- NEW PROSTAGLANDIN (PGF) DERIVATIVES FROM THE SOFT CORAL LOBOPHYTON DEPRESSUM
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Four PGF derivatives (15S)-PGF2α-11-acetate methyl ester (1a), the 18-acetoxy derivative of compound 1a (2a) as well as their two corresponding free carboxylic acids (1b and 2b) were isolated from a soft-coral and their structure elucidated, mainly on basis of their spectral data.
- Carmely, S.,Kashman, Y.,Loya, Y.,Benayahu, Y.
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Read Online
- Concise, scalable and enantioselective total synthesis of prostaglandins
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Prostaglandins are among the most important natural isolates owing to their broad range of bioactivities and unique structures. However, current methods for the synthesis of prostaglandins suffer from low yields and lengthy steps. Here, we report a practicability-oriented synthetic strategy for the enantioselective and divergent synthesis of prostaglandins. In this approach, the multiply substituted five-membered rings in prostaglandins were constructed via the key enyne cycloisomerization with excellent selectivity (>20:1 d.r., 98% e.e.). The crucial chiral centre on the scaffold of the prostaglandins was installed using the asymmetric hydrogenation method (up to 98% yield and 98% e.e.). From our versatile common intermediates, a series of prostaglandins and related drugs could be produced in two steps, and fluprostenol could be prepared on a 20-gram scale. [Figure not available: see fulltext.]
- Zhang, Fuhao,Zeng, Jingwen,Gao, Mohan,Wang, Linzhou,Chen, Gen-Qiang,Lu, Yixin,Zhang, Xumu
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p. 692 - 697
(2021/06/01)
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- Access to a Key Building Block for the Prostaglandin Family via Stereocontrolled Organocatalytic Baeyer–Villiger Oxidation
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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.
- Zhu, Kejie,Hu, Sha,Liu, Minjie,Peng, Haihui,Chen, Fen-Er
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p. 9923 - 9927
(2019/05/16)
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- Total synthesis of PGF2α and 6,15-diketo-PGF1α and formal synthesis of 6-keto-PGF1α via three-component coupling
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The asymmetric total synthesis of PGF2α and 6,15-diketo-PGF1α and formal synthesis of 6-keto-PGF1α from a common key intermediate are described. The key intermediate, which has a chiral cyclopentane backbone possessing suitable functional groups with required stereochemistry for both side chains, was prepared from (R)-4-silyloxy-2-cyclopentenone through a three-component coupling reaction. The Wittig reaction, Nozaki-Hiyama-Kishi (NHK) coupling and cross metathesis completed the synthesis of PGF2α, 6,15-diketo-PGF1α and 6-keto-PGF1α.
- Kim, Taehyeong,Lee, Sung Il,Kim, Sejin,Shim, Su Yong,Ryu, Do Hyun
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- METHOD OF MAKING A CROSS METATHESIS PRODUCT
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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.
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Paragraph 00122; 00123; 00124; 00125
(2019/02/06)
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- Of the trometamol prostaglandin F2 α synthesis method (by machine translation)
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The invention discloses a of the trometamol prostaglandin F2 α synthesis method, as the compound (-) - Corey lactone diol as raw materials, through the oxidation reaction to obtain lactone aldehyde, lactone aldehydechain after the weidiWeidi Greecehuo Naer reaction with - the lower side of the splicing an olefin, the olefin double-carbonyl after reduction to obtain the alcohol, with puncture ylide - wittich reaction the upper side of the obtained prostaglandin F2 α, then the prostaglandin F2 α of the trometamol after crystallization by dissolving of the trometamol prostaglandin F2 α. The synthesis method, without noble metal catalyst, there is little side reaction, high yield, low cost, less pollution, is suitable for industrial production. (by machine translation)
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- 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
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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.
- Xu, Chaofan,Shen, Xiao,Hoveyda, Amir H.
