- A new one-pot synthesis of all E-retinoic acid via a new enaminodiester synthon
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A 'one-pot' synthesis of all E-retinoic acid from a new enaminodiester was described. The enaminodiester was easily produced from methyl isopropylidenemalonate and DMF-DMA.
- Cartier, Dominique,Valla, Alain,Labia, Roger,Le Guillou, Régis,Potier, Pierre
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Read Online
- Stereoselective synthesis of all-trans-, (13Z)- and (9-nor)-retinoic acids via Stille reaction
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Stereoselective construction of retinoic acid and certain analogues were achieved through two successive Stille reactions. First, the coupling of (E)- 1,2-bis(tributylstannyl)ethene and (Z)- or (E)-tributylstannyl 3-iodoalk-2- enoates was performed followed by iododestannylation. The second step involved another vinyltin which was synthesised by stannylmetallation of the Negishi dienyne derived from β-ionone.
- Thibonnet, Jér?me,Abarbri, Mohamed,Duchêne, Alain,Parrain, Jean-Luc
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Read Online
- Design, synthesis, and ex vivo evaluation of a selective inhibitor for retinaldehyde dehydrogenase enzymes
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The retinaldehyde dehydrogenase (RALDH) enzymes, RALDH1, RALDH2, and RALDH3, catalyze the irreversible oxidation of retinaldehyde to all-trans-retinoic acid (ATRA). Despite the importance of the RALDH enzymes in embryonic development, postnatal growth and differentiation, and in several disease states, there are no commercially available inhibitors that specifically target these isozymes. We report here the development and characterization of a small molecule inhibitor dichloro-all-trans-retinone (DAR) (Summers et al., 2017) that is an irreversible inhibitor of RALDH1, 2, and 3 that effectively inhibits RALDH1, 2, and 3 in the nanomolar range but has no inhibitory activity against mitochondrial ALDH2. These results provide support for the development of DAR as a specific ATRA synthesis inhibitor for a variety of experimental and clinical applications.
- Harper, Angelica R.,Le, Anh T.,Mather, Timothy,Burgett, Anthony,Berry, William,Summers, Jody A.
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Read Online
- Impurity analysis of retinoic acid samples
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The structure of an impurity contained in samples of all trans-retinoic acid was established by means of NMR and MS spectra, and confirmed by X-ray diffraction analysis. The chemical structure of the impurity 2 was found to be strictly correlated to the s
- Allegrone, Gianna,Brenna, Elisabetta,Fronza, Giovanni,Fuganti, Claudio,Giovenzana, Tommaso,Malpezzi, Luciana,Barlocchi, Enrico,Pellegatta, Cesare
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Read Online
- Synthesis method of new compounds Potassium all-trans retinoate and Potassium 9-cis retinoate.
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A method for synthesizing all-cis retinoate by adding trans retinoic acid after 9 - cis retinoic acid addition to Hexane-KOH and Potassium all, followed by combining trans retinoate to Potassium all and Potastastastastastastastasy, trans retinoate-cis β LogP-9 which measures the absorption rate at a long time when administered orally, which has an effect of lowering the risk of cancer and cardiovascular diseases carotene. The cardiovascular therapeutic agent of 9, wherein the cardiovascular therapeutic agent is administered orally. The present invention relates to a therapeutic agent for atherosclerosis and a therapeutic agent for angina pectoris.
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Paragraph 0029-0030
(2021/07/07)
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- Iron-Catalyzed Vinylzincation of Terminal Alkynes
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Organozinc reagents are among the most commonly used organometallic reagents in modern synthetic chemistry, and multifunctionalized organozinc reagents can be synthesized from structurally simple, readily available ones by means of alkyne carbozincation. However, this method suffers from poor tolerance for terminal alkynes, and transformation of the newly introduced organic groups is difficult, which limits its applications. Herein, we report a method for vinylzincation of terminal alkynes catalyzed by newly developed iron catalysts bearing 1,10-phenanthroline-imine ligands. This method provides efficient access to novel organozinc reagents with a diverse array of structures and functional groups from readily available vinylzinc reagents and terminal alkynes. The method features excellent functional group tolerance (tolerated functional groups include amino, amide, cyano, ester, hydroxyl, sulfonyl, acetal, phosphono, pyridyl), a good substrate scope (suitable terminal alkynes include aryl, alkenyl, and alkyl acetylenes bearing various functional groups), and high chemoselectivity, regioselectivity, and stereoselectivity. The method could significantly improve the synthetic efficiency of various important bioactive molecules, including vitamin A. Mechanistic studies indicate that the new iron-1,10-phenanthroline-imine catalysts developed in this study have an extremely crowded reaction pocket, which promotes efficient transfer of the vinyl group to the alkynes, disfavors substitution reactions between the zinc reagent and the terminal C–H bond of the alkynes, and prevents the further reactions of the products. Our findings show that iron catalysts can be superior to other metal catalysts in terms of activity, chemoselectivity, regioselectivity, and stereoselectivity when suitable ligands are used.
