- Catalytic synthesis of 9-cis-retinoids: Mechanistic insights
-
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
-
supporting information
p. 10581 - 10595
(2019/07/22)
-
- Z -isomerization of retinoids through combination of monochromatic photoisomerization and metal catalysis
-
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
-
supporting information
p. 8125 - 8139
(2019/09/19)
-
- Synthesis of 11C-labeled retinoic acid, [11C]ATRA, via an alkenylboron precursor by Pd(0)-mediated rapid C-[11C] methylation
-
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
-
supporting information
p. 3622 - 3625
(2014/07/22)
-
- STEREOSPECIFIC SYNTHESIS PROCESS FOR TRETINOIN COMPOUNDS
-
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.
- -
-
Paragraph 0043; 0044
(2014/04/03)
-
- Stereospecific synthesis process for tretinoin compounds
-
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.
- -
-
Page/Page column 9
(2014/09/29)
-
- COMPOUNDS AND COMPOSITIONS FOR TREATING INFECTION
-
Compounds from 14 Kenyan plants, including from the root of Dovyalis abyssinica and Clutia robusta have been characterized and isolated, and their uses are disclosed.
- -
-
-
- A sensitive and specific method for measurement of multiple retinoids in human serum with UHPLC-MS/MS
-
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
-
experimental part
p. 587 - 598
(2012/05/31)
-
- PROCESS FOR PREPARATION OF HIGHLY PURE ISOTRETINOIN
-
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
- -
-
Page/Page column 4
(2008/12/08)
-
- All-Trans-Retinol: All-Trans-13,14-Dihydroretinol Saturase and Methods of Its Use
-
Compositions of all-trans-retinol: all-trans-13,14-dihydroretinal saturase and methods of use thereof are provided.
- -
-
-
- A caged retinoic acid for one- and two-photon excitation in zebrafish embryos
-
(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
-
supporting information; experimental part
p. 3744 - 3746
(2009/02/07)
-
- Synthesis of methyl 3-bromomethylbut-3-enoate and its reactions with aldehydes and tributylchlorostannane in the presence of zinc
-
Methyl 3-bromomethylbut-3-enoate smoothly reacted with prenal, β-ionylideneacetaldehyde, benzyloxyacetaldehyde, and tributylchlorostannane in the presence of zinc and aqueous ammonium chloride in tetrahydrofuran to give the corresponding δ-hydroxy-β-methylidenecarboxylic acid esters. In the absence of ammonium chloride, satisfactory yields of the products were obtained only in the reactions with prenal and benzyloxyacetaldehyde; these reactions involved lactonization of intermediate δ-hydroxy-β- methylidenecarboxylic acid esters, and the double carbon-carbon bond migrated to the conjugated position with the lactone carbonyl group. The condensation of β-ionylideneacetaldehyde with methyl 3-bromomethylbut-3-enoate was successfully used to obtain isotretinoin. Initial methyl 3-bromomethylbut-3- enoate was synthesized in a good yield from readily accessible ethyl 3,3-diethoxypropionate via cyclopropanation with ethylmagnesium bromide in the presence of titanium tetra(isopropoxide), oxidation of the acetal moiety to ester, and cleavage of the cyclopropane ring in intermediate methyl (1-methylsulfonyloxycyclopropyl)acetate.
- Mineeva,Kulinkovich
-
experimental part
p. 1261 - 1266
(2009/07/17)
-
- Caesium fluoride-promoted Stille coupling reaction: An efficient synthesis of 9Z-retinoic acid and its analogues using a practical building block
-
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
-
scheme or table
p. 6330 - 6332
(2009/04/13)
-
- Stereoselective synthesis of trienoic acids: Synthesis of retinoic acids and analogues
-
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
-
p. 2951 - 2970
(2008/02/05)
-
- An efficient commercial process for the preparation of isotretinoin
-
We describe an efficient process for the preparation of isotretinoin (13-cis isomer of vitamin A acid) in a single step starting from β-ionylidene acetaldehyde (5). The process conditions are convenient to operate on a commercial scale and afford isotretinoin of excellent quality; levels of related isomeric impurities such as tretinoin (all trans retinoic acid) and 9,13-di-cis-retinoic acid are extremely low. Thus, condensation of dienolate of methyl 3,3-dimethylacrylate with β-ionylidene acetaldehyde (5) followed by aqueous acidic workup afforded isotretinoin in >95% purity. The condensation reaction proceeds via in situ formation of lactone (8); furthermore, the reaction conditions have been optimized to exploit in situ generated methoxide anion for lactone ring opening to afford the desired product. Distinct advantages of this process are that it does not require isolation of intermediate lactone and utilizes in situ generated methoxide for lactone ring opening, thus obviating the need for an additional step and base. We also describe an optimized process for the preparation of β-ionylidene acetaldehyde (5), a key intermediate for isotretinoin.