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p. 10919 - 10928
(2017/08/15)
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- Decarboxylative alkenylation
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Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, has an essential role in the manipulation of organic matter. Despite its importance, olefin synthesis still relies largely on chemistry introduced more than three decades ago, with metathesis being the most recent addition. Here we describe a simple method of accessing olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids. The activating principles used in amide-bond synthesis can therefore be used, with nickel- or iron-based catalysis, to extract carbon dioxide from a carboxylic acid and economically replace it with an organozinc-derived olefin on a molar scale. We prepare more than 60 olefins across a range of substrate classes, and the ability to simplify retrosynthetic analysis is exemplified with the preparation of 16 different natural products across 10 different families.
- Edwards, Jacob T.,Merchant, Rohan R.,McClymont, Kyle S.,Knouse, Kyle W.,Qin, Tian,Malins, Lara R.,Vokits, Benjamin,Shaw, Scott A.,Bao, Deng-Hui,Wei, Fu-Liang,Zhou, Ting,Eastgate, Martin D.,Baran, Phil S.
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p. 213 - 218
(2017/05/19)
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- Synthesis of Alfaprostol and PGF2α through 1,4-Addition of an Alkyne to an Enal Intermediate as the Key Step
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The veterinary drug Alfaprostol and prostaglandin PGF2α have been synthesized in just nine steps. The strategy involved the conjugate addition of an alkyne to a bicyclic enal, available in three steps by a proline-catalyzed aldol reaction of succinaldehyde. In the case of Alfaprostol, this resulted in the shortest synthesis reported to date. For PGF2α, this approach improved our previous route by making the 1,4-addition and ozonolysis more operationally simple.
- Baars, Hannah,Classen, Moritz J.,Aggarwal, Varinder K.
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p. 6008 - 6011
(2017/11/10)
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- Rh(I)-Catalyzed 1,4-Conjugate Addition of Alkenylboronic Acids to a Cyclopentenone Useful for the Synthesis of Prostaglandins
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An efficient and trans-diastereoselective Rh(I)-catalyzed 1,4-conjugate addition reaction of alkenylboronic acids and a homochiral (R)-4-silyloxycyclopentenone useful for the synthesis of derivatives of prostaglandins E and F is described for the first time. The reaction functions under mild conditions and is particularly rapid (≤6 h) under low power (50 W) microwave irradiation at 30 °C in MeOH in the presence of a catalytic amount of KOH. Under these conditions, 3 mol % of [RhCl(COD)]2 is typically required to produce high yields. The method also functions without microwave irradiation at 3 °C in the presence of a stoichiometric amount of KOH. Under these conditions, only 1.5 mol % of [RhCl(COD)]2 is needed, but the reaction is considerably slower. The method accepts a range of aryl- and alkyl-substituted alkenylboronic acids, and its utility has been demonstrated by the synthesis of PGF2α (dinoprost) and tafluprost.
- Syu, Jin-Fong,Wang, Yun-Ting,Liu, Kung-Cheng,Wu, Ping-Yu,Henschke, Julian P.,Wu, Hsyueh-Liang
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p. 10832 - 10844
(2016/11/29)
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- METAL-CATALYZED ASYMMETRIC 1,4-CONJUGATE ADDITION OF VINYLBORON COMPOUNDS TO 2-SUBSTITUTED-4-OXY-CYCLOPENT-2-EN-1-ONES YIELDING PROSTAGLANDINS AND PROSTAGLANDIN ANALOGS
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This invention provides a novel method for the preparation of 2,3-disubstituted-4-oxy-cyclopentan-1-one compounds that are useful for the synthesis of prostaglandins and prostaglandin analogs of industrial relevance. The method comprises the metal-catalyzed asymmetric 1,4-conjugate addition of vinylboron compounds to 2-substituted-4-oxy-cyclopent-2-en-1-ones. This method relies on the use of less toxic, easily-handled reagents, and can be performed under milder conditions than offered by some conventional methods, affording 2,3-disubstituted-4-oxy-cyclopentan-1-one compounds enantio- and diastereoselectively, which are precursors to the said prostaglandin and prostaglandin analogs, in high yield.