- Hu, Meng-Yang,Huang, Qiang,Su, Yu-Xuan,Sun, Wei,Wang, Wei-Na,Zhu, Shou-Fei
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- Preparation method of tretinoin
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The invention discloses a preparation method of tretinoin. The method comprises the following steps: 1) hydrolyzing vitamin A acetate under an alkaline condition to obtain vitamin A; and 2) in an oxygen atmosphere, carrying out an oxidation reaction on the vitamin A in an ionic liquid bis-(3-methyl-1-imidazole)ethylene tetrafluoroborate under the catalytic action of RuCl2(PPh3)3 to obtain tretinoin. The method has the advantages of mild reaction conditions, easily available reaction raw materials, no need of purification of intermediates, reaction yield of up to 90%, purity of 99%, and good industrial application prospect.
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Paragraph 0020; 0029; 0031-0032; 0043; 0047; 0051
(2020/05/11)
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- Catalytic synthesis of 9-cis-retinoids: Mechanistic insights
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The regioselective Z-isomerization of thermodynamically stable all-trans retinoids remains challenging, and ultimately limits the availability of much needed therapeutics for the treatment of human diseases. We present here a novel, straightforward approach for the catalytic Z-isomerization of retinoids using conventional heat treatment or microwave irradiation. A screen of 20 transition metal-based catalysts identified an optimal approach for the regioselective production of Z-retinoids. The most effective catalytic system was comprised of a palladium complex with labile ligands. Several mechanistic studies, including isotopic H/D exchange and state-of-the-art quantum chemical calculations using coupled cluster methods indicate that the isomerization is initiated by catalyst dimerization followed by the formation of a cyclic, six-membered chloropalladate catalyst-substrate adduct, which eventually opens to produce the desired Z-isomer. The synthetic development described here, combined with thorough mechanistic analysis of the underlying chemistry, highlights the use of readily available transition metal-based catalysts in straightforward formats for gram-scale drug synthesis.
- Kahremany, Shirin,Kubas, Adam,Tochtrop, Gregory P.,Palczewski, Krzysztof
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supporting information
p. 10581 - 10595
(2019/07/22)
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- Z -isomerization of retinoids through combination of monochromatic photoisomerization and metal catalysis
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Catalytic Z-isomerization of retinoids to their thermodynamically less stable Z-isomer remains a challenge. In this report, we present a photochemical approach for the catalytic Z-isomerization of retinoids using monochromatic wavelength UV irradiation treatment. We have developed a straightforward approach for the synthesis of Z-retinoids in high yield, overcoming common obstacles normally associated with their synthesis. Calculations based on density functional theory (DFT) have allowed us to correlate the experimentally observed Z-isomer distribution of retinoids with the energies of chemically important intermediates, which include ground- and excited-state potential energy surfaces. We also demonstrate the application of the current method by synthesizing gram-scale quantities of 9-cis-retinyl acetate 9Z-a. Operational simplicity and gram-scale ability make this chemistry a very practical solution to the problem of Z-isomer retinoid synthesis.
- Kahremany, Shirin,Sander, Christopher Lane,Tochtrop, Gregory P.,Kubas, Adam,Palczewski, Krzysztof
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supporting information
p. 8125 - 8139
(2019/09/19)
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- Methods for treating of skin conditions with retinoid double conjugate compounds
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A double conjugate molecule made of a retinoid, an organic acid, particularly an a-hydroxy acid, and an alcohol or acyl group, is provided which is useful in treating skin conditions, particularly aging. The retinoid, organic acid, and alcohol/acyl group are preferably linked via ester bonds.
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Page/Page column 20
(2018/11/30)
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- Stereospecific synthesis process for tretinoin compounds
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A stereospecific synthesis process for tretinoin compounds comprises the following steps: using substituted triphenyl phosphine salt and β-formyl crotonic acid as raw material to carry out WITTIG reaction under the action of alkali; then adjusting the pH of the reaction liquid to 5-10; adding palladium compound or rhodium compound to carry out isomerization directly and obtain tretinoin compounds with desired configuration. The product yield of the process is high and the intermediate product in the reaction dose not need to be separated. The process is easy to operate and can save the production cost and as well is suitable for industrial production.
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Page/Page column 7; 8
(2014/09/29)
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- Synthesis of 11C-labeled retinoic acid, [11C]ATRA, via an alkenylboron precursor by Pd(0)-mediated rapid C-[11C] methylation
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Retinoids are a class of chemical compounds which include both natural dietary vitamin A (retinol) metabolites and active synthetic analogs. Both experimental and clinical studies have revealed that retinoids regulate a wide variety of essential biological processes. In this study, we synthesized 11C-labeled all-trans-retinoic acid (ATRA), the most potent biologically active metabolite of retinol and used in the treatment of acute promyelocytic leukemia. The synthesis of 11C-labeled ATRA was accomplished by a combination of rapid Pd(0)-mediated C-[11C] methylation of the corresponding pinacol borate precursor prepared by 8 steps and hydrolysis. [11C]ATRA will prove useful as a PET imaging agent, particularly for elucidating the improved therapeutic activity of ATRA (natural retinoid) for acute promyelocytic leukemia by comparing with the corresponding PET probe [11C]Tamibarotene (artificial retinoid).
