Total synthesis of 12-epi-PGF2α

Hwang, Sangwon; Adiyaman, Mustafa; Khanapure, Subhash P.; Rokach, Joshua

doi:10.1016/0040-4039(95)02390-9

Cited by 32 publications

(18 citation statements)

References 19 publications

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“…2). F 2 -isoprostanes are isomers of PGF 2␣ and have been divided into four structural classes (41)(42)(43). To test their possible affinity for the FP, we selected members of the first (IPF 2␣ -I), third (IPF 2␣ -III), and fourth classes (8-iso-PGF 2␣ , 12-iso-PGF 2␣ , and 9␤, 11␤-PGF 2 ) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…One of these, 12-iso-PGF 2␣ (43), activates the FP in a specific and saturable manner. It seems likely that 12-iso-PGF 2␣ may be an abundant member of the F 2 isoprostane family, inasmuch as free radical cyclization rules predict that upon formation of a cyclopentane ring, after oxidative modification of arachidonic acid, the adjacent substituents formed are cis to each other.…”

Section: Characterization Of the Fp Receptormentioning

confidence: 99%

“…F 2 isoprostanes are free radical-catalyzed products of arachidonic acid (28). Up to 64 different isomers may be formed theoretically, belonging to four structural classes (41)(42)(43). Initially, these compounds are formed in situ on the cell membrane, from which they may be cleaved by the action of phospholipases to circulate and, ultimately, be excreted in urine (28).…”

Section: Characterization Of the Fp Receptormentioning

confidence: 99%

“…We have recently synthesized several F 2 isoprostane isomers (43,(53)(54)(55). One of these, 12-iso-PGF 2␣ (43), activates the FP in a specific and saturable manner.…”

Section: Characterization Of the Fp Receptormentioning

confidence: 99%

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Functional Characterization of the Ocular Prostaglandin F2α (PGF2α) Receptor

Kunapuli

Lawson

Rokach

et al. 1997

Journal of Biological Chemistry

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101

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Prostaglandins are arachidonic acid metabolites that may play a major role as mediators of cellular function. PGF 2␣ 1 has diverse physiological actions ranging from being a potent luteolytic agent (1, 2) to causing smooth muscle contraction in the uterus (3, 4), vasculature (5), and gastrointestinal (6) and respiratory tracts (7,8). PGF 2␣ induces DNA synthesis and cell proliferation in 3T3 fibroblasts (9, 10). Neuronal astrocytes respond to PGF 2␣ , which may mediate pain transmission (11). Recently, PGF 2␣ has also been shown to cause hypertrophy of cardiac myocytes and induction of myofibrillar genes, independent of muscle contraction. These observations suggest a role for the eicosanoid during development, in compensatory hypertrophy and/or in recovery of the heart from injury (12). Recently, PGF 2␣ analogs have been shown to reduce intraocular pressure (IOP), in patients with glaucoma (13,14). Although the precise mechanisms involved remain unclear, the effects of PGF 2␣ analogs on IOP may be attributed, at least in part, to their actions on the ciliary muscle. PGF 2␣ reduces IOP by increasing the uveoscleral outflow of aqueous humor (15, 16), possibly by reducing the resistance between the ciliary muscle bundles, via an effect on the extracellular matrix (17).A single PGF 2␣ receptor (FP) has been cloned from myometrial tissue (18 -22). Given that there is evidence consistent with splice variation of the FP (23), as has been described for other prostanoid receptors (24, 25), we wished to address the possibility that a distinct isoform might mediate the actions of PGF 2␣ in the ciliary muscle. Clarification of the nature of the human ciliary FP and development of an antibody that specifically recognized the receptor protein would facilitate investigation of the effects of PGF 2␣ and its analogs on IOP.PGF 2␣ is formed from arachidonic acid via metabolic transformation sequentially catalyzed by phospholipases, cyclooxygenases, and a specific PGF synthase (26). However, it is now appreciated that a series of PGF 2␣ isomers, the F 2 isoprostanes, may also be formed in vivo via a free radical-dependent pathway (27-29). It has been speculated that these F 2 isoprostanes may function as incidental ligands at eicosanoid receptors, and, possibly, activate related receptors of their own (30). To date, attention has focused particularly on 8-iso-PGF 2␣ . This compound is a potent vasoconstrictor. It is also a mitogen and may activate human platelets (31-33). Curiously, despite its F prostaglandin configuration, 8-iso-PGF 2␣ has been shown to activate thromboxane receptors (TPs), and its biological effects are blocked by TP antagonists (31-33).We now report the cloning of an FP receptor from the human ciliary body (hcb) cDNA library and its localization on the cell membrane. The gene product is identical to that cloned from

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Section: Resultsmentioning

confidence: 99%

Section: Characterization Of the Fp Receptormentioning

confidence: 99%

Section: Characterization Of the Fp Receptormentioning

confidence: 99%

“…We have recently synthesized several F 2 isoprostane isomers (43,(53)(54)(55). One of these, 12-iso-PGF 2␣ (43), activates the FP in a specific and saturable manner.…”

Section: Characterization Of the Fp Receptormentioning

confidence: 99%

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Functional Characterization of the Ocular Prostaglandin F2α (PGF2α) Receptor

