363-24-6

Basic information

• Product Name: Prostaglandin E2
• Synonyms: DINOPROSTONE;9-OXO-11ALPHA,15S-DIHYDROXY-PROSTA-5Z,13E-DIEN-1-OIC ACID;7-[3-hydroxy-2-(3-hydroxy-1-octenyl)-5-oxocyclopentyl]-5-heptenoic acid;(5Z,11A,13E,15S)-11,15-DIHYDROXY-9-OXO-PROSTA-5,13-DIEN-1OIC ACID;[5Z,11ALPHA,13E,15S]-11,15-DIHYDROXY-9-OXOPROSTA-5,13-DIEN-1-OIC ACID;[5Z,11ALPHA,13E,15S]-11,15-DIHYDROXY-9-OXOPROSTA-5,13-DIENOIC ACID;PROSTAGLANDIN;PROSTAGLANDIN E2
• CAS NO: 363-24-6
• Molecular Formula: C20H32O5
• Molecular Weight: 352.47
• EINECS: 206-656-6
• Product Categories: Prostaglandins;Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 363-24-6.mol

Chemical Properties

• Melting Point: 66-68 °C
• Boiling Point: 406.07°C (rough estimate)
• Flash Point: 288.5 °C
• Appearance: Clear yellow to amber/powder
• Density: 1.0601 (rough estimate)
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.6120 (estimate)
• Storage Temp.: −20°C
• Solubility: ethanol: 1 mg/mL
• PKA: pKa 4.77± 0.09(H2O,t=25±0.1,I=0.1(NaCl)) (Uncertain)
• Water Solubility: insoluble
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 3 months.
• Merck: 14,7877
• BRN: 4709356
• CAS DataBase Reference: Prostaglandin E2(CAS DataBase Reference)
• NIST Chemistry Reference: Prostaglandin E2(363-24-6)
• EPA Substance Registry System: Prostaglandin E2(363-24-6)

Safety Data

• Hazard Codes: T
• Statements: 60-22-61
• Safety Statements: 53-22-26-36/37/39-45
• WGK Germany: 3
• RTECS: UK8000000
• F: 8-10
• Hazardous Substances Data: 363-24-6(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Applications:
Prostaglandin E2 is used as an abortifacient and oxytocic agent for inducing cervical ripening and labor. It is administered in a single dose of 10 mg by controlled-release (0.3 mg/hr) vaginal insert, potentiating the effects of oxytocin. Brand names include Cervidil, Prepidil, Prostin E2, Minprostin, Prostaglandin, Prostarmon E, and Prostin VR Pediatric.
Used in Cell Culture Applications:
PGE2 is utilized in cell culture applications for the study of prostaglandin-regulated cell signaling and gene regulation, aiding in understanding its diverse biological actions and potential therapeutic applications.
Used in Research and Development:
Prostaglandin E2 is used in research and development for studying its role in various biological processes, including inflammation, cancer, immune modulation, fertility, and smooth muscle relaxation. This helps in the development of targeted therapies and understanding the underlying mechanisms of action for PGE2.