- Suzuki, Masaaki,Takashima-Hirano, Misato,Ishii, Hideki,Watanabe, Chika,Sumi, Kengo,Koyama, Hiroko,Doi, Hisashi
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supporting information
p. 3622 - 3625
(2014/07/22)
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- STEREOSPECIFIC SYNTHESIS PROCESS FOR TRETINOIN COMPOUNDS
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A stereospecific synthesis process for tretinoin compounds comprises the following steps: using substituted triphenyl phosphine salt and β-formyl crotonic acid as raw material to carry out WITTIG reaction under the action of alkali; then adjusting the pH of the reaction liquid to 5-10; adding palladium compound or rhodium compound to carry out isomerization directly and obtain tretinoin compounds with desired configuration. The product yield of the process is high and the intermediate product in the reaction dose not need to be separated. The process is easy to operate and can save the production cost and as well is suitable for industrial production.
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Paragraph 0035; 0036; 0037
(2014/04/03)
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- A sensitive and specific method for measurement of multiple retinoids in human serum with UHPLC-MS/MS
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Retinol (vitamin A) circulates at 1-4 μM concentration and is easily measured in serum. However, retinol is biologically inactive. Its metabolite, retinoic acid (RA), is believed to be responsible for biological effects of vitamin A, and hence the measurement of retinol concentrations is of limited value. A UHPLC-MS/MS method using isotope-labeled internal standards was developed and validated for quantitative analysis of endogenous RA isomers and metabolites. The method was used to measure retinoids in serum samples from 20 healthy men. In the fed state, the measured concentrations were 3.1 ± 0.2 nM for at RA, 0.1 ± 0.02 nM for 9-cisRA, 5.3 ± 1.3 nM for 13-cisRA, 0.4 ± 0.4 nM for 9,13-dicisRA, and 17.2 ± 6.8 nM for 4oxo-13-cisRA. The concentrations of the retinoids were not significantly different when measured after an overnight fast (3.0 ± 0.1 nM for atRA, 0.09 ± 0.01nM for 9-cisRA, 3.9 ± 0.2 nM for 13-cisRA, 0.3 ± 0.1 nM for 9,13-dicisRA, and 11.9 ± 1.6 nM for 4oxo-13-cisRA). 11-cisRA and 4OH-RA were not detected in human serum. The high sensitivity of the MS/MS method combined with the UHPLC separation power allowed detection of endogenous 9-cis RA and 4oxo-atRA for the first time in human serum. Copyright
- Arnold, Samuel L. M.,Amory, John K.,Walsh, Thomas J.,Isoherranen, Nina
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experimental part
p. 587 - 598
(2012/05/31)
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- TOPICAL AQUEOUS COMPOSITION COMPRISING TRETINOIN
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Topical aqueous compositions for the treatment of a skin disorder particularly acne. Topical aqueous composition comprising tretinoin and a hydrophilic cellulose derivative as a gelling agent, wherein the composition has a pH of about 4 to about 6.5 and viscosity of less than about 20,000 cP or provided. The composition also relates to the topical administration of tretinoin in combination with an antibiotic.
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- Novel Imaging Agents for Fibrosis
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The present invention provides a novel imaging agent targeting the mannose-6-phosphate (M6P) receptor suitable for the non-invasive visualization of fibrosis. A method for the preparation of the imaging agent is also provided by the invention, as well as a precursor for use in said method. The invention also provides a pharmaceutical composition comprising the imaging agent and a kit for the preparation of the pharmaceutical composition. In a further aspect, use of the imaging agent for in vivo imaging and in the preparation of a medicament for the diagnosis of a condition in which the mannose-6-phosphate receptor is upregulated is provided.
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- A caged retinoic acid for one- and two-photon excitation in zebrafish embryos
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(Chemical Equation Presented) Escaping the cage: Retinoic acid (RA), a crucial signaling molecule for the embryogenesis of vertebrates, can be photoreleased from a simple caged derivative (cRA) upon illumination. In zebrafish embryos, cRA causes RA-induced phenotypes with one- and two-photon excitation (see picture), which opens a route to the noninvasive generation of controlled RA concentration patterns in vivo.
- Neveu, Pierre,Aujard, Isabelle,Benbrahim, Chouaha,Le Saux, Thomas,Allemand, Jean-Francois,Vriz, Sophie,Bensimon, David,Jullien, Ludovic
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supporting information; experimental part
p. 3744 - 3746
(2009/02/07)
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- All-Trans-Retinol: All-Trans-13,14-Dihydroretinol Saturase and Methods of Its Use
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Compositions of all-trans-retinol: all-trans-13,14-dihydroretinal saturase and methods of use thereof are provided.
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- PROCESS FOR PREPARATION OF HIGHLY PURE ISOTRETINOIN
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The present invention relates to a process for preparation of isotretinoin and more specifically, to a purification process for obtaining highly pure isotretinoin that is useful as a keratolytic agent, particularly useful for the treatment of acne. The process involves treating isotretinoin containing metal contamination and/or other impurities with a base in a suitable solvent to form a solution of isotretinoin, followed by adsorption, precipiation, and filtration or centrifugation
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(2008/12/08)
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- IMPROVED METHOD OF PRODUCTION OF 9-CIS-RETINOIC ACID
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Improved method of production of 9-(Z)-retinoic acid, in which: a) a β-formyl-crotonic acid C1-C10 alkyl or phenyl ester is reacted with an isolated 9-(Z)-C15-triarylphosphonium salt by the Wittig reaction in the presence of a base to the corresponding 9-(Z)-retinoic acid ester, which b) is then saponified with a base to the corresponding 9-(Z)-retinoic acid carboxylate and then, following protonation with an acid, the desired 9-(Z)-retinoic acid is obtained, and improved method for the enrichment and isolation of the 9-(Z)-C15-triarylphosphonium salt.
