18-Vinyldeoxycorticosterone: a potent inhibitor of the bovine cytochrome P-450(11) beta.
18-Vinylprogesterone (18-VP) and 18-ethynylprogesterone (18-EP) have proved to be potent suicide inhibitors of P-450(11) beta, the last enzyme of aldosterone biosynthesis (Delorme, C.; Piffeteau, A.; Viger, A.; Marquet, A. Eur. J. Biochem. 1995, 232, 247; Delorme, C.; Piffeteau, A.; Sobrio, F.; Marquet, A. Eur. J. Biochem. 1997, 248, 252). This paper describes the synthesis of 18-vinyldeoxycorticosterone (18-VDOC), an analogue of deoxycorticosterone (DOC), the physiological substrate of the enzyme, and the evaluation of its reversible inhibiting properties for deoxycorticosterone and corticosterone oxidation by the bovine enzyme. 18-VDOC has been obtained by hydroxylation at C-21 of a 18-VP precursor. Its reversible Ki values are, respectively, 0.3 microM for the 11 beta-hydroxylation and 0.8 microM for the 18-hydroxylation. Hence, 18-VDOC is the strongest competitive inhibitor of bovine P-450(11) beta described so far, but in contrast with 18-VP, it does not inhibit more efficiently the 18-hydroxylation than the 11-hydroxylation.
Davioud
E
E
Laboratoire de Chimie Organique Biologique, Université Pierre et Marie Curie, CNRS UMR 7613, Paris, France.
Piffeteau
A
A
Delorme
C
C
Coustal
S
S
Marquet
A
A
D000818:Animals; D002417:Cattle; D003345:Corticosterone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003900:Desoxycorticosterone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D011374:Progesterone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors*
C116518:18-vinyldeoxycorticosterone; D004791:Enzyme Inhibitors; D003900:Desoxycorticosterone; D011374:Progesterone; C069554:18-vinylprogesterone; D013252:Steroid 11-beta-Hydroxylase; D003345:Corticosterone