Mechanism-based inhibitors of prostaglandin ω-hydroxylase: (R)- and (S)-12-hydroxy-16-heptadecynoic acid and 2,2-dimethyl-12-hydroxy-16-heptadecynoic acid

Alain Burger, Joan E. Clark, Masazumi Nishimoto, A. Scott Muerhoff, Bettie Sue Siler Masters, Paul R. Ortiz De Montellano

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)1418-1424
Number of pages7
JournalJournal of Medicinal Chemistry
Volume36
Issue number10
StatePublished - 1993

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Prostaglandin Antagonists
Enantiomers
Mixed Function Oxygenases
Stereochemistry
Enzyme Inhibitors
Cytochrome P-450 Enzyme System
Prostaglandins
Acids
Lung
Hydroxylation
Chirality
Enzymes
Skeleton
Hydroxyl Radical
Rabbits
Oxidation
2,2-dimethyl-12-hydroxy-16-heptadecynoic acid
cytochrome P-450 CYP4A4 (rabbit)
12-hydroxy-16-heptadecynoic acid

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Burger, A., Clark, J. E., Nishimoto, M., Scott Muerhoff, A., Masters, B. S. S., & Ortiz De Montellano, P. R. (1993). Mechanism-based inhibitors of prostaglandin ω-hydroxylase: (R)- and (S)-12-hydroxy-16-heptadecynoic acid and 2,2-dimethyl-12-hydroxy-16-heptadecynoic acid. Journal of Medicinal Chemistry, 36(10), 1418-1424.

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 journalArticle

Burger, A, Clark, JE, Nishimoto, M, Scott Muerhoff, A, Masters, BSS & Ortiz De Montellano, PR 1993, 'Mechanism-based inhibitors of prostaglandin ω-hydroxylase: (R)- and (S)-12-hydroxy-16-heptadecynoic acid and 2,2-dimethyl-12-hydroxy-16-heptadecynoic acid', Journal of Medicinal Chemistry, vol. 36, no. 10, pp. 1418-1424.
Burger, Alain ; Clark, Joan E. ; Nishimoto, Masazumi ; Scott Muerhoff, A. ; Masters, Bettie Sue Siler ; Ortiz De Montellano, Paul R. / Mechanism-based inhibitors of prostaglandin ω-hydroxylase : (R)- and (S)-12-hydroxy-16-heptadecynoic acid and 2,2-dimethyl-12-hydroxy-16-heptadecynoic acid. In: Journal of Medicinal Chemistry. 1993 ; Vol. 36, No. 10. pp. 1418-1424.
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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.",
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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.

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AU - Masters, Bettie Sue Siler

AU - Ortiz De Montellano, Paul R.

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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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