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(2008/06/13)
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- Caesium fluoride-promoted Stille coupling reaction: An efficient synthesis of 9Z-retinoic acid and its analogues using a practical building block
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A highly efficient and rapid total synthesis of 9Z-retinoic acid was accomplished by caesium fluoride-promoted Stille coupling reaction; using a common building block, 9Z-retinoic acid analogues were also prepared by the same method without isomerisation of the Z-double bond. The Royal Society of Chemistry 2008.
- Okitsu, Takashi,Iwatsuka, Kinya,Wada, Akimori
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scheme or table
p. 6330 - 6332
(2009/04/13)
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- Stereoselective synthesis of trienoic acids: Synthesis of retinoic acids and analogues
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Stereoselective construction of conjugated trienoic acids was achieved through two successive Stille reactions, the first step consisting of the coupling of (E)-1,2-bis(tributylstannyl)ethene and tributylstannyl (Z)- or (E)-3-iodoalk-2-enoates. Two different routes were used for the second step: (1) cross-coupling of the stannyldienoic acid reagents and vinyl iodides, or (2) cross-coupling of vinylstannane reagents and the tributylstannyl 5-iodopenta-2,4-dienoates generated by iododestannylation of stannyldienes. Vinylstannanes synthesized by stannylmetalation of the Negishi dienyne derived from β- or α-ionone and safranal thus provided access to stereodefined retinoic acids. Some retinoid and yne analogues were also prepared by Sonogashira coupling. Georg Thieme Verlag Stuttgart.
- Abarbri, Mohamed,Parrain, Jean-Luc,Duchene, Alain,Thibonnet, Jerome
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p. 2951 - 2970
(2008/02/05)
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- Stereoselective and convergent syntheses of retinoic acid and its ester derivatives by the sulfone olefination reaction
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An extensive study on the stereoselective and convergent syntheses of retinoic acid and its ester derivatives utilizing the Julia sulfone olefination reaction has been reported. Various C5 units of the acid 4a, the esters 4b-e from the chemically and biologically important alcohols, and the furanone 6 have been prepared and coupled with the C15 allylic sulfone 3 to give the C20 compounds 10 and 11, which provided all-(E)-retinoic acid (1a), its ester derivatives 1b-e, and the furanone analogue 12b in a highly stereoselective manner after dehydrosulfonation reaction. The Julia olefination reaction of the C5 diester 13 and the C15 allylic sulfone 3 produced the known C20 diacid 15 which underwent stereoselective mono-decarboxylation to provide either 13-(Z)-retinoic acid (2) or all-(E)-retinoic acid (1) depending on the reagent used.
- Jeon, Hye-Sun,Yeo, Jung Eun,Jeong, Young Cheol,Koo, Sangho
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p. 2813 - 2820
(2007/10/03)
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- Preparation and biological activity of 13-substituted retinoic acids
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13-Demethyl or 13-substituted all-E- and 9Z-retinoic acids were synthesized using a palladium-catalyzed coupling reaction of enol triflates and tributylstannylolefins. Their biological activities were then measured. The 13-ethyl analogs exhibited approximately one-half of the antiproliferative and differentiation-inducing activity of ATRA in HL-60 cells. In contrast, in the 9Z-derivatives, all analogs, except for the 13-butyl derivatives, showed apoptosis-inducing activity.
- Wada, Akimori,Fukunaga, Kouki,Ito, Masayoshi,Mizuguchi, Yukari,Nakagawa, Kimie,Okano, Toshio
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p. 3931 - 3942
(2007/10/03)
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- PROCESS FOR THE PRODUCTION OF 9-CIS RETINOIC ACID
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A new industrially applicable process for the production of 9-(Z)-retinoic acid is described which is characterized by the conversion of an alkali metal salt of 3-methyl-4-oxocrotonic acid with a C15-triphenyl-phosphonium salt. 9-(Z)-retinoic acid is a versatile compound for the treatment of numerous dermatological diseases.
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- A survey of mono- or bis-decarboxylation of β-methyl polyethylenic-malonic acids
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Diverse experimental conditions, leading to mono- or bis-decarboxylation of β-methyl polyethylenic-malonic acids, were examined. A clean and easy bis-decarboxylation was reported.
- Valla, Alain,Le Guillou, Régis,Cartier, Dominique,Labia, Roger
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p. 4737 - 4740
(2007/10/03)
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- New, regioselective, one-pot synthesis of (all-E)-retinoic acid and analogues from enaminodiester synthons
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A one-pot synthesis of (all-E)-retinoic acid and related compounds from new enamino diester synthons is described. The enamino diesters was produced nearly quantitatively from methyl propylidene- and isopropylidenemalonate and DMF-DMA. This easy process allowed retinoic acid to be produced in 1 d and appeared advantageous to current industrial syntheses. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).
