of new therapies. We have discovered that simple coumarines 1 and 2 significantly inhibit 17β-HSD1 in a recombinant enzyme assay, with high selectivity against 17β-HSD2. We postulated that the introduction of various p-substituted phenyl moieties to position 6 or 7 of the coumarin core using the Suzuki-Miyaura cross-coupling reaction would provide mimetics of steroidal structures with improved inhibition of 17β-HSD1. The best inhibitor in the series proved to be 6a, with an IC(50) of 270 nM, and with exceptional selectivity for 17β-HSD1 over 17β-HSD2 and against the α and β estrogen receptors.
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
Stefan
S
Starcević
Petra
P
Brozic
Samo
S
Turk
Jozko
J
Cesar
Tea Lanisnik
TL
Rizner
Stanislav
S
Gobec
D001667:Binding, Competitive; D020134:Catalytic Domain; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors; D006801:Humans; D008958:Models, Molecular; D011869:Radioligand Assay; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
C562243:3-acetyl-7-(4-hydroxyphenyl)-2H-chromen-2-one; D003374:Coumarins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011994:Recombinant Proteins; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human; C523763:HSD17B2 protein, human