- The OSM (Oxidation State Modification) Concept: Application to a New and Rapid Synthesis of Retinoids
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The OSM (oxidation state modification) concept for the elaboration of new synthetic pathways is demonstrated for the synthesis of β-ionylidene acetaldehyde 11 and retinal 13.According to this new scheme, electrophilic addition to ω-heterosubstituted enol ethers 5 of the cationic species 9, generated from β-ionol led to aldehydic intermediates 10 which undergo easy elimination to β-ionylidene acetaldehyde 11.Similarly, retinal 13 was obtained from vinyl-β-ionol 14 and dienol ethers 12, via aldehydes 16.
- Duhamel, Lucette,Duhamel, Pierre,Ancel, Jean-Erick
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- Triplet quantum chain process in the photoisomerization of 9-cis retinal as revealed by nanosecond time-resolved infrared spectroscopy
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The mechanism of the photoisomerization of 9-cis retinal has been studied by nanosecond time-resolved infrared spectroscopy. A cyclohexane solution of 9-cis retinal was photoexcited at 349 nm and the subsequent photodynamics were traced. A singular value decomposition (SVD) analysis of the time-resolved infrared data shows that there are two distinct isomerization pathways. One is the triplet pathway that takes place in the picosecond time regime from 9-cis to all-trans. The other involves the energy transfer between the all-trans triplet state and the 9-cis ground state with the resultant 9-cis triplet state subsequently reproducing the all-trans by fast isomerization on the triplet potential surface. This quantum chain process occurs in the microsecond time regime.
- Yuzawa, Tetsuro,Hamaguchi, Hiro-o
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- Mechanism for the Two-bond Isomerization in the Photoirradiation of 7,9-Di-cis-retinal
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The two-bond isomerization process of 7,9-di-cis-retinal to all-trans-retinal has been shown to proceed by way of an adiabatic, stepwise process.
- Liu, Robert S. H.,Zhu, Yun
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- Efficient, low-cost synthesis of retinal (Vitamin A aldehyde)
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Inexpensive retinyl acetate has been subjected to transesterification followed by allylic oxidation to give retinal in 98% yield as a 92:8 mixture of all-trans/13-cis isomers after chromatographic separation. More convenient methods of isolating the all-trans isomer have also been employed. Georg Thieme Verlag Stuttgart ? New York.
- Hruszkewycz, Damian P.,Cavanaugh, Kathryn R.,Takamura, Kathryn T.,Wayman, Lora M.,Curley Jr., Robert W.
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- Retinal isomer composition in some bacteriorhodopsin mutants under light and dark adaptation conditions
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The isomeric composition of retinal was measured in a number of bacteriorhodopsin (bR) mutants (D85N), D212N, R82A, Y185F, and D115N) under various conditions, using a rapid retinal extraction technique followed by HPLC analysis. Besides the 13-cis and the all-trans retinal isomers observed in wild type (wt) bR under physiological conditions, the 11-cis and 9-cis retinal isomers were observed in variable but minor amounts in the bR mutants. In addition, the values of the equilibrium constant at two temperatures and the enthalpy change for the all-trans to 13-cis isomerization process in the dark-adapted state of D212N, D85N, deionized blue bR, and wt bR were determined. We find that perturbation of the retinal cavity (pocket) by residue replacement changes the relative thermal stability of the different retinal isomers, allowing for thermal-and/or photoisomerization of the retinal chromophore along C9-C10 and C11-C12 bonds to moderately compete with the isomerization around the C13-C14 bond. The bR mutants expressed in Halobacterium salinarium studied in the present work showed normal 13-cis to all-trans light adaptation, in contrast with abnormal all-trans to 13-cis light adaptation observed for D212E, D212A, and D212N expressed in Escherichia coli, suggesting an influence of the purple membrane lattice and/or the lipids on the stability of the different retinal isomers within the protein.
- Song,Yang,El-Sayed,Lanyi
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- Photophysical and Photochemical Behavior of 11-cis-Retinal and Its Schiff Base in a Micelle
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The photophysical and photochemical behaviors of 11-cis-retinal and its Schiff base have been studied in a micelle made from Triton X-100.Both microsecond laser flash and steady-state techniques were employed.The photoisomerization yield (ca. 0.19) and the triplet quantum yield (ca. 0.13) were determined in the case of 11-cis-retinal.In the case of the 11-cis Schiff base, a long-lived (240 s) non-excited-state transient was seen and very little isomerization appears to have occured.The relative location of the 11-cis-retinal and its Schiff base in the micelle could be determined.The retinal was found to be in a polar region, Stern layer, of the micelle while the 11-cis Schiff base was found to be located in a dry, hydrocarbon-core region of the micelle.The nonionic micellar environment did not favor in any manner the photoisomerization of the 11-cis-retinal or the 11-cis Schiff base compared to any other solvents (polar or nonpolar).
- Becker, Ralph S.,Freedman, Kenn,Lenoble, Christian
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- Exploratory study of β-carotene autoxidation
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The main products in the early stages of β-carotene autoxidation were epoxides, β-ionone, β-apo-13-carotenone, retinal, and related carbonyl compounds; in the final mixture short chain carbonyl compounds predominated.
- Mordi,Walton,Burton,Hughes,Ingold,Lindsay
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- Prenylation reaction performed with catalytically generated potassium prenal dienolate
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A new prenylation method based on the reaction of catalytically generated potassium dienolate of prenal with α,β-unsaturated aldehydes is described. The reaction is highly regioselective, via a γ-1,2-addition, and provides an efficient route to retinal.
- Cahard, Dominique,Duhamel, Lucette,Lecomte, Sandrine,Poirier, Jean-Marie
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- 146. Retro-Aldol Reaction of Retinylidene-1,3-Diketones; Correlation with Biological Activity
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Retro-Aldol reaction of retinylidene-dimedone is reported.
- Acton, Nancy,Brossi, Arnold
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- Polyunsaturated aldehydes by direct polyvinylogation of carbonyl compounds using functionalized phosphonates.
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Carbonyl compounds are converted into polyethylenic aldehydes in a one pot reaction with the anions of phosphonates 1. followed by a mild acidic hydrolysis.
- Duhamel, Lucette,Guillemont, Jerome,Gallic, Yann Le,Ple, Gerard,Poirier, Jean-Marie,et al.