- Cartier, Dominique,Valla, Alain,Le Guillou, Regis,Labia, Roger,Potier, Pierre
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p. 2250 - 2253
(2007/10/03)
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- Stereocontrolled synthesis of 13-substituted retinoic acids by palladium-catalyzed coupling reaction of alkenyl stannane with vinyl triflate
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A novel method for the stereoselective synthesis of all-E-, 13Z- and 9Z- retionic acid esters was developed by palladium-catalyzed cross coupling reactions of tetraenyl stannanes with E- or Z-vinyl triflates in good yields. Applying this methodology, 13-substituted all-E- and 9Z- retinoic acids were prepared in satisfactory yields.
- Wada,Fukunaga,Ito
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p. 800 - 802
(2007/10/03)
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- The suzuki coupling reaction in the stereocontrolled synthesis of 9-cis-retinoic acid and its ring-demethylated analogues
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The thallium-accelerated Suzuki coupling reaction of tetraenyl iodide 19 and cyclohexenyl boronate 18 afforded ethyl 9-cis-retinoate (12) in high yield. Both coupling partners of the Suzuki reaction are better reacted immediately after generation from their precursors, tetraenylstannane 10 and cyclohexenyl iodide 13. The geometrically homogeneous tetraenylstannane 10, comprising the polyenic side chain of ethyl 9-cis-retinoate and its ring-demethylated analogues, was synthesized by a stereoselective Horner - Wadsworth - Emmons reaction. On the other hand, easily available cyclohexanones are ideal starting materials for preparation of the cyclohexenyl boronates required for the synthesis of the ring-modified 9-cis-retinoic acid analogues. For hindered cyclohexanones, hydrazones were converted to cyclohexenyl iodides. Iodine - lithium exchange and trapping with B(OMe)3 then afforded the cyclohexenyl boronates. If the precursor cyclohexanone has secondary carbons, the alkenyllithium species was conveniently formed by elimination of the C,N-dilithiated intermediate obtained upon treating the trisylhydrazone with n-BuLi (Shapiro reaction). None of the above procedures allowed the generation of the more substituted organolithium from 2-methylcyclohexanone. However, the alternative Stille cross-coupling of 34 and 10 afforded 9-cis-1,1-bisdemethylretinoic acid 7. Both Suzuki and Stille coupling reactions took place under mild conditions, and the preservation of the retinoid side-chain geometry was therefore secured.
- Pazos,Iglesias,De Lera
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p. 8483 - 8489
(2007/10/03)
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- Design and synthesis of a cephalosporin-retinoic acid prodrug activated by a monoclonal antibody-β-lactamase conjugate
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Two novel series of all-trans-β-retinoic acid derivatives were synthesized and found to possess anticancer activity. The first series, cephalosporin 3′-retinoic esters 6 and 7 were, respectively, obtained by the condensation of all-trans-β-retinoic acid (2) with cephalosporins 4 and 5. The second series, 7-(retinamido)cephalosporins 11 and 12, were synthesized, respectively, by the condensation of 2 with cephalosporins 9 and 10. These four heretofore undescribed compounds 6, 7, 11, and 12 showed inhibitory activity against murine leukemias (L1210 and P388), sarcoma 180, breast carcinoma (MCF7), and human T-lymphocytes (Molt4/C8 and CEM/0). They also inhibited squamous metaplasia and keratinization in tracheal organ cultures derived from vitamin-A-deficient hamsters. Moreover, cephalosporin 3′-retinoic ester 7 exhibited enhanced activity against keratinization with ED50 = 3.91 × 10-11 M in the presence of a β-lactamase from Staphylococcus aureus 95. A tumor targeting fusion protein (dsFv3-β-lactamase) was also used in conjunction with cephem-based retinoid 7 and the potency of 7 toward L1210, P388, and MCF7 was found to approach that of the free retinoic acid (2). In the presence of dsFv3-β-lactamase, tumor cells were found to be much more susceptible to retinoid 7 than normal human embryonic lung cells. These notions provide a new approach to the use of β-retinoic acid for antitumor therapy.
- Hakimelahi, Gholam H.,Ly, Tai Wei,Yu, Sheng-Fa,Zakerinia, Maryam,Khalafi-Nezhad, Ali,Soltani, Mohammad N.,Gorgani, Mohsen N.,Chadegani, Azra R.,Moosavi-Movahedi, Ali A.
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p. 2139 - 2147
(2007/10/03)
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- Stereoselective syntheses of 13E and 13Z retinoic acids via a new intermediate C-15 β-methylenealdehyde
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The methylene-de-oxo-bisubstitution reaction between dimethyl isopropylidene malonate and the C-15 β-methylenealdehyde 1 which could serve as substitute for E β-ionylideneacetaldehyde 2, produces stereoselectively the E,E olefin. Hence, new stereoselective syntheses of 13 E and 13 Z retinoic acids were described. (C) 2000 Elsevier Science Ltd.