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- Compound And Method
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A compound of formula (I): (I) wherein Y is, Z is OR10, NR11R11 SR11, S(0)R11 S02R11, R10 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, CO—R11, or a protecting group, and R11 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or alkoxyl; a process for making a compound of formula (I); and a process for making a prostaglandin or a prostaglandin analogue using a compound of formula (I). wherein Y is
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- COMPOUND AND METHOD
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A compound of formula (I): (I) wherein Y is, Z is OR10, NR11R11 SR11, S(0)R11 S02R11, R10 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, CO-R11, or a protecting group, and R11 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or alkoxyl; a process for making a compound of formula (I); and a process for making a prostaglandin or a prostaglandin analogue using a compound of formula (I).
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- Stereocontrolled organocatalytic synthesis of prostaglandin PGF 2α in seven steps
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Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction. Their biological activities and their complex molecular architectures have made prostaglandins popular targets for synthetic organic chemists for over 40 years. Prostaglandin analogues are widely used as pharmaceuticals and some, such as latanoprost, which is used to treat glaucoma, have become billion-dollar drugs. Previously reported syntheses of these compounds are quite lengthy, and every chemical step costs time and energy, generates waste and is accompanied by material losses. Using a new bond disconnection, here we report a concise synthesis of the most complex prostaglandin, PGF 2α, with high levels of control of relative and absolute stereochemistry, and fewer steps. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step and an enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups. Access to this bicyclic enal will not only render existing prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of related chemical structures around the ubiquitous five-membered ring motif, such as potentially therapeutic prostaglandin analogues.
- Coulthard, Graeme,Erb, William,Aggarwal, Varinder K.
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p. 278 - 281,4
(2020/07/31)
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- Improved synthesis of (E)-12-nitrooctadec-12-enoic acid, a potent PPARγ activator. development of a "buffer-Free" enzymatic method for hydrolysis of methyl esters
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Endogenous nitro-fatty acids, acting as partial agonist of PPARγ, are able to lower the insulin and glucose levels without the side effects associated with common antidiabetic drugs. (E)-12-Nitrooctadec-12-enoic acid, a potent activator of this peroxisome receptor, was synthesized in a very efficient sequence via a Henry-retro-Claisen ring fragmentation, followed by a novel enzymatic cleavage of methyl esters. The latter method was then applied in the last step of the synthesis of a few labile natural products, such as prostaglandins, isoprostanes, and phytoprostanes.
- Zanoni, Giuseppe,Valli, Matteo,Bendjeddou, Lyamin,Porta, Alessio,Bruno, Paolo,Vidari, Giovanni
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supporting information; experimental part
p. 8311 - 8314
(2011/02/28)
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- The Meyer-Schuster rearrangement: A new synthetic strategy leading to prostaglandins and their drug analogs, Bimatoprost and Latanoprost
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Gold(I) mediated Meyer-Schuster rearrangement for the installation of the 'lower' side chain of prostaglandins and their analogs has been developed. This Au-mediated rearrangement, featuring a low catalyst loading and mild reaction conditions, has been demonstrated to be an efficient alternative to the standard Horner-Wadsworth-Emmons reaction in prostaglandin chemistry. Moreover, the present results provide a new synthetic process leading to pharmacologically active prostanoids: Latanoprost and Bimatoprost, that continue to hold key positions in the anti-glaucoma drug market.
- Zanoni, Giuseppe,D'Alfonso, Alessandro,Porta, Alessio,Feliciani, Lazzaro,Nolan, Steven P.,Vidari, Giovanni
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experimental part
p. 7472 - 7478
(2010/12/25)
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- Inhibition of cyclooxygenases by dipyrone
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Background and Purpose: Dipyrone is a potent analgesic drug that has been demonstrated to inhibit cyclooxygenase (COX). In contrast to classical COX-inhibitors, such as aspirin-like drugs, dipyrone has no anti-inflammatory effect and a low gastrointestinal toxicity, indicating a different mode of action. Here, we aimed to investigate the effects of dipyrone on COX. Experimental approach: The four major metabolites of dipyrone, including the two pharmacologically active metabolites, 4-methyl-amino-antipyrine (MAA) and amino-antipyrine (AA), were used to characterise their binding to COX and haem as well as their effects on the biochemical properties of COX. Mass spectrometry, UV and visible photometry were used to study binding and prostaglandin production. Levels of anti-oxidant enzymes were assessed by Western blotting. Key results: The pharmacologically active metabolites of dipyrone, MAA and AA, did not inhibit COX activity in vitro like classical COX inhibitors, but instead redirected the prostaglandin synthesis, ruling out inhibition of COX through binding to its active site. We found that MAA and AA formed stable complexes with haem and reacted with hydrogen peroxide in presence of haem, ferrous ions (Fe2+) or COX. Moreover, MAA reduced Fe 3+ to Fe2+ and accordingly increased lipid peroxidation and the expression of anti-oxidant enzymes in cultured cells and in vivo. Conclusions and implications: Our data suggest that the pharmacologically active metabolites of dipyrone inhibit COX activity by sequestering radicals which initiate the catalytic activity of this enzyme or through the reduction of the oxidative states of the COX protein.