Kunapuli

Lawson

Rokach

et al. 1997

Journal of Biological Chemistry

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101

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“…F 2 isoprostanes (iPs) are PGF 2␣ isomers that are generated by free radical-catalyzed peroxidation of arachidonic acid (10). We have performed total stereospecific synthesis of several iPs, including 8,12-iso-iPF 2␣ -III (previously known as 12-iso-PGF 2␣ ) (11) and iPF 2␣ -VI (previously known as IPF 2␣ -I) (12) and have recently demonstrated that the iP, 8,12-iso-iPF 2␣ -III, may activate FP in a specific and saturable manner (13). The iP, 8,12-iso-iPF 2␣ -III is a member of the group III isoprostanes, which also includes 8-iso-iPF 2␣ -III.…”

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confidence: 99%

Prostaglandin F2α (PGF2α) and the Isoprostane, 8,12-iso-Isoprostane F2α-III, Induce Cardiomyocyte Hypertrophy

Kunapuli¹,

Lawson²,

Rokach³

et al. 1998

Journal of Biological Chemistry

119

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Prostaglandin receptors may be activated by their cognate ligand or by free radical catalyzed isoprostanes, products of arachidonic acid peroxidation. For example, prostaglandin F 2␣ (PGF 2␣ ) causes hypertrophy of neonatal rat ventricular myocytes, via the PGF 2␣ receptor (FP). However, the FP may also be activated by the isoprostane, 8,12-iso-iPF 2␣ -III (Kunapuli, P., Lawson, J. A., Rokach, J., and FitzGerald, G. A. (1997) J. Biol. Chem. 272, 27147-27154). Both ligands induce myocyte hypertrophy with overlapping potencies. Interestingly, the hypertrophic effects of these two agonists on cardiomyocytes are additive. Furthermore, the preference of these two agonists for activation of intracellular signal transduction pathways differs in several respects. Thus, PGF 2␣ and 8,12-isoiPF 2␣ -III stimulate inositol phosphate formation with EC 50 values of 50 ؎ 12 nM and 3.5 ؎ 0.6 M, respectively. Moreover, PGF 2␣ causes a robust activation (ϳ50-fold) of Erk2, whereas 8,12-iso-iPF 2␣ -III has no effect. Similarly, PGF 2␣ causes translocation of cytosolic phospholipase A 2 and also results in a 7-fold increment in the formation of 6-keto-PGF 1␣ , whereas 8,12-iso-iPF 2␣ -III exerts no effect on this pathway. On the other hand, both agonists are equally potent in activating JNK1 and c-Jun, whereas neither activates the p38 kinase. Both PGF 2␣ and 8,12-isoiPF 2␣ -III activate the p70S6 kinase (p70 S6K ), but not Akt, downstream of phosphatidylinositol-3-kinase (PI3K). However, both wortmannin, a PI3K inhibitor, and rapamycin, an inhibitor of p70 S6K activity, inhibit 8,12-isoiPF 2␣ -III -induced myocyte hypertrophy, with IC 50 values of 60 ؎ 12 and 3 ؎ 1.7 nM, respectively, whereas neither compound abrogates the PGF 2␣ -mediated response. Thus, both PGF 2␣ and 8,12-iso-iPF 2␣ -III induce myocyte hypertrophy via discrete signaling pathways. Although both agonists signal via the JNK pathway to initiate changes in c-Jun-dependent gene transcription, PGF 2␣ preferentially activates the MEK-Erk2-cytosolic phospholipase A 2 pathway. In contrast, the PI3K-p70 S6K pathway appears to be essential for 8,12-iso-iPF 2␣ -III-induced myocyte hypertrophy. Prostaglandins (PGs)1 are arachidonic acid metabolites that are produced in a wide variety of tissues in response to mechanical and chemical stimuli. The actions of PGF 2␣ are thought to be mediated via the PGF 2␣ receptor (FP), which is a member of the G protein-coupled receptor (GPCR) superfamily (1). PGF 2␣ has diverse physiological actions, ranging from being a potent luteolytic agent (2) to causing vascular smooth muscle contraction (3). In the myocardium, the formation of PGs is induced by pressure overload (4) which can result in cardiac hypertrophy (5, 6). Conversely, PG synthase inhibitors diminish the hypertrophic response induced by hypertension (7).Prostaglandin F 2␣ (PGF 2␣ ) has recently been shown to stimulate hypertrophy of neonatal rat ventricular myocytes and to induce the expression of myofibrillar genes, independent of muscle contraction (8). Paoni and co-workers (...

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Oxidative Enolate Cyclizations of 6,8-Nonadienoates: Towards the Synthesis of Prostanes

et al. 2002

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Keywords: Enolates / Hydroxy esters / Oxidation / Prostaglandins / Radical reactions 6,8-Nonadienoate enolates, which undergo radical 5-exo cyclization on SET oxidation with ferrocenium hexafluorophosphate, were studied as radical cyclization precursors. The trapping of the cyclized allylic radicals occurred with good regioselectivity through dimerization, TEMPO trapping, or SET oxidation/deprotonation reactions. 3-Alkoxido

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Total synthesis of 12-epi-PGF2α

Cited by 32 publications

References 19 publications

Functional Characterization of the Ocular Prostaglandin F2α (PGF2α) Receptor

Functional Characterization of the Ocular Prostaglandin F2α (PGF2α) Receptor

Prostaglandin F2α (PGF2α) and the Isoprostane, 8,12-iso-Isoprostane F2α-III, Induce Cardiomyocyte Hypertrophy

Oxidative Enolate Cyclizations of 6,8-Nonadienoates: Towards the Synthesis of Prostanes

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