- Valla, Alain,Andriamialisoa, Zo,Prat, Virginie,Laurent, Alain,Giraud, Michel,Labia, Roger,Potier, Pierre
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p. 7211 - 7215
(2007/10/03)
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- A pericyclic cascade to the stereocontrolled synthesis of 9-cis- retinoids
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A domino reaction that is pericyclic in nature is thought to be triggered upon treatment of alkenynol 10 with arylsulfenyl chlorides. The process comprises an ordered sequence of sigmatropic rearrangements: a reversible [2,3]-allyl sulfenate to allyl sulfoxide shift, followed by a [2,3]-propargyl sulfenate to allenyl sulfoxide rearrangement, and last a stereodifferentiating [1,5]-sigmatropic hydrogen migration leading to polyene 13. The occurrence of the C7 to C11 hydrogen migration has been demonstrated by labeling experiments. The double diastereoselection of the [1,5]- sigmatropic hydrogen shift to afford a single isomer of the final polyene 13 is thought to arise from a combination of the electronic effect of the sulfoxide at one terminus, and the steric effect imparted by the bulky trimethylcyclohexenyl substituent at the other terminus. The overall process thus constitutes a stereoselective synthesis of an E,Z,Z-triene fragment from an alkenynol and, in particular, a retinoid with the 7E,9Z,11Z,13E configuration on the conjugated polyenic side chain. Application of this method to the synthesis of retinoids, including labeled analogues, is straightforward.
- Iglesias, Beatriz,Torrado, Alicia,De Lera, Angel R.,Lopez, Susana
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p. 2696 - 2705
(2007/10/03)
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- Kinetic properties of the human liver cytosolic aldehyde dehydrogenase for retinal isomers
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Retinoic acid exerts pleiotropic effects by acting through two families of nuclear receptors, RAR and RXR. All-trans and 9-cis retinoic acid bind RARs, whereas 9-cis retinoic acid binds and activates only the RXRs. To understand the role of human liver cytosolic aldehyde dehydrogenase (ALDH1) in retinoic acid synthesis, we examined the ability of ALDH1 to catalyze the oxidation of the naturally occurring retinal isomers. ALDH1 catalyzed the oxidation of all-trans, 9-cis, and 13-cis retinal with equal efficiency. However, the affinity to all-trans retinal (K(m) = 2.2 μM) was twofold higher than to 9-cis (K(m) = 5.5 μM) and 13-cis (K(m) = 4.6μM) retinal. All-trans retinol was a potent inhibitor of ALDH1 activity, and inhibited all-trans retinal oxidation uncompetitively. Comparison of the kinetic properties of ALDH1 for retinal isomers with those of previously reported rat kidney retinal dehydrogenase showed distinct differences, suggesting that ALDH1 may play a different role in retinal metabolism in liver. Copyright (C) 1999 Elsevier Science Inc.
- Bhat, Pangala V.,Samaha, Hiba
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p. 195 - 197
(2007/10/03)
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- Stereoselective synthesis of 9-cis-retinoic acid by Suzuki reaction
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The entire polyenic side chain of ethyl 9-cis-retinoate (7) has been stereoselectively synthesized and attached to the hydrophobic ring by a high-yielding thallium-accelerated Suzuki cross-coupling reaction. The Suzuki reaction partners, tetraenyl iodide 18 and alkenyl organoborane 19, are more conveniently used immediately after generation from their precursors. Alternative approaches using either the Stille reaction or a Suzuki reaction with a shorter polyenic component proved less efficient. The highly convergent sequence can be adapted to the preparation of analogs of 9-cis-retinoic acid (2), the natural ligand for the retinoid X (RXR) subfamily of nuclear receptors.
- Pazos, Yolanda,De Lera, Angel R.
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p. 8287 - 8290
(2007/10/03)
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- PROCESS FOR IDENTIFYING RAR-RECEPTOR-ANTAGONIST COMPOUNDS
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The present invention relates to a process for identifying RAR-antagonist molecules, characterized in that it comprises the following steps: (i) a sufficient amount of an RAR-agonist molecule is applied topically to a part of the skin of a mammal, (ii) a molecule capable of having an RAR-antagonist activity is administered systemically or topically to this same mammal, or to this same part of the skin of the mammal, before, during or after step (i) , and (iii) the response on that part of the skin of the mammal thus treated is evaluated.
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- Stereoselective isomerization of 10-arylsulfenate-11,12- dehydroretinoids to 9-cis-retinoids
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The C7-C12 triene fragment of 9-cis-retinoids 8 was stereoselectively generated by treatment of propargylic alcohol 3 with phenylsulfenyl chloride/triethylamine at -78 °C, followed by stereospecific reduction of the resulting vinylsulfoxide (t-BuLi, MeLi, MeOH, -78 °C). Thus, 9-cis- retinoic acid 2, the natural ligand of the retinoid X receptor (RXR) was straightforwardly synthesized from 8 in two steps.
- De Lera, Angel R.,Castro, Alejandro,Torrado, Alicia,Lopez, Susana
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p. 4575 - 4578
(2007/10/03)
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- Mechanism-based screen for retinoid X receptor agonists and antagonists
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A method is described for screening retinoid X receptor agonists or antagonists using a retinoid X receptor expressed by a yeast expression system to screen a compound having a retinoid X receptor agonist or antagonist activity. Another screen is described for detecting a compound having retinoid X receptor agonist or antagonist activity by: (1) providing a yeast strain which expresses the retinoic acid receptor and activates a reporter plasmid containing apolipoprotein AI gene site A or a mutated variant thereof; (2) incubating the compound in suitable media and a colorless chromogenic substrate; and (3) examining the media for development of color. Mutated variants of apolipoprotein AI gene site A which respond selectively to the retinoid X receptor or respond to receptors other than RXRα are also described.