- Pierre,Schmidt,Brenneis,Michaelis,Geisslinger,Scholich
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p. 494 - 503
(2008/02/07)
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- Novel pyrimidine carboxamides
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The present invention relates to novel compounds of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts and compositions, their metabolites and prodrugs thereof. The present invention more particularly relates to novel pyrimidine carboxamides of the general formula (I). Also included is a method of prophylaxis or treatment of a pain disorder, immunological diseases, inflammation, rheumatoid arthritis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; ischemic heart disease; atherosclerosis; cancer; ischemic-induced cell damage; pancreatic beta cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; muscle degeneration; cachexia; asthma; bone resorption diseases; ischemia reperfusion injury; brain trauma; multiple sclerosis; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection in a mammal comprising administering an effective amount of a compound of formula (I) as described above.
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Page/Page column 29
(2008/06/13)
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- Processes and intermediates for the preparations of prostaglandins
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The present invention provides novel processes for the preparation of a cyclopentanone of Formula II and a lactone of Formula I, which are useful in the production of prostaglandins: wherein Z, R2, R3, X1, X2, and are as defined in the specification. The invention also provides novel enantiomerically enriched compounds.
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Page/Page column 16
(2008/06/13)
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- Processes and intermediates for the preparations of prostaglandins
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The present invention provides novel processes for the preparation of a cyclopentanone of Formula II and a lactone of Formula I, which are useful in the production of prostaglandins: wherein Z, R2, R3, X1, X2, and ------------ are as defined in the specification. The invention also provides novel enantiomerically enriched compounds.
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Page/Page column 23
(2010/11/28)
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- Effect of allylic and homoallylic substituents on cross metathesis: syntheses of prostaglandins F2α and J2
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We describe the effect of allylic (C15) and homoallylic (C11) substituents on cross metathesis reactions with Corey lactone derivatives. This strategy has led to the successful syntheses of PGF2α and PGJ2.
- Sheddan, Neil A.,Arion, Vladimir B.,Mulzer, Johann
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p. 6689 - 6693
(2007/10/03)
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- Cross metathesis as a general strategy for the synthesis of prostacyclin and prostaglandin analogues
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A cross metathesis (CM) approach has been successfully applied to introduce fully functionalized ω-side chain appendages of various prostacyclin and prostaglandin analogues, resulting in high (E)-selectivities for the C13-C14 double bond and leading to the total syntheses of isocarbacyclin, 15R-TIC, carbacyclin, and PGF2α, and the formal syntheses of 15-deoxy-TIC and PGJ2.
- Sheddan, Neil A.,Mulzer, Johann
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p. 3101 - 3104
(2007/10/03)
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- Cyclopentane 1-hydroxy alkyl or alkenyl-2-one or 2-hydroxy derivatives as therapeutic agents
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The present invention provides a novel compound represented by the general formula I; wherein R is H or COR3;R1 is H, R2, phenyl, or COR3, wherein R2 is C1-C5 lower alkyl and R3 is R2 or phenyl;Z is CH2 or O;Y is OH or OCOR3;x is 0 or 1; andX is C1-C5 n-alkyl, C3-C7 cycloalkyl, phenyl, furanyl, thienyl or substituted derivatives thereof, wherein the substituents maybe selected from the group consisting of C1-C5 alkyl, halogen, CF3, CN, NO2, NR42, CO2R4 and OR4 wherein R4 is hydrogen or C1-C5 alkyl and dotted lines represent the presence or absence of a double bond and wavy lines represent a cis or trans bond. These novel compounds are especially useful for treating elevated intraocular pressure (ocular hypertension) and glaucoma.
