Prostaglandins and congeners. 22. Synthesis of 11-substituted derivatives of 11-deoxyprostaglandins E1 and E2. Potential bronchodilators

Floyd, M. Brawner; Schaub, Robert E.; Siuta, G. J.; Skotnicki, Jerauld S.; Grudzinskas, Charles; Weiss, Martin J.; Dessy, F.; VanHumbeeck, L.

doi:10.1021/jm00182a018

“…The treatment of PGE 2 and PGD 2 with base induces dehydration of the hydroxyl groups at C-11 or C-9, respectively, resulting in the formation of the respective enone prostanoids. , Base treatment dehydrates PGE 2 (λmax 205 nm) to the cyclopentenone PGA 2 (λmax 217 nm) that further rearranges to the dienone PGB 2 with λmax at 278 nm (Figure A) . Likewise, PGD 2 dehydrates to PGJ 2 that rearranges to Δ 12 -PGJ 2 and undergoes a second dehydration to yield 15-deoxy-Δ 12,14 -PGJ 2 . , …”

Section: Resultsmentioning

confidence: 99%

Biosynthetic Crossover of 5-Lipoxygenase and Cyclooxygenase-2 Yields 5-Hydroxy-PGE₂ and 5-Hydroxy-PGD₂

Nakashima

¹

,

Suzuki

²

,

Gordon

³

et al. 2021

JACS Au

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The biosynthetic crossover of 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) enzymatic activities is a productive pathway to convert arachidonic acid into unique eicosanoids. Here, we show that COX-2 catalysis with 5-LOX derived 5-hydroxy-eicosatetraenoic acid yields the endoperoxide 5-hydroxy-PGH 2 that spontaneously rearranges to 5-OH-PGE 2 and 5-OH-PGD 2 , the 5-hydroxy analogs of arachidonic acid derived PGE 2 and PGD 2 . The endoperoxide was identified via its predicted degradation product, 5,12-dihydroxy-heptadecatri-6 E ,8 E ,10 E -enoic acid, and by SnCl 2 -mediated reduction to 5-OH-PGF 2α . Both 5-OH-PGE 2 and 5-OH-PGD 2 were unstable and degraded rapidly upon treatment with weak base. This instability hampered detection in biologic samples which was overcome by in situ reduction using NaBH 4 to yield the corresponding stable 5-OH-PGF 2 diastereomers and enabled detection of 5-OH-PGF 2α in activated primary human leukocytes. 5-OH-PGE 2 and 5-OH-PGD 2 were unable to activate EP and DP prostanoid receptors, suggesting their bioactivity is distinct from PGE 2 and PGD 2 .

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“…Base treatment dehydrates PGE2 (lmax 205 nm) to the enone PGA2 (lmax 217 nm) ( 23) that further rearranges to the dienone PGB2 with lmax at 278 nm (Fig. 3A) (24). Likewise, PGD2 dehydrates to PGJ2 that rearranges to D 12 -PGJ2 and undergoes a second dehydration to yield 15-deoxy-D 12,14 -PGJ2 (22,25).…”

Section: Stability Of 5-oh-pgd2 and 5-oh-pge2mentioning

confidence: 99%

Biosynthetic Crossover of 5-Lipoxygenase and Cyclooxygenase-2 Yields 5-Hydroxy-PGE2 and 5-Hydroxy-PGD2

Nakashima¹,

Suzuki²,

Gordon³

et al. 2021

Preprint

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Biosynthetic crossover of 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) enzymatic activities is a productive pathway to convert arachidonic acid into unique eicosanoids. Here we show that COX-2 catalysis with 5-LOX derived 5-hydroxy-eicosatetraenoic acid yields the endoperoxide 5-hydroxy-PGH2 that spontaneously rearranges to 5-OH-PGE2 and 5-OH-PGD2, the 5-hydroxy analogs of arachidonic acid derived PGE2 and PGD2. The endoperoxide was identified via its predicted degradation product, 5,12-dihydroxy-heptadecatri-6E,8E,10E-enoic acid, and by SnCl2-mediated reduction to 5-OH-PGF2a. Both 5-OH-PGE2 and 5-OH-PGD2 were unstable and degraded rapidly upon treatment with weak base. The instability hampered detection in biologic samples which was overcome by in situ reduction using NaBH4 to yield the corresponding stable 5-OH-PGF2 diastereomers and enabled detection of 5-OH-PGF2a in activated primary human leukocytes. 5-OH-PGE2 and 5-OH-PGD2 were unable to activate EP and DP prostanoid receptors suggesting their bioactivity is distinct from PGE2 and PGD2.

show abstract

“…Base treatment dehydrates PGE2 (lmax 205 nm) to the enone PGA2 (lmax 217 nm) ( 23) that further rearranges to the dienone PGB2 with lmax at 278 nm (Fig. 3A) (24). Likewise, PGD2 dehydrates to PGJ2 that rearranges to D 12 -PGJ2 and undergoes a second dehydration to yield 15-deoxy-D 12,14 -PGJ2 (22,25).…”

Section: Stability Of 5-oh-pgd2 and 5-oh-pge2mentioning

confidence: 99%

Biosynthetic Crossover of 5-Lipoxygenase and Cyclooxygenase-2 Yields 5-Hydroxy-PGE2 and 5-Hydroxy-PGD2

Nakashima¹,

Suzuki²,

Gordon³

et al. 2021

Preprint

0

View full text Add to dashboard Cite

Biosynthetic crossover of 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) enzymatic activities is a productive pathway to convert arachidonic acid into unique eicosanoids. Here we show that COX-2 catalysis with 5-LOX derived 5-hydroxy-eicosatetraenoic acid yields the endoperoxide 5-hydroxy-PGH2 that spontaneously rearranges to 5-OH-PGE2 and 5-OH-PGD2, the 5-hydroxy analogs of arachidonic acid derived PGE2 and PGD2. The endoperoxide was identified via its predicted degradation product, 5,12-dihydroxy-heptadecatri-6E,8E,10E-enoic acid, and by SnCl2-mediated reduction to 5-OH-PGF2a. Both 5-OH-PGE2 and 5-OH-PGD2 were unstable and degraded rapidly upon treatment with weak base. The instability hampered detection in biologic samples which was overcome by in situ reduction using NaBH4 to yield the corresponding stable 5-OH-PGF2 diastereomers and enabled detection of 5-OH-PGF2a in activated primary human leukocytes. 5-OH-PGE2 and 5-OH-PGD2 were unable to activate EP and DP prostanoid receptors suggesting their bioactivity is distinct from PGE2 and PGD2.

show abstract

Prostaglandins and congeners. 22. Synthesis of 11-substituted derivatives of 11-deoxyprostaglandins E1 and E2. Potential bronchodilators

Cited by 15 publications

References 5 publications

Biosynthetic Crossover of 5-Lipoxygenase and Cyclooxygenase-2 Yields 5-Hydroxy-PGE₂ and 5-Hydroxy-PGD₂

Biosynthetic Crossover of 5-Lipoxygenase and Cyclooxygenase-2 Yields 5-Hydroxy-PGE₂ and 5-Hydroxy-PGD₂

Biosynthetic Crossover of 5-Lipoxygenase and Cyclooxygenase-2 Yields 5-Hydroxy-PGE2 and 5-Hydroxy-PGD2

Biosynthetic Crossover of 5-Lipoxygenase and Cyclooxygenase-2 Yields 5-Hydroxy-PGE2 and 5-Hydroxy-PGD2

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