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- Silica Gel Mediated Photoisomerization of Retinal Isomers and Comparisons with Other Forms of Environmental Pertubation
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The electronic spectra and photoreactivity of slurries of retinal isomers, prepared by adsorbing the isomers onto wet silica gel and suspending the support in cyclohexane, have been investigated.Adsorption of 9-cis-, 11-cis-, 13-cis-, and all-trans-retinal is accompanied by an ca. 3000-cm-1 red shift of their lowest energy absorption band maxima relative to their band positions in homogeneous cyclohexane solution.Irradiation of the slurries at 514.5 nm, a wavelength inefficiently absorbed in the absence of silica gel, leads to reasonably efficient photoisomerization of each of these isomers.Prolonged photolysis yields a mixture of the four isomers that is photostationary with respect to relative concentrations and richest in 11-cis-retinal, which constitutes ca. 35percent of this mixture.Although small quantities of other isomers are present, the photostationary composition of the heterogeneous photolysate can be predicted with reasonable accuracy from the relative absorptivities and primary photoprocesses of the four principal isomers comprising the photolysate.Comparisons with primary photoprocesses reported for retinal isomers in polar and nonpolar solvents reveal that adsorption onto silica gel can result in novel patterns of photoisomerization.Complementary comparisons are made with the electronic spectra and photoreactivity of adducts formed in hydrocarbon solution from retinal isomers and a lanthanide β-diketonate complex.The excited-state properties of these various retinal-based systems highlight the impotance of environment in controlling photoreactivity.Steric and electronic factors that may contribute to the observed features of silica gel mediated photoisomerization are discussed in this context.
- Zawadzki, Mary E.,Ellis, Arthur B.
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- Reactivity of retinoids and carotenoids in autoxidation
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The autoxidation of various retinyl polyenes and carotenoids in chlorobenzene at 45 °C and in thin solid films on a support at room temperature was investigated. The compounds used were β-carotene, canthaxanthin, retinyl acetate, methyl (all-E)-retinoate, methyl (13Z)-retinoate, retinal, C18 ketone, β-ionylidene acetaldehyde, ψionone, β-ionone and ethyl sorbate as a model compound. It was shown that the isomerization of polyenyl peroxy radicals occurs during autoxidation of all the compounds studied, excepting β-ionone. A kinetic scheme for the polyene autoxidation process was considered and analysed. The conditions under which the rate constants of elementary reactions may be determined were defined and the rate constants of propagation and termination reactions for different polyenes were evaluated. The disappearance and formation of different functional groups were monitored by the spectroscopic investigation of autoxidation of polyene solid films. Mechanisms of the initial stages of the process are proposed for different polyenes.
- Finkelshtein,Krasnokutskaya
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- Palladium-catalysed vinylation of tertiary allylic alcohols: A new protocol for the synthesis of isoprenoid aldehydes.
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Heck vinylation of tertiary allylic alcohols with iodo-acetal Ic, followed by an acid catalysed acetal hydrolysis-dehydration reaction, furnished isoprenoid aldehydes regioselectively in high yields.
- Bienayme,Yezeguelian
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- Preparation and characterization of metal-substituted carotenoid cleavage oxygenases
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Carotenoid cleavage oxygenases (CCO) are non-heme iron enzymes that catalyze oxidative cleavage of alkene bonds in carotenoid and stilbenoid substrates. Previously, we showed that the iron cofactor of CAO1, a resveratrol-cleaving member of this family, can be substituted with cobalt to yield a catalytically inert enzyme useful for trapping active site-bound stilbenoid substrates for structural characterization. Metal substitution may provide a general method for identifying the natural substrates for CCOs in addition to facilitating structural and biophysical characterization of CCO-carotenoid complexes under normal aerobic conditions. Here, we demonstrate the general applicability of cobalt substitution in a prototypical carotenoid cleaving CCO, apocarotenoid oxygenase (ACO) from Synechocystis. Among the non-native divalent metals investigated, cobalt was uniquely able to stably occupy the ACO metal binding site and inhibit catalysis. Analysis by X-ray crystallography and X-ray absorption spectroscopy demonstrate that the Co(II) forms of both ACO and CAO1 exhibit a close structural correspondence to the native Fe(II) enzyme forms. Hence, cobalt substitution is an effective strategy for generating catalytically inert but structurally intact forms of CCOs.
- Sui, Xuewu,Farquhar, Erik R.,Hill, Hannah E.,von Lintig, Johannes,Shi, Wuxian,Kiser, Philip D.
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- Studies on the Catalyzed Interconversions of Vitamin A Derivatives
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The kinetics of the I2-catalyzed isomerization of the retinal isomers were studied.The all-trans isomer formed 13-cis-retinal rapidly with a rate constant 1.9E-4 s-1.The reverse reaction occurred with a rate constant of 4.5E-4 s-1.The 11-cis isomer was first converted to all-trans-retinal with a rate constant of 3.1E-4 s-1, although the 13-cis isomer was also rapidly formed.The 9-cis isomer was isomerized to the 9-cis, 13-cis isomer before the other isomers were generated and the 13-cis isomer was converted to its all-trans congener prior to the formation of the other isomers.Similar results appear to occur when other methods of catalysis are used.This isomerization about the C13-C14 double bond appears to be kinetically favored event, eliminating the possibility that 11-cis might be a kinetic product formed from the all-trans isomer.At equilibrium, only 0.1percent of 11-cis-retinal is found.Equilibration of all-trans-retinol palmitate also generated very little of the 11-cis-isomer (/= 0.2percent) 11-cis-retinol palmitate at equilibrium.The implications of these results for an 11-cis-retinal regeneration mechanism in the eye are discussed.
- Rando, Robert R.,Chang, Andrew
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- Cyclopropyl and isopropyl derivatives of 11- cis and 9- cis retinals at C-9 and C-13: Subtle steric differences with major effects on ligand efficacy in rhodopsin
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Retinal is the natural ligand (chromophore) of the vertebrate rod visual pigment. It occurs in either the 11-cis (rhodopsin) or the 9-cis (isorhodopsin) configuration. In its evolution to a G protein coupled photoreceptor, rhodopsin has acquired exceptional photochemical properties. Illumination isomerizes the chromophore to the all-trans isomer, which acts as a full agonist. This process is extremely efficient, and there is abundant evidence that the C-9 and C-13 methyl groups of retinal play a pivotal role in this process. To examine the steric limits of the C-9 and C-13 methyl binding pocket of the binding site, we have prepared C-9 and C-13 cyclopropyl and isopropyl derivatives of its native ligands and of α-retinal at C-9. Most isopropyl analogues show very poor binding, except for 9-cis-13-isopropylretinal. Most cyclopropyl derivatives exhibit intermediate binding activity, except for 9-cis-13-cyclopropylretinal, which presents good binding activity. In general, the binding site shows preference for the 9-cis analogues over the 11-cis analogues. In fact, 13-isopropyl-9-cis-retinal acts as a superagonist after illumination. Another surprising finding was that 9-cyclopropylisorhodopsin is more like native rhodopsin with respect to spectral and photochemical properties, whereas 9-cyclopropylrhodopsin behaves more like native isorhodopsin in these aspects.