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- Total synthesis of prostaglandin F(2α) using nickel-catalyzed stereoselective cyclization of 1,3-diene and tethered aldehyde via transmetalation of nickelacycle with diisobutylaluminum acetylacetonate
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Total synthesis of prostaglandin F(2α) utilizing a nickel(0)-catalyzed cyclization of 1,3-diene and tethered aldehyde was achieved. The cyclization proceeded via a transmetalation of nickelacycle with dilsobutylaluminum acetylacetonate ((i)Bu2-ALAC). Thus, the reaction of 19, having a side chain corresponding to the α-chain in PGF(2α) with Ni(cod)2 (10 mol %), PPh3 (20 mol %), and 1,3-cyclohexadiene (25 mol %) in the presence of (i)Bu2-ALAC (1.5 eq) proceeded stereoselectively to give the cyclized product 26 in 54% yield. During the cyclization of 19, the Z-olefin at C-5 in the side chain completely retained its geometry, and the four contiguous chiral carbon centers in PGF(2α) were stereoselectively constructed. Transformation of the key intermediate 19 into PGF(2α) was successfully achieved.
- Sato,Takimoto,Mori
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p. 1753 - 1760
(2007/10/03)
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- Total Synthesis of Prostaglandin F2α via Nickel-Promoted Stereoselective Cyclization of 1,3-Diene and Aldehyde
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The total synthesis of prostaglandin F2α (PGF2α) was accomplished via nickel-promoted cyclization of 1,3-diene and aldehyde in a chain in the presence of 1,3-cyclohexadiene (1,3-CHD). The cyclization of 16 prepared in an optically active form from chiral epoxy alcohol 10 stereoselectively gave the key intermediate 18, which has both an α-chain and the four contiguous chiral carbon centers in PGF2α, in a one-pot reaction. Intermediate 18 was successfully transformed into PGF2α.
- Sato, Yoshihiro,Takimoto, Masanori,Mori, Miwako
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p. 734 - 736
(2007/10/03)
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- Selective induction of cyclo-oxygenase-2 activity in the permanent human endothelial cell line HUV-EC-C: Biochemical and pharmacological characterization
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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.
- Miralpeix, Montserrat,Camacho, Mercedes,Lopez-Belmonte, Jesus,Canalias, Francesca,Beleta, Jordi,Palacios, Jose Ma.,Vila, Luis
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p. 171 - 180
(2007/10/03)
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- Studies on the Properties of Prostaglandin Synthetase of Caprine Seminal Vesicles
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The prostaglandin (PG) synthetase complex in the microsomal fraction of caprine (goat) seminal vesicles was found to have the highest PGE2 synthetase activity in comparison to that in similar other animal sources. The results of the investigations on the kinetics of PGE2 synthesis, factors influencing product formation, cofactor requirement and stability of the enzyme system show that the PG-synthetase complex from goat vesicular gland was very unstable, and its properties were generally comparable to that from the highly active ovine seminal vesicular multienzyme complex.
- Das, Mallika,Ghosh, Dolly
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p. 319 - 322
(2007/10/03)
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- Endoperoxide pathway in prostaglandin biosynthesis in the soft coral Gersemia fruticosa
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An acetone powder preparation of the White Sea soft coral Gersemia converts exogenous arachidonic acid to a prostaglandin-endoperoxide, identified as PGG2 by chemical and spectral studies. The latter serves as a key intermediate from which, evidently by nonenzymic transformations, all optically active coral prostaglandins are formed.
- Varvas, Kuelliki,Koljak, Reet,Jaerving, Ivar,Pehk, Tonis,Samel, Nigulas
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p. 8267 - 8270
(2007/10/02)
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- New chiral synthetic intermediate for prostaglandins
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Preparation of an optically active synthetic intermediate 3 starting from D-mannitol and its conversion to PGF2α (1) by using [3+2] cycloaddition of the nitrile oxide derivative of 3 followed by conjugate addition of the vinylzincate to exocyclic enone 2 are described.