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- Biotenside solvents for pharmaceuticals and cosmetics
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New biotenside esters, processes for their preparation and their use as solvents and hydrotropic agents (coemulgators) in the preparation of spontaneously dispersible concentrates containing therapeutic or cosmetic agents are described.
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- A Novel Method for a Stereoselective Synthesis of Trisubstituted Olefin Using Tricarbonyliron Complex: A Highly Stereoselective Synthesis of (all-E)- and (9Z)-Retinoic Acids
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In order to establish the stereoselective synthesis of retinoic acids, which are ligand molecules of the retinoic acid receptors (RARs, all-E-isomer) and the retinoid X receptors (RXRs, 9Z-isomer), the reaction of β-ionone-tricarbonyliron complex 7 with carbanions was investigated. Treatment of 7 with the lithium salt of acetonitrile afforded (7E,9E)-β-ionylideneacetonitrile-tricarbonyliron complex 8 exclusively, via addition, dehydration, and migration of tricarbonyliron complex. On the contrary, the reaction of 7 with the lithium enolate of ethyl acetate and subsequent dehydration by thionyl chloride afforded the ethyl (7E,9Z)-β-ionylideneacetate-tricarbonyliron complex 16b predominantly. These compounds (8 and 16b) were converted to the corresponding β-ionylidene-acetaldehyde-tricarbonyliron complexes (10 and 22) in excellent yields, respectively. The Emmons-Horner reaction of these compounds with C5-phosphonate followed by the sequence of decomplexation and alkaline hydrolysis gave the corresponding retinoic acids (26 and 29).
- Wada, Akimori,Hiraishi, Saeko,Takamura, Norio,Date, Tadamasa,Aoe, Keiichi,Ito, Masayoshi
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p. 4343 - 4348
(2007/10/03)
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- Synthesis of 9-cis-retinoic acid and C-20-[3H3C]-9-cis-retinoic acid with high specific activity
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The synthesis of 9-cis-retinoic acid starting from 2,2,6-trimethylcyclohexanone is described. The same methodology was extended for the synthesis of deuterium and tritium labeled 9-cis-retinoic acid with high specific activity (73 Ci/mmol). In this methodology, a Grignard reaction was utilized for introducing three tritium atoms simultaneously in the final synthetic steps.
- Tadikonda, Praveen K.,Lacy, James M.,Rigdon, Michael G.,Deluca, Hector F.
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- Metabolism of all-trans, 9-cis, and 13-cis isomers of retinal by purified isozymes of microsomal cytochrome P450 and mechanism-based inhibition of retinoid oxidation by citral
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The involvement of a series of microsomal cytochrome P450 (P450) isozymes in all-trans-retinoid metabolism, including the conversion of all-trans- retinal to all-trans-retinoic acid, was previously described. In the current study, we examined the role of seven liver microsomal P450 isozymes in the oxidation of three isomers of retinal. P450 1A1, which was not tested previously, is by far the most active in the conversion of all-trans-, 9- cis-, and 13-cis-retinal to the corresponding acids, as well as in the 4- hydroxylation of all-trans- and 13-cis retinal. In contrast, P450s 2B4 and 2C3 are the most active in the 4-hydroxylation of 9-cis-retinal, with turnover numbers ~7 times as great as that of P450 1A1. The inclusion of cytochrome b5 in the reconstituted enzyme system is without effect or inhibitory in most cases but stimulates the 4-hydroxylation of 9-cis-retinal by P450 2B4, giving a turnover of 3.7 nmol of product/min/nmol of this isozyme, the highest for any of the retinoid conversions we have studied. Evidence was obtained for two additional catalytic reactions not previously attributed to P450 oxygenases: the oxidation of all-trans- and 9-cis-retinal to the corresponding 4-oxo derivatives by isoform 1A2, and the oxidative cleavage of the acetyl ester of vitamin A (retinyl acetate) to all-trans- retinal, also by isoform 1A2. The physiological significance of the latter reaction, with a K(m) for the ester of 32 μM and a V(max) of 18 pmol/min/nmol of P450, remains to be established. We also examined the effect on P450 of citral, a terpenoid α,β-unsaturated aldehyde and a known inhibitor of cytosolic retinoid dehydrogenases. Evidence was obtained that citral is an effective mechanism-based inactivator of isozyme 2B4, with a K1 of 44 μM as determined by the oxidation of 1-phenylethanol to acetophenone, and by isozyme 1A2 in the oxidation of all-trans-retinal to the corresponding acid and by isozyme 2B4 in the 4-hydroxylation of all-trans-retinol and retinoic acid. Thus, citral is not suitable for use in attempts to distinguish between retinoid conversions catalyzed by dehydrogenases in the cytoplasm and by P450 cytochromes in the endoplasmic reticulum.
- Raner, Gregory M.,Vaz, Alfin D. N.,Coon, Minor J.