- DeGrip, Willem J.,Bovee-Geurts, Petra H. M.,Wang, Yajie,Verhoeven, Michiel A.,Lugtenburg, Johan
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- Configurational Changes of Retinal in the Triplet State: Picosecond Time-Resolved Absorption Spectroscopy on the 7-Cis, 11-Cis, and 13-Cis Isomers and High-Performance Liquid Chromatography Analysis of Photoisomerization
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The triplet state of retinal was produced from the 7-cis, 11-cis, and 13-cis isomers by direct excitation with 355-nm ca. 10-ps pulses in deoxygenated n-hexane solution at room temperature.A set of transient absorption spectra was recorded for each isomer, in the time domain within 5 ns after excitation.The results indicated the following: (1) The 7-cis and 11-cis isomers initially produce their own short-lived, primary "7-cis" and "11-cis" triplet species which relax into the common, stationary "all-trans" triplet species. (2) The 13-cis isomer produces two different stationary triplet species, i.e., one its own "13-cis" and the other the above "all-trans" triplet species. (3) The above cis-isomers produce also "all-trans" triplet species immediately after excitation.The presence of two different long-lived, stationary triplet species, which were revealed by a previous study by resonance Raman spectroscopy, is confirmed, and short-lived, primary triplet species produced from the 7-cis and 11-cis isomers have been identified, in addition to the one from the 9-cis isomer, which was identified in a previous transient absorption study.The products of isomerization by benzil-sensitized triplet excitation of the all-trans, 7-cis, 9-cis, 11-cis, and 13-cis isomers were analyzed by means of high-performance liquid chromatography.The major product of isomerization from the cis isomers was the all-trans isomer.On the basis of the above results, the mechanisms of isomerization via the triplet state are discussed.
- Mukai, Yumiko,Koyama, Yasushi,Hirata, Yoshinori,Mataga, Noboru
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- Broad-spectrum antiviral activity including human immunodeficiency and hepatitis C viruses mediated by a novel retinoid thiosemicarbazone derivative
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Aromatic aldehyde-derived thiosemicarbazones 4-6, the S-substituted modified thiosemicarbazones 7/8, and a vitamin A-derived (retinoid) thiosemicarbazone derivative 12 were investigated as inhibitors of human hepatitis C virus (HCV) subgenomic RNA replicon Huh7 ET (luc-ubi-neo/ET) replication. Compounds 4-6 and 12 were found to be potent suppressors of HCV RNA replicon replication. The trifluoromethoxy-substituted thiosemicarbazone 6 and the retinoid thiosemicarbazone derivative 12 were even superior in selectivity to the included reference agent recombinant human alpha-interferon-2b, showing potencies in the nanomolar range of concentration. In addition, compounds 5, 6, 8 and 12 were tested as inhibitors of cytopathic effect (CPE) induced by human varicella-zoster virus (VZV) and/or human cytomegalovirus (HCMV). Compounds 4-6, 8 and 12 were additionally examined as inhibitors of CPE induced by cowpox virus and vaccinia virus. Thiosemicarbazone 4 was inhibitory on cowpox and vaccinia virus replication comparable in potency and selectivity to the reference agent cidofovir. Retinoid thiosemicarbazone derivative 12 was active as micromolar inhibitor of VZV, HCMV, and, in addition, human immunodeficiency virus type 1 (HIV-1) replication. These results indicate that thiosemicarbazone derivatives are appropriate lead structures to be evaluated in targeted antiviral therapies for hepatitis C (STAT-C), and that the vitamin A-related thiosemicarbazone derivative 12 emerges as a broad-spectrum antiviral agent, co-suppressing the multiplication of important RNA and DNA viruses.
- Kesel, Andreas J.
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- Urea unfolding of opsin in phospholipid bicelles
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Opsin is the unstable apo-protein of the light-activated G protein-coupled receptor rhodopsin. We investigated the stability of bovine opsin, solubilized in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/detergent bicelles, against urea-induced unfold
- McKibbin, Craig,Farmer, Nicola A.,Edwards, Patricia C.,Villa, Claudio,Booth, Paula J.
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- Reaction of retinol with peroxynitrite
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The reactivity of retinol with peroxynitrite, which is a strong oxidant and has been reported to induce several biological damages, was investigated. 13-cis-14-nitroretinol (1), 13-trans-14-nitroretinol (2), 13-apo-β- carotenone (3), retinal (4), 11,14-epoxyretinol (5), and 11,15-epoxyretinol (6) were identified as reaction products of retinol with peroxynitrite. From these results, it was observed that retinol can undergo a nitration reaction with peroxynitrite. Furthermore, the formation mechanisms of 1, 2, and 3 from retinol with peroxynitrite are discussed.
- Suzuki, Rie,Kulkarni, Aditya,Yomoda, Yuya,Kawagishi, Hirokazu,Terada, Yukimasa,Maoka, Takashi,Etoh, Hideo
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- Catalytic activities of tumor-specific human cytochrome P450 CYP2W1 toward endogenous substrates
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CYP2W1 is a recently discovered human cytochrome P450 enzyme with a distinctive tumor-specific expression pattern. We show here that CYP2W1 exhibits tight binding affinities for retinoids, which have lownanomolar binding constants, andmuch poorer binding constants in the micromolar range for four other ligands. CYP2W1 converts alltrans retinoic acid (atRA) to 4-hydroxy atRA and all-Trans retinol to 4-OH all-Trans retinol, and it also oxidizes retinal. The enzyme much less efficiently oxidizes 17b-estradiol to 2-hydroxy-(17b)-estradiol and farnesol to a monohydroxylated product; arachidonic acid is, at best, a negligible substrate. These findings indicate that CYP2W1 probably plays an important role in localized retinoid metabolism that may be intimately linked to its involvement in tumor development.