- Salman, Mohammad,Babu, Suresh J.,Kaul, Vijay K.,Ray, Purna C.,Kumar, Naresh
-
p. 302 - 305
(2012/12/24)
-
- Process for the preparation of 13-cis-retinoic acid
-
A process for the preparation of 13-cis-retinoic acid (I) from 3-methyl-5-(2,6,6-trimethyl-1-cyclohexan-1-yl)-2,4-pentadienyl)-triphenylphosphonium chloride (IIa) and 5-hydroxy-4-methyl-2(5H)-furanone (III) is herein disclosed. Compounds (IIa) and (III) are reacted in ethanol as the solvent and KOH as the base at a temperature ranging from -5 to 0°C to give a mixture of retinoic acids which is isomerised to (I) by treatment with a palladium complex.
- -
-
-
- Preparation and biological activity of 13-substituted retinoic acids
-
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
-
p. 3931 - 3942
(2007/10/03)
-
- Stereoselective and convergent syntheses of retinoic acid and its ester derivatives by the sulfone olefination reaction
-
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
-
p. 2813 - 2820
(2007/10/03)
-
- PROCESS FOR THE PRODUCTION OF 9-CIS RETINOIC ACID
-
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.
- -
-
-
- A survey of mono- or bis-decarboxylation of β-methyl polyethylenic-malonic acids
-
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
-
p. 4737 - 4740
(2007/10/03)
-
- New, regioselective, one-pot synthesis of (all-E)-retinoic acid and analogues from enaminodiester synthons
-
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
-
p. 2250 - 2253
(2007/10/03)
-
- Process for the preparation of isotretinoin
-
The present invention relates to a process for the preparation of 13-cis isomer of Vitamin A acid, commonly known as isotretinoin, in a single step.
- -
-
-
- Stereocontrolled synthesis of 13-substituted retinoic acids by palladium-catalyzed coupling reaction of alkenyl stannane with vinyl triflate
-
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
-
p. 800 - 802
(2007/10/03)
-
- The suzuki coupling reaction in the stereocontrolled synthesis of 9-cis-retinoic acid and its ring-demethylated analogues
-
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
-
p. 8483 - 8489
(2007/10/03)
-
- A pericyclic cascade to the stereocontrolled synthesis of 9-cis- retinoids
-
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
-
p. 2696 - 2705
(2007/10/03)
-
- Stereoselective syntheses of 13E and 13Z retinoic acids via a new intermediate C-15 β-methylenealdehyde
-
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
-
p. 7211 - 7215
(2007/10/03)
-
- Process for producing 13-cis retinoic acid
-
The process of the present invention relates to a process for producing 1 3-cis retinoic acid. The process of the present invention involves reacting a Wittig salt in a solvent with a butenolide in the presence of a weak base and a Lewis acid.
- -
-
-
- Stereoselective synthesis of 9-cis-retinoic acid by Suzuki reaction
-
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.
-
p. 8287 - 8290
(2007/10/03)
-
- Stereoselective synthesis of all-trans-, (13Z)- and (9-nor)-retinoic acids via Stille reaction
-
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
-
p. 141 - 143
(2007/10/03)
-
- Kinetic properties of the human liver cytosolic aldehyde dehydrogenase for retinal isomers
-
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
-
p. 195 - 197
(2007/10/03)
-
- Stereoselective synthesis of 13Z retinoic acids via β-methylenealdehydes as synthons
-
A stereoselective synthesis of 13Z retinoic acids via β-methylenealdehydes is described. In methylene-de-oxo-bisubstitution reactions (Knoevenagel, Stobbe, etc.), these new synthons produce stereoselectively E olefins. Hence, a synthesis of 13Z retinoic acids is described, via a stereospecific monodecarboxylation of carboxy-14-retinoic acids.
- Valla, Alain,Andriamialisoa, Zo,Giraud, Michel,Prat, Virginie,Laurent, Alain,Potier, Pierre
-
p. 9235 - 9237
(2007/10/03)
-
- Synthesis of the 3-o-retinoyl-l-ascorbic acid and related compounds: Characterization and reducing activity against DPPH
-
Novel hybrid vitamin, 3-O-retinoyl-L-ascorbic acid (3a) was conveniently prepared by reaction of sodium L-ascorbate with retinoyl fluoride. The 3-O-acylated structure was confirmed by the comparison of spectral data of its methylated compound with those of 3-O-methyl-2-O-retinoyl-L-ascorbic acid (20) prepared from 5,6-O-isopropylidene-3-O-methyl-L-ascorbic acid. 3-O-Retinoyl-L-ascorbic acid (3a) showed a reducing activity against the stable radical, α,α-diphenyl-β-picrylhydrazyl (DPPH).
- Yamano, Yumiko,Ito, Masayoshi
-
p. 289 - 299
(2007/10/03)
-
- Stereoselective isomerization of 10-arylsulfenate-11,12- dehydroretinoids to 9-cis-retinoids
-
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
-
p. 4575 - 4578
(2007/10/03)
-
- PROCESS FOR IDENTIFYING RAR-RECEPTOR-ANTAGONIST COMPOUNDS
-
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.
- -
-
-
- Mechanism-based screen for retinoid X receptor agonists and antagonists
-
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.