Originator

Prostin E2,Upjohn,UK,1972

Manufacturing Process

Hexamethyldisilazane (1 ml) and trimethylchlorosilane (0.2 ml) are added with stirring to a solution of PGA2 (250 mg) in 4 ml of tetrahydrofuran at 0°C under nitrogen. This mixture is maintained at 5°C for 15 hours. The mixture is then evaporated under reduced pressure. Toluene is added and evaporated twice. Then the residue is dissolved in 6 ml of methanol, and the solution is cooled to -20°C. Hydrogen peroxide (0.45 ml; 30% aqueous) is added. Then, 1N sodium hydroxide solution (0.9 ml) is added dropwise with stirring at - 20°C. After 2 hours at -20°C, an additional 0.3 ml of the sodium hydroxide solution is added with stirring at -20°C. After another hour in the range -10°C to -20°C, an additional 0.1 ml of the sodium hydroxide solution is added. Then, 1.5 ml of 1 N hydrochloric acid is added, and the mixture is evaporated under reduced pressure. The residue is extracted with ethyl acetate, and the extract is washed successively with 1 N hydrochloric acid and ine, dried with anhydrous sodium sulfate and evaporated. The residue is dissolved in 5 ml of diethyl ether. To this solution is added 0.5 ml of methanol and 0.1 ml of water. Amalgamated aluminum made from 0.5 g of aluminum metal is then added in small portions during 3 hours at 25°C. Then, ethyl acetate and 3 N hydrochloric acid are added, and the ethyl acetate layer is separated and washed successively with 1 N hydrochloric acid and ine, dried with anhydrous sodium sulfate, and evaporated. The residue is chromatographed on 50 g of acid-washed silica gel, eluting first with 400 ml of a gradient of 50- 100% ethyl acetate in Skellysolve B, and then with 100 ml of 5% methanol in ethyl acetate, collecting 25 ml fractions. Fractions 9 and 10 are combined and evaporated to give 18 mg of 11β-PGE2. Fractions 17-25 are combined and evaporated to give 39 mg of PGE2.

Therapeutic Function

Oxytocic, Abortifacient

World Health Organization (WHO)

Dinoprostone, prostaglandin E2, was introduced into medicine in 1971 and is primarily used for cervical ripening during the induction of labour. It is available in various formulations for oral, parenteral and vaginal administration. Tablets, ampoules and vaginal dosage forms (tablets, pessaries, gel) remain registered in many countries.

Biological Activity

Endogenous prostaglandin and primary product of arachidonic acid/cyclooxygenase pathway. Binds with high affinity to EP 1 , EP 2 , EP 3 and EP 4 receptors (K d values range between ~ 1-10 nM). Influences a wide range of processes including inflammation, smooth muscle relaxation, fertility and gastric mucosal integrity. Regulates vertebrate hematopoietic stem cell (HSC) homeostasis.

Biochem/physiol Actions

Most biologically active prostaglandin. PGE2 induces cervical ripening and parturition; mediates bradykinin-induced vasodilation; regulates adenylyl cyclase. Tumor cells that over-express cyclooxygenase 2 display increased invasiveness, angiogenesis, and resistance to apoptosis that may be due to the PGE2-induced expression of angiogenic factors and stabilization of the anti-apoptotic protein, survivin.The effect of PGE2 on the immune system is mixed. It inhibits T cell activation in vitro, suggesting it is an immunosuppressant. However, in vivo, it appears to effect expansion of the Th17 subset and differentiation of the Th1 subset of T helper cells, marking it as an immunoactivator.

Safety Profile

Poison by subcutaneous and intravenous routes. Moderately toxic by ingestion and intraperitoneal routes. An experimental teratogen. Human reproductive effects by intravenous, intraplacental, and intravaginal routes: changes in the uterus, cervix and vagina; termination of pregnancy; and changes in ferthty. Experimental reproductive effects. Mutation data reported. When heated to decomposition it emits acrid smoke and irritating fumes.

in vitro

pge2 can stimulate the gastric nonparietal secretion [3] and has been shown to regulate the function of many cell types including dendritic cells, macrophages, t and b lymphocytes leading to both pro- and anti-inflammatory effects [2].

in vivo

pge2 regulates many physiological systems including the gastrointestinal and immune systems. in the gastrointestinal tract, pge2 plays a protective role in maintaining the integrity of the gastric mucosa. pge2 has also been shown to play a role in the maintenance of blood pressure, particularly in the setting of salt overload [2].

References

1) Healy (1990) Progesterone receptor antagonist and prostaglandins in human fertility regulation: a clinical review; Reprod. Fertil. Dev. 2 477 2) Greenhough et al. (2009) The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment; Carcinogenesis, 30 377 3) Kalinski (2012) Regulation of Immune Responses by Prostaglandin E2; J. Immunol., 188 21 4) North et al. (2007) Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis; Nature, 447 1007 5) Hoggatt et al. (2013) Differential stem- and progenitor-cell trafficking by prostaglandin E2; Nature, 495 365 6) Coleman et al. (1994) Classification of prostanoid receptors: Properties, distribution and structure of the receptors and their subtypes; Pharmacol. Rev. 46 205