- Zhao, Yan,Wan, Debin,Yang, Jun,Hammock, Bruce D.,De Montellano, Paul R. Ortiz
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- Femtosecond transient absorption spectroscopic study of a carbonyl-containing carotenoid analogue, 2-(all- trans -retinylidene)-indan-1,3- dione
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The photophysical properties of a carbonyl-containing carotenoid analogue in an s-cis configuration, relative to the conjugated π system, 2-(all-trans-retinylidene)-indan-1,3-dione (C20Ind), were investigated by femtosecond time-resolved spectroscopy in various solvents. The lifetime of the optically forbidden S1 state of C20Ind becomes long as solvent polarity increases. This trend is completely opposite to the situation of S 1-ICT dynamics of carbonyl-containing carotenoids, such as peridinin and fucoxanthin. Excitation energy dependence of the transient absorption measurements shows that the transient absorption spectra in nonpolar solvents were originated from two distinct transient species, while those in polar and protic solvents are due to a single transient species. By referring to the results of MNDO-PSDCI (modified neglect of differential overlap with partial single- and double-configuration interaction) calculations, we conclude: (1) in polar and protic solvents, the S1 state is generated following excitation up to the S2 state; (2) in nonpolar solvents, however, both the S1 and the 1nπ* states are generated; and (3) C20Ind does not generate the S1-ICT state, despite the fact that it has two conjugated carbonyl groups.
- Kusumoto, Toshiyuki,Kosumi, Daisuke,Uragami, Chiasa,Frank, Harry A.,Birge, Robert R.,Cogdell, Richard J.,Hashimoto, Hideki
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- Sensitized photoisomerization of all-trans- and 11-cis-retinal
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The photoisomerization of all-trans-retinal (all-trans) and 11-cis-retinal (11-cis) sensitized by a range of sensitizers (porphyrins, Zn-porphyrins, naphthacene and a Zn-phthalocyanine) with varying triplet energies above and below the vertical triplet energy of all-trans-retinal (E(T) = 149 kJ/mol) has been investigated by continuous illumination and HPLC analysis of the products. The composition of the photostationary states, the relative isomerization quantum yields of all-trans and 11-cis, and the primary product ratios are reported. One photon-one bond isomerizations are dominant. With Zn-TPP as sensitizer it is shown that 11-cis and possibly all-trans undergoes one photon-two bond isomerizations as well. The quantum yields of photoisomerization of 11-cis sensitized by biphenyl (E(T) = 275 kJ/mol) and anthracene (E(T) = 178 kJ/mol) were found to be identical. Absolute measurements allowed evaluation of the overall triplet isomerization quantum yield of 11-cis, Φ(iso)(T)(11-cis→) = 1.0 ± 0.2, from which the corresponding quantity for all-trans, Φ(iso)(T)(trans-→) = 0.15 ± 0.05, was obtained. The overall photoisomerization quantum yield of 11-cis with direct excitation at 254 nm was determined as Φ(iso)(d)(11-cis→) = 0.42 ± 0.05 assuming all-trans and 13-cis to be the primary products. Quenching rate constants of several of the sensitizer triplet states by retinal were measured by laser flash photolysis. Possible mechanisms that could account for the experimental results are discussed, and it is concluded that the photoisomerizations most likely involve the retinal triplet states as intermediates. Within this model the observed sensitizer triplet energy dependence of the primary product ratios suggests that the triplet states of the different retinal isomers are different mixtures of triplet excited species, and that the composition of these mixtures depends on the starting isomers as well as on the sensitizer triplet energy for energies below the vertical triplet energy of all-trans-retinal. In the light of a review of the existing literature on the direct and the sensitized photoisomerization of retinals these conclusions suggest substantial corrections to the accepted picture of retinal photochemistry.
- Jensen,Wilbrandt,Bensasson
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- Retinal-based polyene fluorescent probe for selectively detection of Cu2+ in physiological saline and serum
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Retinal is a flexible natural chromophore and widely present in organisms. The slender conjugated polyene structure retinal is conducive to entering protein structure. In this work, a novel turn-on fluorescent probe for Cu2+ based on retinal and phenylenediamine was designed and synthesized. The probe achieved recognition of copper ions in human serum complex protein environment. Furthermore, the high sensitivity, selectivity for Cu2+ and the sensing mechanism was also investigated.
- Li, Yang,Lan, Haichuang,Yan, Xia,Shi, Xiaotao,Liu, Xiao,Xiao, Shuzhang
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- A synthesis method of 9-cis Beta-carotene
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The present invention relates to a method for synthesizing 9 - cis Beta-carotene (9 - cis beta-carotene) compounds having high purity and easy mass production through a chemical reaction, and a reaction for substituting 9 - cis Retinol groups of Alcohol with 9 - cis Phosphonium salt. The reaction of β - (3 - Methyl-2-butenal to Knoevenagel condensation) to synthesize All-trans Aldehyde. In step 9 - cis Retinoic Phosphonium salt) and in step), the completed All-trans Aldehyde is subjected to Wittig Olefination reaction with carbon double bonds, and 9. cis Beta-carotene obtained by the reaction of carbon double bonds.
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(2021/05/18)
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- Mimicking light-sensing chromophore in visual pigments and determination isomerization site
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Three retinal derivatives are designed and synthesized under the inspiration of natural visual pigments. The retinal derivative V3 (retinal-phenylenediamine) is able to respond sensitively to visual light in the absence of a protein environment through isomerization and deprotonation. The response process is applied to verification of information security.
- Li, Yang,Lan, Haichuang,Yan, Xia,Shi, Xiaotao,Liu, Xiao,Xiao, Shuzhang
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- SPECIFIC DEHYDROGENATION PROCESS (I)
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The present invention relates to a new dehydrogenation process of specific compounds.
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(2020/10/28)
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- NEW PROCESS FOR THE PRODUCTION OF RETINAL
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The present invention relates to a new process for the production of retinal or hydrogenated form of retinal.