- Takahashi,Shimayama,Miyazawa,Nakazawa,Yamada,Takatori,Kajiwara
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p. 5973 - 5976
(2007/10/02)
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- PROSTANOIDS. XXXII. SYNTHESIS OF (+)-PROSTAGLANDIN F2α
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Natural prostaglandin F2α was obtained from cyclopentadiene monoxide.The key stages of the synthesis included the following: Optical resolution of (+/-)-trans-2-carboxymethylcyclopent-3-en-1-ol with the transformation of its (-)-enantiomer into (-)-cis-2-oxabicyclooct-6-en-3-one and then into (-)-7α-triethylsilyloxy-6β-triethylsilyloxymethyl-cis-2-oxabicyclooctan-3-one; selective oxidation of the latter by the DMSO-(COCl)2 system; condensation of the intermediate (-)-7α-triethylsilyloxy-6β-formyl-cis-2-oxabicyclooctan-3-one with dimethyl 2-oxoheptylphosphonate under the conditions of phase-transfer catalysis with the production of (-)-7α-hydroxy-6β-(3-oxo-1E-octenyl)-cis-2-oxabicyclooctan-3-one; conversion of the latter into (+)-PGF2α by standard methods.
- Miftakhov, M. S.,Adler, M. E.,Komissarova, N. G.,Tolstikov, G. A.
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p. 1274 - 1280
(2007/10/02)
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- Prostaglandins and Prostaglandin Intermediates. Part 26 A Novel Route to PGF2α using Triisopropoxy-hept-1-ynyl-titanium as Precursor for the β-Side Chain
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The benzoylated Corey aldehyde 1a can be alkynylated with hept-1-ynyl-triisopropoxytitanium in good chemical yield and high diastereoselectivity to the (R)-alcohol 3c admixed with about 10percent of the diastereomeric (S)-alcohol 2c.Without removal of thi
- Mahrwald, Rainer,Schick, Hans,Pivnitsky, Kasimir K.,Schwarz, Sigfrid
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p. 403 - 413
(2007/10/02)
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- BF3-MEDIATED REACTION OF A SULPHONE WITH ALDEHYDES. A METHOD FOR STEREOSPECIFIC CONSTRUCTION OF PROSTAGLANDIN ω-CHAIN
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A new method for stereospecific construction of the allylic alcohol moiety of prostaglandins, based on application of optically active α-hydroxy aldehydes, is described.In the presence of BF3*Et2O, lithiated sulphones 1 prepared from Corey aldehyde, and carbonyl compounds 2 give the corresponding adducts 3 in moderate to excellent yields, while in the absence of the Lewis acid either no products or only their traces were formed.The addition products 3, in the form of benzoates, mesylates or free alcohols, were subjected to reductive elimination by means of sodium amalgam to give the alkenes 4.Compounds 4d and 4f were transformed into racemic and natural PGF2α, respectively, in line with the known method.
- Achmatowicz, B.,Baranowska, E.,Daniewski, A. R.,Pankowski, J.,Wicha, J.
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p. 4989 - 4998
(2007/10/02)
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- Regio- and Stereoselectivity of the Reaction between Cyanocuprates and Cyclopentene Epoxides. Application to the Total Synthesis of Prostaglandins
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A systematic study of the reaction between cyclopentene epoxides and alkyl-, alkenyl-, and arylcyanocuprates is described.Alkylcyanocuprates react with complete regio- and stereoselectivity to provide trans-4-alkylcyclopent-2-enols in excellent yields.Vin
- Marino, Joseph P.,Pradilla, Roberto F. de la,Laborde, Edgardo
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p. 4898 - 4913
(2007/10/02)
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- A NOVEL APPROACH TO PROSTAGLANDINS FROM THE COREY LACTONE INVOLVING BF3-MEDIATED REACTIONS OF A SULPHONE AND ALDEHYDES
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Transformation of the diol 1 via epimeric sulphones 7 to PGF2α is described.Alkylation of lithiated sulphones 7 with aldehydes 8a, 8b or 8c in the presence of BF3 efficiently gives corresponding adducts.