InChI:InChI=1/C20H32O5/c1-2-3-6-9-15(21)12-13-17-16(18(22)14-19(17)23)10-7-4-5-8-11-20(24)25/h4,7,12-13,15-17,19,21,23H,2-3,5-6,8-11,14H2,1H3,(H,24,25)/p-1/b7-4-,13-12+/t15-,16+,17+,19+/m0/s1

Upstream product

• 26054-67-1 (-)-7α-hydroxy-6β-(3α-hydroxy-1E-octenyl)-cis-2-oxabicyclo<3.3.0>octan-3-one 
• 506-32-1 all cis 5,8,11,14-eicosatetraenoic acid 
• 85548-85-2 Bis(tert-butyldimethylsilyl)-PGE₂ oxime 
• 85610-68-0 (Z)-7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((S,E)-3-((tert-butyldimethylsilyl)oxy)oct-1-en-1-yl)-5-oxocyclopentyl)hept-5-enoic acid 
• 551-11-1 dinoprost 
• 1239683-12-5 (Z)-7-((1R,2R,3R,5S)-3-[(tert-butyldimethylsilanyl)oxy]-2-{(S,E)-3-[(tert-butyldimethylsilanyl)oxy]oct-1-en-1-yl}-5-hydroxycyclopentyl)hept-5-enoic acid 
• 61628-05-5 (3aR,4R,5R,6aS)-hexahydro-5-tert-butyldimethylsilyloxy-4-[(1E,3S)-3-tert-butyldimethylsilyloxy-(1E)-octenyl]-2H-cyclopenta[β]furan-2-one 
• 60623-67-8 (-)-7α-Hydroxy-3-oxo-6β-<3-oxo-1(E)-octenyl>-cis-2-oxabicyclo<3.3.0>octane 
• 62961-72-2 Corey aldehyde 
• 87422-39-7 (3aR,6aS)-3,3-dichloro-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-one 
• 32233-40-2 (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one 
• 542-92-7 cyclopenta-1,3-diene 
• 26054-46-6 (-)-(1S,5R)-2-oxabicyclo[3.3.0]oct-6-en-3-one 
• 5307-99-3 (+/-)-7,7-dichlorobicyclo[3.2.0]hept-2-en-6-one 

Downstream Products

• 13345-50-1 prostaglandin A₂ 
• 551-11-1 dinoprost 
• 4510-16-1 Prostaglandin F₂b 
• 55392-90-0 15-acetyl-prostaglandin A₂ 
• 58790-94-6 11,15-diacetyl-prostaglandin E₂ 
• 23453-26-1 (+/-)-prostaglandin E₂ methyl ester 
• 194935-38-1 Prostaglandin E2 ethanolamide 
• 39003-20-8 C₂₉H₅₆O₅Si₃ 
• 62410-93-9 PGE2-1,15-lactone 
• 241472-13-9 C₇₃H₈₄O₁₂P₂Si 
• 241472-14-0 4-[2,2-Bis-(bis-benzyloxy-phosphoryl)-ethyl]-benzoic acid (S)-1-{(E)-2-[(1R,2R,5R)-2-((Z)-6-carboxy-hex-2-enyl)-5-hydroxy-3-oxo-cyclopentyl]-vinyl}-hexyl ester 
• 241472-17-3 C₃₈H₅₁BrO₆Si 
• 26441-05-4 15-Oxoprostaglandin E₂ 
• 143-07-7 lauric acid 

Relevant articles and documents

A NEW SYNTHETIC ROUTE TO PROSTAGLANDINS

A short synthetic route to prostaglandins is described which depends on oxime-based methodology and which involves the joining of intermediates 9, 11, and 12 in a one-flask operation.