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(2020/10/27)
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- Synthesis of C11-to-C14 methyl-shifted all-: Trans -retinal analogues and their activities on human aldo-keto reductases
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Human aldo-keto reductases (AKRs) are enzymes involved in the reduction, among other substrates, of all-trans-retinal to all-trans-retinol (vitamin A), thus contributing to the control of the levels of retinoids in organisms. Structure-activity relationship studies of a series of C11-to-C14 methyl-shifted (relative to natural C13-methyl) all-trans-retinal analogues as putative substrates of AKRs have been reported. The synthesis of these retinoids was based on the formation of a C10-C11 single bond of the pentaene skeleton starting from a trienyl iodide and the corresponding dienylstannanes and dienylsilanes, using the Stille-Kosugi-Migita and Hiyama-Denmark cross-coupling reactions, respectively. Since these reagents differ by the location and presence of methyl groups at the dienylorganometallic fragment, the study also provided insights into the ability of the different positional isomers to undergo cross-coupling and the sensitivity of these processes to steric hindrance. The resulting C11-to-C14 methyl-shifted all-trans-retinal analogues were found to be active substrates when tested with AKR1B1 and AKR1B10 enzymes, although relevant differences in substrate specificities were noted. For AKR1B1, all analogues exhibited higher catalytic efficiency (kcat/Km) than parent all-trans-retinal. In addition, only all-trans-11-methylretinal, the most hydrophobic derivative, showed a higher value of kcat/Km = 106 000 ± 23 200 mM-1 min-1 for AKR1B10, which is in fact the highest value from all known retinoid substrates of this enzyme. The novel structures, identified as efficient AKR substrates, may serve in the design of selective inhibitors with potential pharmacological interest. This journal is
- Alvarez, Rosana,Barracco, Vito,De Lera, Angel R.,Domínguez, Marta,Farrés, Jaume,Jiménez, Rafael,López, Susana,Parés, Xavier,Pequerul, Raquel,Rivas, Aurea
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p. 4788 - 4801
(2020/07/13)
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- Retinal synthesis method promoted by copper complex
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The invention belongs to the fields of organic synthesis, medical care and daily chemicals, and particularly relates to a method used for synthesizing retinal from beta-carotene and promoted by a copper complex. As a key for realizing the method, the copper complex mainly acts on the middle double bond in the beta-carotene and activates and promotes the double bond to be oxidized and broken into two identical aldehyde groups, so that the retinal is prepared. The method has the advantages of simple operation, cheap and easily available reagents, and good industrial application prospect.
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Paragraph 0013-0018
(2019/12/02)
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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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(2018/11/30)
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- Expansion of first-in-class drug candidates that sequester toxic all-trans-retinal and prevent light-induced retinal degeneration
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All-trans-retinal, a retinoid metabolite naturally produced upon photoreceptor light activation, is cytotoxic when present at elevated levels in the retina. To lower its toxicity, two experimentally validated methods have been developed involving inhibition of the retinoid cycle and sequestration of excess of all-trans-retinal by drugs containing a primary amine group. We identified the first-in-class drug candidates that transiently sequester this metabolite or slow down its production by inhibiting regeneration of the visual chromophore, 11-cis-retinal. Two enzymes are critical for retinoid recycling in the eye. Lecithin:retinol acyltransferase (LRAT) is the enzyme that traps vitamin A (all-trans-retinol) from the circulation and photoreceptor cells to produce the esterified substrate for retinoid isomerase (RPE65), which converts all-trans-retinyl ester into 11-cis-retinol. Here we investigated retinylamine and its derivatives to assess their inhibitor/substrate specificities for RPE65 and LRAT, mechanisms of action, potency, retention in the eye, and protection against acute light-induced retinal degeneration in mice. We correlated levels of visual cycle inhibition with retinal protective effects and outlined chemical boundaries for LRAT substrates and RPE65 inhibitors to obtain critical insights into therapeutic properties needed for retinal preservation.
- Zhang, Jianye,Dong, Zhiqian,Mundla, Sreenivasa Reddy,Hu, X. Eric,Seibel, William,Papoian, Ruben,Palczewski, Krzysztof,Golczak, Marcin
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supporting information
p. 477 - 491
(2015/01/30)
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- AUTOMATED SYNTHESIS OF SMALL MOLECULES USING CHIRAL, NON-RACEMIC BORONATES
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Provided are methods for making and using chiral, non-racemic protected organoboronic acids, including pinene-derived iminodiacetic acid (PIDA) boronates, to direct and enable stereoselective synthesis of organic molecules. Also provided are methods for purifying PIDA boronates from solution. Also provided are methods for deprotection of boronic acids from their PIDA ligands. The purification and deprotection methods may be used in conjunction with methods for coupling or otherwise reacting boronic acids. Iterative cycles of deprotection, coupling, and purification can be performed to synthesize chiral, non-racemic compounds. The methods are suitable for use in an automated chemical synthesis process. Also provided is an automated small molecule synthesizer apparatus for performing automated stereoselective synthesis of chiral, non-racemic small molecules using iterative cycles of deprotection, coupling, and purification.
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Page/Page column 173-178
(2012/11/13)
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- APPARATUS AND METHODS FOR THE AUTOMATED SYNTHESIS OF SMALL MOLECULES
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Provided are methods for purifying N-methyliminodiacetic acid (MID A) boronates from solution. Also provided are methods for deprotection of boronic acids from their MIDA ligands. The purification and deprotection methods can be used in conjunction with methods for coupling or otherwise reacting boronic acids. Iterative cycles of deprotection, coupling, and purification can be performed to synthesize chemical compounds of interest. The methods are suitable for use in an automated chemical synthesis process. Also provided is an automated small molecule synthesizer apparatus for performing automated synthesis of small molecules using iterative cycles of deprotection, coupling, and purification in accordance with methods of the invention. Coupling and other reactions embraced by the invention include, without limitation, Suzuki-Miyaura coupling, oxidation, Swern oxidation, "Jones reagents" oxidation, reduction, Evans' aldol reaction, HWE olefmation, Takai olefmation, alcohol silylation, desilylation, /?-methoxybenzylation, iodination, Negishi cross-coupling, Heck coupling, Miyaura borylation, Stille coupling, and Sonogashira coupling.
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Page/Page column 62-63
(2012/02/05)
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- Synthesis of 11-cis-retinoids by hydrosilylation-protodesilylation of an 11,12-didehydro precursor: Easy access to 11- and 12-mono- and 11,12-dideuteroretinoids
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An expeditious, highly efficient approach to 11-cis-retinoids was achieved by semihydrogenation of a readily available 11-yne precursor through a hydrosilylation-protodesilylation protocol. The complete chemo-, regio-, and syn-stereoselectivity of the method also allowed direct access to 11- and 12-monodeutero-, and 11,12-dideutero-11-cis-retinoids. The analogous trans series was not accessible by this route, and was synthesized by means of Hiyama coupling. Copyright
- Bergueiro, Julián,Montenegro, Javier,Saá, Carlos,López, Susana
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p. 14100 - 14107
(2013/01/15)
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- Syntheses of 13C2-labelled 11Z-retinals
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To enable solid-state NMR investigations of the rhodopsin chromophore and its photointermediates, a series of 11Z-retinal isotopomers have been synthesised containing pairs of adjacent 13C labels at C9/C10, C10/C11 or C11/C12, respectively. The C9 labelled carbon atom was introduced through the Heck reaction of a 13C-labelled Weinreb acrylamide derivative, and the label at the C12 position derived from a 13C-containing ethoxy Bestmann-Ohira reagent. The 13C labels at C10 and C11 were introduced through the reaction of β-ionone with labelled triethyl phosphonoacetate.
