Abstract
12-Hydroxy-16-heptadecynoic acid has been shown to selectively inactivate cytochrome P450 4A4, a pulmonary cytochrome P450 enzyme that catalyzes the ω-hydroxylation of prostaglandins [Muerhoff, A. S.; Williams, D. E.; Reich, N. O.; CaJacob, C. A.; Ortiz de Montellano, P. R.; Masters, B. S. S. J. Biol. Chem. 1989, 264, 749-756]. Potent, specific inhibitors of this enzyme are required to explore its physiological role. In a continuing effort to develop such agents, the two enantiomers of 12-hydroxy-16-heptadecynoic acid have been stereospecifically synthesized, their absolute stereochemistry confirmed, and the dependence of enzyme inactivation on absolute stereochemistry determined using cytochrome P450 4A4 purified from the lungs of pregnant rabbits. The 12S enantiomer is roughly twice as active (KI = 1.8 μM, t1/2 = 0.7 min) as the 12R enantiomer (KI = 3.6 μM, t1/2 = 0.8 min), but the chirality of the hydroxyl group is not a major determinant of the specificity for the prostaglandin ω-hydroxylase. The flexibility of the acyclic skeleton of the inhibitor may account for the relatively low enantiomeric discrimination. 2,2-Dimethyl-12-hydroxy-16-heptadecynoic acid, an analogue that cannot undergo β-oxidation, has also been synthesized as a potential in vivo inhibitor of the enzyme and has been shown to inactivate the purified enzyme with KI = 4.9 μM and t1/2 = 1.0 min. These acetylenic agents, particularly the dimethyl analog, are promising in vivo inhibitors of cytochrome P450 4A4.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1418-1424 |
| Number of pages | 7 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 36 |
| Issue number | 10 |
| State | Published - 1993 |
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ASJC Scopus subject areas
- Organic Chemistry
Cite this
Mechanism-based inhibitors of prostaglandin ω-hydroxylase : (R)- and (S)-12-hydroxy-16-heptadecynoic acid and 2,2-dimethyl-12-hydroxy-16-heptadecynoic acid. / Burger, Alain; Clark, Joan E.; Nishimoto, Masazumi; Scott Muerhoff, A.; Masters, Bettie Sue Siler; Ortiz De Montellano, Paul R.
In: Journal of Medicinal Chemistry, Vol. 36, No. 10, 1993, p. 1418-1424.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mechanism-based inhibitors of prostaglandin ω-hydroxylase
T2 - (R)- and (S)-12-hydroxy-16-heptadecynoic acid and 2,2-dimethyl-12-hydroxy-16-heptadecynoic acid
AU - Burger, Alain
AU - Clark, Joan E.
AU - Nishimoto, Masazumi
AU - Scott Muerhoff, A.
AU - Masters, Bettie Sue Siler
AU - Ortiz De Montellano, Paul R.
PY - 1993
Y1 - 1993
N2 - 12-Hydroxy-16-heptadecynoic acid has been shown to selectively inactivate cytochrome P450 4A4, a pulmonary cytochrome P450 enzyme that catalyzes the ω-hydroxylation of prostaglandins [Muerhoff, A. S.; Williams, D. E.; Reich, N. O.; CaJacob, C. A.; Ortiz de Montellano, P. R.; Masters, B. S. S. J. Biol. Chem. 1989, 264, 749-756]. Potent, specific inhibitors of this enzyme are required to explore its physiological role. In a continuing effort to develop such agents, the two enantiomers of 12-hydroxy-16-heptadecynoic acid have been stereospecifically synthesized, their absolute stereochemistry confirmed, and the dependence of enzyme inactivation on absolute stereochemistry determined using cytochrome P450 4A4 purified from the lungs of pregnant rabbits. The 12S enantiomer is roughly twice as active (KI = 1.8 μM, t1/2 = 0.7 min) as the 12R enantiomer (KI = 3.6 μM, t1/2 = 0.8 min), but the chirality of the hydroxyl group is not a major determinant of the specificity for the prostaglandin ω-hydroxylase. The flexibility of the acyclic skeleton of the inhibitor may account for the relatively low enantiomeric discrimination. 2,2-Dimethyl-12-hydroxy-16-heptadecynoic acid, an analogue that cannot undergo β-oxidation, has also been synthesized as a potential in vivo inhibitor of the enzyme and has been shown to inactivate the purified enzyme with KI = 4.9 μM and t1/2 = 1.0 min. These acetylenic agents, particularly the dimethyl analog, are promising in vivo inhibitors of cytochrome P450 4A4.
AB - 12-Hydroxy-16-heptadecynoic acid has been shown to selectively inactivate cytochrome P450 4A4, a pulmonary cytochrome P450 enzyme that catalyzes the ω-hydroxylation of prostaglandins [Muerhoff, A. S.; Williams, D. E.; Reich, N. O.; CaJacob, C. A.; Ortiz de Montellano, P. R.; Masters, B. S. S. J. Biol. Chem. 1989, 264, 749-756]. Potent, specific inhibitors of this enzyme are required to explore its physiological role. In a continuing effort to develop such agents, the two enantiomers of 12-hydroxy-16-heptadecynoic acid have been stereospecifically synthesized, their absolute stereochemistry confirmed, and the dependence of enzyme inactivation on absolute stereochemistry determined using cytochrome P450 4A4 purified from the lungs of pregnant rabbits. The 12S enantiomer is roughly twice as active (KI = 1.8 μM, t1/2 = 0.7 min) as the 12R enantiomer (KI = 3.6 μM, t1/2 = 0.8 min), but the chirality of the hydroxyl group is not a major determinant of the specificity for the prostaglandin ω-hydroxylase. The flexibility of the acyclic skeleton of the inhibitor may account for the relatively low enantiomeric discrimination. 2,2-Dimethyl-12-hydroxy-16-heptadecynoic acid, an analogue that cannot undergo β-oxidation, has also been synthesized as a potential in vivo inhibitor of the enzyme and has been shown to inactivate the purified enzyme with KI = 4.9 μM and t1/2 = 1.0 min. These acetylenic agents, particularly the dimethyl analog, are promising in vivo inhibitors of cytochrome P450 4A4.
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M3 - Article
C2 - 8496909
AN - SCOPUS:0027204799
VL - 36
SP - 1418
EP - 1424
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 10
ER -