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p. 515 - 522
(2007/10/03)
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- Preparation of 9-(Z)-retinoic acid
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A process for preparing 9-(Z)-retinoic acid from mother liquors from the industrial preparation of C15 -triarylphosphonium salts of the general formula I STR1 where R1 to R3 are each aryl and X? is halogen or (HSO4)?, in an organic solvent, which comprises A. increasing the proportion of 9-(Z)-C15 -triarylphosphonium salt in the C15 -triarylphosphonium salts isolated from the mother liquor by treatment with isopropanol at elevated temperature, cooling and separating off the all-(E)-C15 -triarylphosphonium salt which has crystallized out, B. subjecting the resulting C15 -triarylphosphonium salt to a Wittig reaction with an alkyl β-formylcrotonate of the general formula STR2 and C. hydrolyzing the resulting oily retinoic ester mixture in a C3 -C9 -alkanol, preferably in a propanol or butanol, precipitating the resulting 9-(Z)-retinoic acid where appropriate by adding methanol as crystals, with all-(E)-retinoic acid and other retinoic acid isomers remaining in the alkanolic solution.
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- Preparation of 13-(Z)-retinoic acid
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13-(Z)-Retinoic acid is prepared by a) reacting 5-hydroxy-4-methyl-2(5H)-furanone with a [3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienyl]triarylphosphonium salt and b) subsequently partially isomerizing the resulting mixture of 13-(Z)- and 11,13-di-(Z)-retinoic acid, where the reaction in step a) is carried out in the presence of lithium hydroxide as alkali metal hydroxide and in dimethylformamide as solvent at from +10° to -9° C. and/or the isomerization in step b) is carried out by irradiating the mixture of isomers obtained in a) in an organic solvent in the presence of a photosensitizer with light in the wavelength range from 200 to 600 nm.
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- Syntheses of high specific activity 2,3- and 3,4-[3H]2-9-cis-retinoic acid
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9-cis-Retinoic acid (9-cis-RA) is an endogenous hormone which binds and activates the retinoic acid receptors (RARs) and the retinoic X receptors (RXRs). In order to investigate the function of 9-cis-RA in vitro and in vivo high specific activity labeled 9-cis-RA was prepared. Two tritium labels were efficiently introduced at the 2,3- or 3,4-positions, respectively, in the cyclohexene ring moiety resulting in labeled 9-cis-RA with specific activity of 58-60 Ci/mmol. The critical ring-labeling step relies on a highly regioselective tritiation of either a terminal or an isolated double bond in the presence of the conjugated retinoate side chain. Moreover, the labeling is performed at the penultimate synthetic step resulting in optimization of radiochemical yields and ease of synthesis. This is the first reported synthesis of ring-labeled [3H]2-9-cis-Ra, and the methodology described herein is applicable to the synthesis of other retinoic acid isomers.
- Bennani,Boehm
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p. 1195 - 1200
(2007/10/02)
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- Trienediolates of hexadienoic acids in synthesis. Addition to unsaturated ketones. A convergent approach to the synthesis of retinoic acids
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The regioselectivity of the addition of the lithium trienediolates generated from hexa-2,4-dienoic acids 1 and 2 or the dihydropyran-2-ones 4 and 5 to unsaturated ketones 6 is studied. Equilibration conditions favour reaction of the trienediolates through their ω carbon, and the ketones according to 1,2- and 1,4-additions. β-Ionone 6a and the aryl-butenone 6b lead to the 1,2-ω-adducts 8, which undergo a facile acid catalyzed dehydration to retinoic acids 11. On reaction with the unsaturated ketone 6b or with the aryl ketones 21, the trimethyldihydropyran-2-one 5 leads to γ'-adducts derived from deprotonation of the chain methyl substituent along with the 1,4-ω-adducts.
- Aurell, Maria J.,Ceita, Luisa,Mestres, Ramon,Parra, Margarita,Tortajada, Amparo
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p. 3915 - 3928
(2007/10/02)
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- Process for producing vitamin A acid
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A process for producing vitamin A acid, having useful biological activity, which comprises oxidizing vitamin A aldehyde with an aqueous solution of an alkali metal chlorite in the presence of an acid.
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- Stereoselective synthesis of 7E,9E- and 7E,9Z-β-ionylidene-acetaldehydes by use of tricarbonyl iron complex
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Stereoselective synthesis of 7E,9E- and 7E,9Z-β-ionylideneacetaldehydes was accomplished from the β-ionone tricarbonyl iron complex, and the latter was converted to 9Z-retinoic acid.
- Wada,Hiraishi,Ito
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p. 757 - 759
(2007/10/02)
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- Synthesis of High Specific Activity -9-cis-Retinoic Acid and Its Application for Identifying Retinoids with Unusual Binding Properties
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all-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity.In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an additional endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs).These distinct properties have raised questions as to the biological role governed by these two retinoic acid isomers and the set of target genes that they regulate.Herein, we report the synthesis of high specific activity -9-cis-RA and its application to study the ligand-binding properties of the various retinoid receptor subtypes.We examined the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay.The utilization of the -9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.
- Boehm, Marcus F.,McClurg, Michael R.,Pathirana, Charles,Mangelsdorf, David,White, Steven K.,et al.
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p. 408 - 414
(2007/10/02)
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