- McLean, Neville J.,Gansmuller, Axel,Concistre, Maria,Brown, Lynda J.,Levitt, Malcom H.,Brown, Richard C.D.
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supporting information; experimental part
p. 8404 - 8410
(2011/11/12)
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- Synthesis of C40-symmetrical fully conjugated carotenoids by olefin metathesis
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In an effort to push olefin metathesis to the limits of conjugation in reactants and products, the C40-symmetrical carotenoids β,β-carotene (1), lycopene (2), (3R,3′R)-zeaxanthin (3), and rac-isozeaxanthin (4), which are conjugated undecaenes, have been synthesized from C21-terminal hexaenes by treatment with Grubbs' second-generation Ru catalyst in dichloromethane at 50 °C.
- Fontan, Noelia,Dominguez, Marta,Ulvarez, Rosana,De Lera, Ungel R.
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p. 6704 - 6712
(2012/01/03)
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- Novel Polyunsaturated Compounds, Method for Preparing Same and Compositions Containing the Same
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The invention concerns novel polyunsaturated compounds of formula (I) wherein: R1 represents a R′1, -A-R′1 group, R′1 being selected from —COOH, —COOR3, —CONH2, —CONHR3, —CONR3, R4, —CHO, —CH2OH, —CH2OR5, and A represents a C2-C16 alkylene, alkenylene or alkynylene; R2 represents: an optionally substituted aryl group or an optionally substituted heteroaryl group; a sugar residue or, a fatty acid residue optionally branched and/or substituted preferably at the chain terminus and particularly by hydroxy, acetoxy radical or by an optionally protected amino radical; a —OC—(CH2)n CO-tocopheryl (alpha, beta or gamma or delta) group, with 2 μ(F) n μ(F) 10; a —R′2—O—R6 group, wherein R′2 is an optionally substituted arylene group or an optionally substituted heteroarylene group, and R6 represents a hydrogen atom, a straight or branched optionally substituted C1-C16 alkyl, a straight or branched optionally substituted C2-C16 alkenyl, or a straight or branched C2-C16 alkynyl group, an optionally substituted tocopheryl radical or the like, an amino acid residue, or a sugar residue. The invention also concerns the compositions, in particular cosmetic and/or dermatological compositions containing at least one compound of formula (I) as well as their use as whitening and/or depigmenting agent, and the cosmetic method using said compositions.
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- Retinylisoflavonoid as a novel membrane antioxidant
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We report a novel molecular dyad as an antioxidant, retinylisoflavonoid, with a retinal analogue C22-aldehyde and the isoflavonoid daidzein covalently linked. Its physicochemical properties, pKa (pK a1 = 8.45, pKa2 = 11.42), oxidation potential (1.03 V vs NHE), and Log10 partition (Log P = 1.96), as well as the Trolox equivalent antioxidant capacity (TEAC = 0.4), have been characterized. Spectroscopic and quantum chemical investigations have revealed the following unique structural characters: (i) Either free in solution or included in liposomal membranes, the C22-aldehyde moiety of retinylisoflavonoid is coplanar with the B-ring of daidzein owing to the strong intramolecular hydrogen bonding C 14-=O···HO-B4′. Accordingly, the C 22-aldehyde moiety extends its π-conjugation significantly to the B-ring. (ii) The inherent amphiphilicity of retinylisoflavonoid allows the C22-aldehyde moiety embedded in the lipid phase of the liposomes, whereas the daidzein counterpart stays at the membrane surface, in effect facilitating interior-to-surface radical communication. As the result, the antilipooxidation activity of retinylisoflavonoid is improved significantly in protecting membrane lipids compared to the parent compounds alone or in combination, and importantly, the performance is more prominent under higher-level oxidative stress. This work provides an advanced case study of new antioxidant development based on optimized electronic and molecular structures.
- An, Cun-Bin,Liang, Ran,Ma, Xiao-Hua,Fu, Li-Min,Zhang, Jian-Ping,Wang, Peng,Han, Rui-Min,Ai, Xi-Cheng,Skibsted, Leif H.
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p. 13904 - 13910
(2011/03/16)
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- The Mycobacterium tuberculosis ORF Rv0654 encodes a carotenoid oxygenase mediating central and excentric cleavage of conventional and aromatic carotenoids
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Mycobacterium tuberculosis, the causative agent of tuberculosis, is assumed to lack carotenoids, which are widespread pigments fulfilling important functions as radical scavengers and as a source of apocarotenoids. In mammals, the synthesis of apocarotenoids, including retinoic acid, is initiated by the β-carotene cleavage oxygenases I and II catalyzing either a central or an excentric cleavage of β-carotene, respectively. The M. tuberculosis ORF Rv0654 codes for a putative carotenoid oxygenase conserved in other mycobacteria. In the present study, we investigated the corresponding enzyme, here named M. tuberculosis carotenoid cleavage oxygenase (MtCCO). Using heterologously expressed and purified protein, we show that MtCCO converts several carotenoids and apocarotenoids in vitro. Moreover, the identification of the products suggests that, in contrast to other carotenoid oxygenases, MtCCO cleaves the central C15-C15' and an excentric double bond at the C13-C14 position, leading to retinal (C20), β-apo-14'-carotenal (C22) and β-apo-13-carotenone (C18) from β-carotene, as well as the corresponding hydroxylated products from zeaxanthin and lutein. Moreover, the enzyme cleaves also 3,3'-dihydroxy-isorenieratene representing aromatic carotenoids synthesized by other mycobacteria. Quantification of the products from different substrates indicates that the preference for each of the cleavage positions is determined by the hydroxylation and the nature of the ionone ring. The data obtained in the present study reveal MtCCO to be a novel carotenoid oxygenase and indicate that M. tuberculosis may utilize carotenoids from host cells and interfere with their retinoid metabolism. 2010 The Authors Journal compilation
- Scherzinger, Daniel,Scheffer, Erdmann,Baer, Cornelia,Ernst, Hansgeorg,Al-Babili, Salim
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experimental part
p. 4662 - 4673
(2011/12/04)
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- Preparation of 3-bromomethyl-3-butenal diethylacetal and its conversion into isoprenoid aldehydes derivatives
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The cyclopropanation of ethyl 3,3-diethoxypropionate with alkoxytitanacyclopropane reagents followed by the cleavage of the three-membered carbocycle in the formed cyclopropyl mesylate provided in a good yield 3-bromomethyl-3-butenal diethylacetal. The la
- Mineeva,Kulinkovich
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experimental part
p. 1623 - 1632
(2010/04/27)
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- 6-s-cis conformation and polar binding pocket of the retinal chromophore in the photoactivated state of rhodopsin
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The visual pigment rhodopsin is unique among the G protein-coupled receptors in having an 11-cis retinal chromophore covalently bound to the protein through a protonated Schiff base linkage. The chromophore locks the visual receptor in an inactive conformation through specific steric and electrostatic interactions. This efficient inverse agonist is rapidly converted to an agonist, the unprotonated Schiff base of all-trans retinal, upon light activation. Here, we use magic angle spinning NMR spectroscopy to obtain the 13C chemical shifts (C5-C20) of the all-trans retinylidene chromophore and the 15N chemical shift of the Schiff base nitrogen in the active metarhodopsin II intermediate. The retinal chemical shifts are sensitive to the conformation of the chromophore and its molecular interactions within the protein-binding site. Comparison of the retinal chemical shifts in metarhodopsin II with those of retinal model compounds reveals that the Schiff base environment is polar. In particular, the 13C15 and 15Nε chemical shifts indicate that the CdN bond is highly polarized in a manner that would facilitate Schiff base hydrolysis. We show that a strong perturbation of the retinal 13C12 chemical shift observed in rhodopsin is reduced in wild-type metarhodopsin II and in the E181Q mutant of rhodopsin. On the basis of the T1 relaxation time of the retinal 13C18 methyl group and the conjugated retinal 13C5 and 13C8 chemical shifts, we have determined that the conformation of the retinal C6-C7 single bond connecting the β-ionone ring and the retinylidene chain is 6-s-cis in both the inactive and the active states of rhodopsin. These results are discussed within the general framework of ligand-activated G protein-coupled receptors.