Selective induction of cyclo-oxygenase-2 activity in the permanent human endothelial cell line HUV-EC-C: Biochemical and pharmacological characterization

1. Cyclo-oxygenase (COX), the enzyme responsible for the conversion of arachidonic acid (AA) to prostaglandin H2 (PGH2), exists in two forms, termed COX-1 and COX-2 which are encoded by different genes. COX-1 is expressed constitutively and is known to be the site of action of aspirin and other nonsteroidal anti-inflammatory drugs. COX-2 may be induced by a series of pro-inflammatory stimuli and its role in the development of inflammation has been claimed. 2. Endothelial cells are an important physiological source of prostanoids and the selective induction of COX-2 activity has been described for finite cultures of endothelial cells, but not for permanent endothelial cell lines. 3. The HUV-EC-C line is a permanent endothelial cell line of human origin. We have determined the COX activity of these cells under basal conditions and after its exposure to two different stimuli, phorbol 12-myristate 13-acetate (PMA) and interleukin-1β (IL-1β). 4. Both PMA and IL-1β produced dose- and time-dependent increases of the synthesis of the COX-derived eicosanoids. These increases were maximal after the treatment with 10 nM PMA for 6 to 9 h. Under these conditions, the main eicosanoid produced by the cells was PGE2. 5. The increase of COX activity by PMA or IL-1β correlated with an increase of the enzyme's apparent V(max), whilst the affinity for the substrate, measured as apparent K(m), remained unaffected. 6. Treatment of the cells with PMA induced a time-dependent increase in the expression of both COX-1 and COX-2 mRNAs. Nevertheless, this increase was reflected only as an increase of the COX-2 isoenzyme at the protein level. 7. The enzymatic activity of the PMA-induced COX was measured in the presence of a panel of enzyme inhibitors, and the IC50 values obtained were compared with those obtained for the inhibition of human platelet COX activity, a COX-1 selective assay. Classical non-steroidal anti-inflammatory drugs (NSAIDs) inhibited both enzymes with varying potencies but only the three compounds previously shown to be selective COX-2 inhibitors (SC-58125, NS-398 and nimesulide) showed higher potency towards the COX of PMA-treated HUV-EC-C. 8. Overall, it appears that the stimulation of the HUV-EC-C line with PMA selectively induces the COX-2 isoenzyme. This appears to be a suitable model for the study of the physiology and pharmacology of this important isoenzyme, with a permanent endothelial cell line of human origin.

ARACHIDONIC ACID AND METHODS FOR ITS ISOLATION FROM NATURAL MATERIALS

Methods that have been developed for isolating arachidonic or, in full, cis-eicosa-5,8,11,14-tetraenoic acid from the wastes of the endocrine industry are described.The acid isolated has been characterized by physicochemical and spectral features.Prostaglandin E2 has been obtained by enzymatic synthesis from arachidonic acid.

Inhibition of cyclooxygenase and prostaglandin E2 synthesis by γ-mangostin, a xanthone derivative in mangosteen, in C6 rat glioma cells

The fruit hull of mangosteen, Garcinia mangostana L., has been used for many years as a medicine for treatment of skin infection, wounds, and diarrhea in Southeast Asia. In the present study, we examined the effect of γ-mangostin, a tetraoxygenated diprenylated xanthone contained in mangosteen, on arachidonic acid (AA) cascade in C6 rat glioma cells. γ-Mangostin had a potent inhibitory activity of prostaglandin E2 (PGE2) release induced by A23187, a Ca2+ ionophore. The inhibition was concentration-dependent, with the IC50 value of about 5 μM. γ-Mangostin had no inhibitory effect on A23187-induced phosphorylation of p42/p44 extracellular signal regulated kinase/mitogen-activated protein kinase or on the liberation of [14C]-AA from the cells labeled with [14C]-AA. However, γ-mangostin concentration-dependently inhibited the conversion of AA to PGE2 in microsomal preparations, showing its possible inhibition of cyclooxygenase (COX). In enzyme assay in vitro, γ-mangostin inhibited the activities of both constitutive COX (COX-1) and inducible COX (COX-2) in a concentration-dependent manner, with the IC50 values of about 0.8 and 2 μM, respectively. Lineweaver-Burk plot analysis indicated that γ-mangostin competitively inhibited the activities of both COX-1 and -2. This study is a first demonstration that γ-mangostin, a xanthone derivative, directly inhibits COX activity.