- Achmatowicz, B.,Baranowska, E.,Daniewski, A. R.,Pankowski, J.,Wicha, J.
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p. 5597 - 5600
(2007/10/02)
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- Stereocontrolled Synthesis of Prostaglandins from Cyclopentadiene Monoepoxide
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Two complementary syntheses of prostaglandins from the same key intermediate 3, available in four steps from cyclopentadiene monoepoxide, are described.In one approach, a saturated α-chain is introduced via a 1,4-addition of an appropriately functionalized cyanocuprate reagent onto silyl enol ether 3.The resulting prostanoid compound was converted into the bronchodilator 1-decarboxy-1-hydroxymethyl PGE1, PGE1, and PGF1α.The second approach involves the transformation of silyl enol ether 3 into the known prostanoid precursor 11 via selective addition of carbethoxycarbene and subsequent fluoride-induced ring opening of the resulting (silyloxy)cyclopropane carboxylate ester.
- Marino, Joseph P.,Pradilla, Roberto Fernandez de la,Laborde, Edgardo
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p. 5279 - 5280
(2007/10/02)
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- Synthesis of Aromatic Modified Prostaglandins from PGA2
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A general synthetic scheme, starting from PGA2 (obtained from the marine coral Plexaura homomalla), of prostaglandins modified in the upper chain is detailed.Key aldehyde intermediates have been secured from 11-deoxy-PGF2α and PGF2α by an efficient regioselective hydroxylation procedure followed by cleavage of the 5,6-double bond.Witting reaction with these aldehydes provided the novel prostaglandins (5)-(8), belonging to the E and F families, and containing an aromatic ring in the upper chain.
- Cai, Zuyun,Nassium, Bahman,Crabbe, Pierre
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p. 1573 - 1578
(2007/10/02)
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- Enantio-complementary Total Asymmetric Syntheses of Prostaglandin E2 and Prostaglandin F2α
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The racemic ketone (6) was converted into the diastereoisomeric alcohols (7) and (8) using actively fermenting yeast.These alcohols were separated and converted into the bromohydrins (-)-(9) and (+)-(9).The bromohydrin (-)-(9) was converted into prostaglandin E2 (1) and prostaglandin F2α (2) by reaction of the chiral cuprate reagent (15) with the tricyclic ketone (10), while the bromohydrin (+)-(9) was converted into the prostaglandins by reaction of the epoxyacetal (11) with the same cuprate reagent (15).
- Davies, John,Roberts, Stanley M.,Reynolds, Derek P.,Newton, Roger F.
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p. 1317 - 1320
(2007/10/02)
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- Total Synthesis of Prostaglandin-F2α, and the 9-O-Benzyl Derivatives of Prostaglandins-F2α, -F1α, -D2, and -D1
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As an extension of the method whereby prostaglandin-F2α may be prepared by homoconjugate addition of an organocuprate reagent to the 3-endo-silyloxytricyclo2,7>heptan-6-one (3), 3-endo-benzyloxytricyclo2,7
- Cave,Richard J.,Newton, Roger F.,Reynolds, Derek P.,Roberts, Stanley M.
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p. 646 - 652
(2007/10/02)
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- Biosynthesis of a prostaglandin by a plant enzyme.
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Lipoxygenase-2 from soybeans catalyzes the oxygenation of arachidonic acid to form significant amounts of a prostaglandin product. Results obtained with the dithionite-reduced derivatized product upon combined gas chromatography-mass spectroscopy are consistent with structures of the stereoisomers of 9,11,15-trihydroxyprosta-5,13-dienoic acid. A portion of the material formed by reduction of the enzyme product with dithionite reacts positively in a radioimmunoassay against rabbit anti-prostaglandin F2alpha antibody. This appears to be the first report of the synthesis of a prostaglandin by a non-animal enzyme.
- Bild,Bhat,Ramadoss,Axelrod
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- Racemic fluoro-substituted PGF2 α analogs
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This invention is racemic PGE2, racemic PGF2α, racemic PGF2β, racemic PGA2, racemic PGB2, analogs of those, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibiton of platelet aggregation, increase of nasal patency, abortion, and wound healing.
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