- Ahuja, Shivani,Eilers, Markus,Hirshfeld, Amiram,Yan, Elsa C. Y.,Ziliox, Martine,Sakmar, Thomas P.,Sheves, Mordechai,Smith, Steven O.
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body text
p. 15160 - 15169
(2010/01/29)
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- Complex thermal behavior of 11-cis-retinal, the ligand of the visual pigments
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Upon heating to 80 °C, 11-cis-retinal yields a mixture of all-trans-retinal and 13-cis-retinal. This isomerization has been studied by means of density functional theory methods, and the computational results suggest a close competition between two mechanisms of very different nature. A classical internal rotation around the C11-C12 cis double bond, via a diradical transition state, accounts for the formation of the all-trans isomer. An intricate sequence of pericyclic reactions, namely a reversible [1,7]-H sigmatropic shift and a reversible 6-π-oxa-electrocyclic reaction, is responsible for the formation of 13-cis-retinal. Experiments using 11-cis-retinal labeled with deuterium at C19 confirmed the mechanistic proposal and also revealed an unprecedented outcome on the product composition of isotopologues.
- Lopez, Carlos Silva,Alvarez, Rosana,Dominguez, Marta,Faza, Olalla Nieto,De Lera, Angel R.
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experimental part
p. 1007 - 1013
(2009/07/04)
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- SYSTEM FOR CONTROLLING THE REACTIVITY OF BORONIC ACIDS
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A protected organoboronic acid includes a boron having an sp3 hybridization, a conformationally rigid protecting group bonded to the boron, and an organic group bonded to the boron through a boron-carbon bond. A method of performing a chemical reaction includes contacting a protected organoboronic acid with a reagent, the protected organoboronic acid including a boron having an sp3 hybridization, a conformationally rigid protecting group bonded to the boron, and an organic group bonded to the boron through a boron-carbon bond. The organic group is chemically transformed, and the boron is not chemically transformed.
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Page/Page column 20
(2009/02/11)
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- Simple, efficient, and modular syntheses of polyene natural products via iterative cross-coupling
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This communication describes the discovery of air-stable and highly versatile B-protected haloalkenylboronic acid building blocks for iterative cross-coupling. These reagents enable the total synthesis of polyene natural products with extraordinary levels of simplicity, efficiency, and modularity. Specifically, all-trans-retinal, β-parinaric acid, and one-half of the amphotericin B macrolide skeleton were prepared using only the Suzuki-Miyaura reaction in an iterative manner to bring together collections of simple and readily accessible building blocks. In contrast to their boronic acid counterparts, the intermediate polyenylboronate esters are remarkably stable (to both column purification and storage), which is critical to their successful utilization. Moreover, the reactive boronic acids can be cleanly liberated using very mild aqueous base. These advances have enabled preparation of the longest polyene ever synthesized using the SM reaction. We additionally report, to the best of our knowledge, the first triply metal selective (Zn vs Sn and B) cross-coupling reaction, the first selective cross-coupling with a differentially ligated diboron reagent, and the first cross-couplings between polyenylchlorides and vinylboronic acids. Collectively, these new building blocks and methods can dramatically improve the way polyene natural products and their derivatives are synthesized in the laboratory. Copyright
- Suk, Joong Lee,Gray, Kaitlyn C.,Paek, James S.,Burke, Martin D.
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p. 466 - 468
(2008/10/09)
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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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Page/Page column 2; 27; 29-31; Sheet 12/24; 24/24
(2008/12/08)
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- New syntheses of retinal and its acyclic analog γ-retinal by an extended aldol reaction with a C6 building block that incorporates a C5 unit after decarboxylation. A formal route to lycopene and β-carotene
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Since the C15 β-end-group aldehyde 10 ((β-ionylidene) acetaldehyde), an excellent intermediate in the syntheses of retinoids, can be synthesized in many ways from β-ionone, and since the corresponding acyclic C15 ψ-end-group aldehyde 5 can easily be synthesized from citral (1) (Scheme 3), we applied the C15 + C5 route to the syntheses of γ-retinal ((all-E)-8) (Scheme 3) and retinal ((all-E)-13) (Scheme 4), and therefore, by coupling (2 x C20 → C 40), to the preparation of lycopene (14) and β-carotene (15) (Scheme 5). Our new syntheses of retinal ((all-E)-13) and γ-retinal ((all-E)-8 use an extended aldol reaction with a C6 building block that incorporates a C5 unit after decarboxylation.
- Valla, Alain,Valla, Benoist,Le Guillou, Regis,Cartier, Dominique,Dufosse, Laurent,Labia, Roger
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p. 512 - 520
(2008/02/07)
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- Cyclodextrin retinylidene: A biomimetic kinetic trap model for rhodopsin
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All trans retinal was attached to both the primary face and the secondary face of β-cyclodextrin via a Schiff base linkage, analogous to that in rhodopsin. The new models were evaluated and compared with n-butylamine retinylidene Schiff base for their rates of hydrolysis, and factors that influence such rates. Competition studies using adamantane carboxylate demonstrated the kinetic trap theory by diminishing the binding of retinal in the cyclodextrin, thereby augmenting the rate of hydrolysis. NMR experiments indicate that the retinylidene is most probably bound in the form of a dimer.