- -
-
-
- Synthesis of 9-cis-retinoic acid and C-20-[3H3C]-9-cis-retinoic acid with high specific activity
-
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.
-
-
- A Novel Method for a Stereoselective Synthesis of Trisubstituted Olefin Using Tricarbonyliron Complex: A Highly Stereoselective Synthesis of (all-E)- and (9Z)-Retinoic Acids
-
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
-
p. 4343 - 4348
(2007/10/03)
-
- 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
-
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.
-
p. 515 - 522
(2007/10/03)
-
- Preparation of 9-(Z)-retinoic acid
-
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.
- -
-
-
- Photochemical method for the preparation of 13-cis-retinoic acid
-
Photochemical isomerization of 11-cis,13-cis-retinoic acid to 13-cis-retinoic acid.
- -
-
-
- Syntheses of high specific activity 2,3- and 3,4-[3H]2-9-cis-retinoic acid
-
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
-
p. 1195 - 1200
(2007/10/02)
-
- Stereoselective synthesis of 7E,9E- and 7E,9Z-β-ionylidene-acetaldehydes by use of tricarbonyl iron complex
-
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
-
p. 757 - 759
(2007/10/02)
-
- Synthesis of High Specific Activity -9-cis-Retinoic Acid and Its Application for Identifying Retinoids with Unusual Binding Properties
-
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.
-
p. 408 - 414
(2007/10/02)
-
- Process for the synthesis of vitamin A and certain ones of derivatives
-
According to this process, one effects a stereospecific reduction of the two hydroxyl groups of an ether-diol by a mixture (titanium trichloride, lithium aluminum hydride) at a temperature between 5° C. and about 40° C. and that optionally, one converts the resulting ether into vitamin A, retinol or retinoic acid.Application to the synthesis of all-trans compounds selected from the group consisting of vitamin A and its ethers, retinol and retinoic acid, and their 13-cis isomers.
- -
-
-
- Low-valent titanium reductive elimination: a direct and highly stereoselective synthesis of vitamin A aldehyde and all-trans retinoic acid orthothioester
-
It is shown that low-valent titanium reductive elimination can be carried out in the presence of a thioacetal or an orthothioester group.The application to the synthesis of vitamin A aldehyde and all-trans retinoic acid orthothioester is described.Keywords - Ti(0) reductive elimination / vitamin A aldehyde / all-trans retinoic acid
- Solladie, G.,Berl, V.
-
p. 568 - 574
(2007/10/02)
-
- Base-catalyzed isomerization of retinoic acid. Synthesis and differentiation-inducing activities of 14-alkylated all-trans-, 13-cis-, and 20,14-retro-retinoic acids
-
Retinoic acid (1) is isomerized regioselectively by excess amounts of lithium diisopropylamide (LDA) to give 20,14-retro-retinoic acid (3). Alkylation of the intermediate dianion of retinoic acid gave 14-alkylated derivatives of 3. By isomerization of the alkylated retro isomers under basic conditions, several 14-alkyl-all-trans- and -13-cis-retinoic acids were synthesized. The retinoidal activities of these derivatives were examined, based on the ability to induce differentiation of human promyelocytic leukemia cell line HL-60. 20,14-retro-Retinoic acid (3) is 1/50 as active as retinoic acid (1). Although 14-methyl-20,14-retro-retinoic acid (4) is as active as 3, the introduction of a 14-methyl group into all-trans- and 13- cis-retinoic acid resulted in decreased activity. Introduction of bulkier alkyl groups at the C-14 position caused the disappearance of the activity.
- Tanaka,Kagechika,Kawachi,Fukasawa,Hashimoto,Shudo
-
p. 567 - 572
(2007/10/02)
-
- Phosphonate reagent compositions
-
Novel phosphonate compounds of the formula STR1 are disclosed and claimed, as well as methods for manufacturing the phosphonates from C-14 through C-16 aldehydes. The phosphonate compounds of the present invention can be employed to form 13-cis retinoic acid, retin-A and beta-carotene.
- -
-
-
- Polyenolates of unsaturated carboxylic acids in synthesis. A straightforward synthesis of retinoic acids
-
Retinoic acids are prepared in a two step procedure by addition of lithium trienediolates of sorbic acid and 3-methyl-sorbic acid to β-ionone.
- Aurell,Parra,Tortajada,Gil,Mestres
-
p. 5791 - 5794
(2007/10/02)
-
- Synthesis of New Aromatic Retinoid Analogues by Low-Valent Titanium Induced Reductive Elimination
-
The low-valent titanium reductive elimination reaction, already applied to the stereospecific synthesis of vitamin A and 13-cis-retinol, was used to prepare several retinoic acid analogues in the all-trans configuration or in the 13-cis configuration.This highly stereospecific trans-diene formation allowed an improved synthesis of the title compounds without any purification of the intermediates before the final stage.
- Solladie, Guy,Girardin, Andre,Lang, Gerard
-
p. 2620 - 2628
(2007/10/02)
-