Structural and functional characterization of human microsomal prostaglandin E synthase-1 by computational modeling and site-directed mutagenesis

Microsomal prostaglandin (PG) E synthase-1 (mPGES-1) has recently been recognized as a novel, promising drug target for inflammation-related diseases. Functional and pathological studies on this enzyme further stimulate to understand its structure and the structure-function relationships. Using an approach of the combined structure prediction, molecular docking, site-directed mutagenesis, and enzymatic activity assay, we have developed the first three-dimensional (3D) model of the substrate-binding domain (SBD) of mPGES-1 and its binding with substrates prostaglandin H2 (PGH2) and glutathione (GSH). In light of the 3D model, key amino acid residues have been identified for the substrate binding and the obtained experimental activity data have confirmed the computationally determined substrate-enzyme binding mode. Both the computational and experimental results show that Y130 plays a vital role in the binding with PGH2 and, probably, in the catalytic reaction process. R110 and T114 interact intensively with the carboxyl tail of PGH2, whereas Q36 and Q134 only enhance the PGH2-binding affinity. The modeled binding structure indicates that substrate PGH2 interacts with GSH through hydrogen binding between the peroxy group of PGH2 and the -SH group of GSH. The -SH group of GSH is expected to attack the peroxy group of PGH2, initializing the catalytic reaction transforming PGH2 to prostaglandin E2 (PGE2). The overall agreement between the calculated and experimental results demonstrates that the predicted 3D model could be valuable in future rational design of potent inhibitors of mPGES-1 as the next-generation inflammation-related therapeutic.

Characterization of aldo-keto reductase 1C subfamily members encoded in two rat genes (akr1c19 and RGD1564865). Relationship to 9-hydroxyprostaglandin dehydrogenase

Rat genes, akr1c19 and RGD1564865, encode members (R1C19 and 20HSDL, respectively) of the aldo-keto reductase (AKR) 1C subfamily, whose functions, however, remain unknown. Here, we show that recombinant R1C19 and 20HSDL exhibit NAD+-dependent dehydrogenase activity for prostaglandins (PGs) with 9α-hydroxy group (PGF2α, its 13,14-dihydro- and 15-keto derivatives, 9α,11β-PGF2 and PGD2). 20HSDL oxidized the PGs with much lower Km (0.3–14 μM) and higher kcat/Km values (0.064–2.6 min?1μM?1) than those of R1C19. They also differed in other properties: R1C19, but not 20HSDL, oxidized some 17β-hydroxysteroids (5β-androstane-3α,17β-diol and 5β-androstan-17β-ol-3-one). 20HSDL was specifically inhibited by zomepirac, but not by R1C19-selective inhibitors (hexestrol, flavonoids, ibuprofen and flufenamic acid), although the two enzymes were sensitive to indomethacin and cis-unsaturated fatty acids. The mRNA for 20HSDL was expressed abundantly in rat kidney and at low levels in the liver, testis, brain, heart and colon, in contrast to ubiquitous expression of R1C19 mRNA. The comparison of enzymic features of R1C19 and 20HSDL with rat PG dehydrogenases and other AKRs suggests not only a close relationship of 20HSDL with 9-hydroxy-PG dehydrogenase in rat kidney, but also roles of R1C19 and rat AKRs (1C16 and 1C24) in the metabolism of PGF2α, PGD2 and 9α,11β-PGF2 in other tissues.

Access to a Key Building Block for the Prostaglandin Family via Stereocontrolled Organocatalytic Baeyer–Villiger Oxidation

A new protocol for the construction of a crucial bicyclic lactone of prostaglandins using a stereocontrolled organocatalytic Baeyer–Villiger (B-V) oxidation was developed. The key B-V oxidation of a racemic cyclobutanone derivative with aqueous hydrogen peroxide has enabled an early-stage construction of a bicyclic lactone skeleton in high enantiomeric excess (up to 95 %). The generated bicyclic lactone is fully primed with two desired stereocenters and enabled the synthesis of the entire family of prostaglandins according to Corey′s route. Furthermore, the reactivity and enantioselectivity of B-V oxidation of racemic bicyclic cyclobutanones were evaluated and 90–99 % ee was obtained, representing one of the most efficient routes to chiral lactones. This study further facilitates the synthesis of prostaglandins and chiral lactone-containing natural products to promote drug discovery.

