Some coumarins and triphenylethene derivatives as inhibitors of human testes microsomal 17beta-hydroxysteroid dehydrogenase (17beta-HSD type 3): further studies with tamoxifen on the rat testes microsomal enzyme.
The 7-hydroxycoumarins, umbelliferone and 4-methylumbelliferone (IC50 = 1.4 and 1.9 microM, respectively) were potent inhibitors of human testes microsomal 17beta-HSD (type 3) enzyme whereas 7-methoxycoumarin, 4-hydroxycoumarin and 7-ethoxycoumarin had little or no inhibitory activity. Analogues of the weak inhibitory triphenylethenes tamoxifen and clomiphene but lacking the basic substituent, were weak inhibitors of the human microsomal enzyme. Inhibitory activity was improved by replacement of the triphenylethene structure with a triphenylmethyl (17, 52.6% inhibition) or phenylpropyl (16, 94.8%, IC50 = 42.1 microM) skeleton. Further studies on tamoxifen using rat testes microsomal 17beta-HSD showed that the inhibition was time-dependent and irreversible but not specifically mechanism-based.
LE Lain
R
R
Welsh School of Pharmacy, Cardiff University, UK.
Barrell
K J
KJ
Saeed
G S
GS
Nicholls
P J
PJ
Simons
C
C
Kirby
A
A
Smith
H J
HJ
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000818:Animals; D003374:Coumarins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008861:Microsomes / Q000201:enzymology*; D015394:Molecular Structure; D051381:Rats; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013737:Testis / Q000201:enzymology*
D003374:Coumarins; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D013267:Stilbenes; D015067:17-Hydroxysteroid Dehydrogenases; C037749:triphenylethylene