- Kpegba, Kafui,Murtha, Matthew,Nesnas, Nasri
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p. 1523 - 1526
(2007/10/03)
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- METHODS FOR TREATMENT OF RETINAL DEGENERATIVE DISEASE
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A method is provided for treating a degenerative disease in a vertebrate eye. A method is further provided for preventing photoreceptor degeneration in a vertebrate eye.
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Page/Page column 35-36; 8/17
(2008/06/13)
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- 9-Demethyl-9-haloretinals by Wadsworth-Emmons coupling - Easy preparation of pure (all-E), (9Z) and (11Z) isomers
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5-(2′,6′,6′-Trimethyl-1′-cyclohexen-1′-yl) -4-penten-2-yn-1-al has been prepared in a one-pot process starting from β-ionone in almost quantitative yield. Using 1,4-nucleophilic addition reactions, the corresponding 9-Cl, 9-Br, 9-1 β-ionylideneacetaldehyde systems could be obtained in one step in quantitative yield as a mixture of (9Z) and (all-E) isomers. Even the corresponding fluoro derivative could be obtained in good yield as (9Z) and (all-E) isomers. In the case of a double bond having a halogen substituent, the IUPAC rules have the (E) nomenclature for a cis double bond and the (Z) for a trans double bond. Simple column chromatography gave the pure (9Z) and (all-E) form. Optimizing the Wadsworth-Emmons coupling gave the corresponding (all-E)- and (9Z)-retinonitriles in quantitative yield. Subsequent DIBAL-H reduction gave the corresponding retinals. For the preparation of the (UZ) isomers essential to vision, we found that Wadsworth-Emmons reactions with the diphenyl phosphonate group gave retinonitriles in quantitative yield, where the newly formed double bond is predominantly the (11Z) form (> 60%), together with the (9Z) isomer as minor component. The nitriles could be isolated in pure (9Z.11Z) and (9Z) forms by simple column chromatography. In the case of the (9Z,11Z)-9-demethyl-9-halo systems, a complication arose due to the unprecedented acid lability of these (9Z,11Z) aldehydes. By adjusting the DIBAL-H reduction workup procedure, these aldehydes are now available in pure form. We used this strategy to rationally synthesize (11Z)-retinal starting from β-cyclocitral as a first test for the generality of our new approach. β-Ionylideneacetaldehyde could be prepared in the (all-E) form in almost quantitative yield. Extending the conjugated chain of this molecule gave an almost quantitative yield of a mixture containing 80% (11Z)-retinal and 20% (all-E) as the minor component. Simple column chromatography gave pure (11Z)-retinal in 75% overall yield. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Wang, Yajie,Woo, Wei Sein,Van Der Hoef, Ineke,Lugtenburg, Johan
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p. 2166 - 2175
(2007/10/03)
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- Selective isomerization of retinal upon two-photon excitation
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The products of photo-isomerization when excited directly up to the two-photon-allowed 1Ag- excited state of alltrans and five cis isomers of retinal were determined. The composition of the isomers at the photo-stationary state was drastically changed as compared to one-photon excitation. The production of the 13-cis isomer was selectively increased, and the production of the dicis isomers was observed in the case of a direct excitation upon the 31Ag- state, although they were hard to be produced by one-photon excitation in n-hexane solution. These results clearly evidenced that there exist isomerization pathways via two-photon-allowed excited states.
- Sashima, Tokutake,Hashimoto, Hideki,Koshihara, Shin-ya
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p. 380 - 385
(2007/10/03)
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- Process for producing vitamin A aldehyde and intermediate for producing the same
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There are disclosed an alcohol derivative of formula (1): wherein Ar is an optionally substituted aryl group and R is a straight or branched C1-C3 lower alkyl group, and the wavy line depicted by indicates a single bond and stereochemistry relating to a double bond bound therewith is E or Z or a mixture thereof, and a process for producing the same and a process for producing Vitamin A aldehyde using the same.
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- Method for preparing vitamin A
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The invention relates to a process for making vitamin A from ethynyl-retro-α-ionol using an allene acetate as intermediate.
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Page column 5
(2010/01/31)
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- Vinyltin acetals in terpenic and nor-terpenic synthesis
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Vinyltin acetals obtained by stannylmetallation of homopropargyl acetals with Bu3SnMgMe/CuCN (E configuration) or by titanation of the corresponding alkyltin acetals (Z configuration) have been proved to be efficient storable precursors for the stereoselective synthesis of terpenoids, under mild experimental conditions.Due to the presence of a nucleophilic centre (Csp2-Sn bond) and of a protected electrophilic centre, they are also useful intermediates for an iterative synthesis of retinal and nor-retinoids. - Keywords: vinyltin; acetal; vinyllithium; monoterpenoid; retinal; nor-retinoid
- Launay, Valerie,Beaudet, Isabelle,Quintard, Jean-Paul
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p. 937 - 946
(2007/10/03)
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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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- Synthesis and characterization of N-retinylidene derivatives of polar amino acids
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Water-soluble N-retinylideneamino acids were synthesized and their physicochemical characteristics studied. The latter included the kinetics of hydrolysis in water, aqueous ethanol, physiological solution, and 0.1 M phosphate buffer, pH 7.0. The observed hydrolysis rate constants for N-retinylideneamino acids were shown to decrease in the order Ser > Asp > Taur > Met > Lys.
- Pshenichnikova,Karnaukhova,Mitsner,Shvets
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p. 744 - 747
(2007/10/03)
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- Pyrylium salts in polyene natural product synthesis: organometallic additions to 4-methylpyrylium tetrafluoroborate
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The synthetic utility of organometallic additions to pyrylium salts as a procedure for the stereocontrolled preparation of 2Z,4E-dienals, and the use of these compounds in polyene natural product synthesis, is summarised.The extension of this methodology to 4-methylpyrylium tetrafluoroborate to give a new route to 3-methyl-2Z,4E-dienals via a six-carbon organometallic homologation procedure is then described.Finally, the utilisation of this methodology to provide a concise synthetic approach to 13Z-retinal, retinal and a range of retinal analogues is then elaborated.
- Taylor, Richard J. K.,Hemming, Karl,Medeiros, Edna Faria De
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p. 2385 - 2392
(2007/10/02)
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