15-Hydroperoxy-PGE2: Intermediate in Mammalian and Algal Prostaglandin Biosynthesis

Arachidonic-acid-derived prostaglandins (PGs), specifically PGE2, play a central role in inflammation and numerous immunological reactions. The enzymes of PGE2 biosynthesis are important pharmacological targets for anti-inflammatory drugs. Besides mammals, certain edible marine algae possess a comprehensive repertoire of bioactive arachidonic-acid-derived oxylipins including PGs that may account for food poisoning. Described here is the analysis of PGE2 biosynthesis in the red macroalga Gracilaria vermiculophylla that led to the identification of 15-hydroperoxy-PGE2, a novel precursor of PGE2 and 15-keto-PGE2. Interestingly, this novel precursor is also produced in human macrophages where it represents a key metabolite in an alternative biosynthetic PGE2 pathway in addition to the well-established arachidonic acid-PGG2-PGH2-PGE2 route. This alternative pathway of mammalian PGE2 biosynthesis may open novel opportunities to intervene with inflammation-related diseases.

METHOD OF MAKING A CROSS METATHESIS PRODUCT

Method of making a cross metathesis product, the method comprising at least step (X) or step (Y): (X) reacting in a cross metathesis reaction a first compound comprising a terminal olefinic group with a second compound comprising a terminal olefinic group, wherein the first and the second compound may be identical or may be different from one another; or (Y) reacting in a ring-closing metathesis reaction two terminal olefinic groups which are comprised in a third compound; wherein the reacting in step (X) or step (Y) is performed in the presence of a ruthenium carbene complex comprising a [Ru=C]-moiety and an internal olefin.

In Situ Methylene Capping: A General Strategy for Efficient Stereoretentive Catalytic Olefin Metathesis. the Concept, Methodological Implications, and Applications to Synthesis of Biologically Active Compounds

In situ methylene capping is introduced as a practical and broadly applicable strategy that can expand the scope of catalyst-controlled stereoselective olefin metathesis considerably. By incorporation of commercially available Z-butene together with robust and readily accessible Ru-based dithiolate catalysts developed in these laboratories, a large variety of transformations can be made to proceed with terminal alkenes, without the need for a priori synthesis of a stereochemically defined disubstituted olefin. Reactions thus proceed with significantly higher efficiency and Z selectivity as compared to when other Ru-, Mo-, or W-based complexes are utilized. Cross-metathesis with olefins that contain a carboxylic acid, an aldehyde, an allylic alcohol, an aryl olefin, an α substituent, or amino acid residues was carried out to generate the desired products in 47-88% yield and 90:10 to >98:2 Z:E selectivity. Transformations were equally efficient and stereoselective with a ～70:30 Z-:E-butene mixture, which is a byproduct of crude oil cracking. The in situ methylene capping strategy was used with the same Ru catechothiolate complex (no catalyst modification necessary) to perform ring-closing metathesis reactions, generating 14- to 21-membered ring macrocyclic alkenes in 40-70% yield and 96:4-98:2 Z:E selectivity; here too, reactions were more efficient and Z-selective than when the other catalyst classes are employed. The utility of the approach is highlighted by applications to efficient and stereoselective syntheses of several biologically active molecules. This includes a platelet aggregate inhibitor and two members of the prostaglandin family of compounds by catalytic cross-metathesis reactions, and a strained 14-membered ring stapled peptide by means of macrocyclic ring-closing metathesis. The approach presented herein is likely to have a notable effect on broadening the scope of olefin metathesis, as the stability of methylidene complexes is a generally debilitating issue with all types of catalyst systems. Illustrative examples of kinetically controlled E-selective cross-metathesis and macrocyclic ring-closing reactions, where E-butene serves as the methylene capping agent, are provided.