- Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin
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Inherited blinding diseases retinitis pigmentosa (RP) and a subset of Leber's congenital amaurosis (LCA) are caused by the misfolding and mistrafficking of rhodopsin molecules, which aggregate and accumulate in the endoplasmic reticulum (ER), leading to photoreceptor cell death. One potential therapeutic strategy to prevent the loss of photoreceptors in these conditions is to identify opsin-binding compounds that act as chemical chaperones for opsin, aiding its proper folding and trafficking to the outer cell membrane. Aiming to identify novel compounds with such effect, a rational ligand-based approach was applied to the structure of the visual pigment chromophore, 11-cis-retinal, and its locked analogue 11-cis-6mr-retinal. Following molecular docking studies on the main chromophore binding site of rhodopsin, 49 novel compounds were synthesized according to optimized one-to seven-step synthetic routes. These agents were evaluated for their ability to compete for the chromophore binding site of opsin, and their capacity to increase the trafficking of the P23H opsin mutant from the ER to the cell membrane. Different new molecules displayed an effect in at least one assay, acting either as chemical chaperones or as stabilizers of the 9-cis-retinal-rhodopsin complex. These compounds could provide the basis to develop novel therapeutics for RP and LCA.
- Bassetto, Marcella,Brancale, Andrea,Pasqualetto, Gaia,Pileggi, Elisa,Rozanowska, Malgorzata,Schepelmann, Martin,Varricchio, Carmine
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supporting information
(2021/09/24)
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- Photocatalytic e → Z Isomerization of β-Ionyl Derivatives
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An operationally simple E → Z isomerization of activated dienes, based on the β-ionyl motif intrinsic to retinal, is reported using inexpensive (-)-riboflavin (vitamin B2) under irradiation at 402 nm. Selective energy transfer from photoexcited (-)-riboflavin to the starting E-isomer enables geometrical isomerization. Since the analogous process with the Z-isomer is inefficient, microscopic reversibility is circumvented, thereby enabling a directional isomerization to generate the contra-thermodynamic product (up to 99% yield, up to 99:1 Z/E). Prudent choice of photocatalyst enables chemoselective isomerization to be achieved in both inter- and intramolecular systems. The principles established from this study, together with a molecular editing approach, have facilitated the development of a regioselective isomerization of a truncated triene based on the retinal scaffold.
- Livingstone, Keith,Tenberge, Marius,Pape, Felix,Daniliuc, Constantin G.,Jamieson, Craig,Gilmour, Ryan
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p. 9677 - 9680
(2019/11/29)
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- Synthesis of short retinoidal amides related to fenretinide: antioxidant activities and differentiation-inducing ability
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Purpose: By a scaffold shortening strategy, a small series of retinoidal amides fenretinide (4-HPR) analogs have been synthesized from α, β-ionones and tested for their antiproliferative and differentiating activities, and antioxidant effect. Methods: The
- Anzaldi, Maria,Viale, Maurizio,Macciò, Chiara,Castagnola, Patrizio,Oliveri, Valentina,Rosano, Camillo,Balbi, Alessandro
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p. 725 - 736
(2017/03/29)
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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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- OPSIN-BINDING LIGANDS, COMPOSITIONS AND METHODS OF USE
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Compounds and compositions of said compounds along with methods of use of compounds are disclosed for treating ophthalmic conditions related to mislocalization of opsin proteins, the misfolding of mutant opsin proteins and the production of toxic visual cycle products that accumulate in the eye. Compounds and compositions useful in the these methods, either alone or in combination with other therapeutic agents, are also described.
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Page/Page column 94
(2010/12/31)
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- Synthesis, olfactory evaluation and determination of the absolute configuration of the β- and γ-Iralia isomers
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The regioselective synthesis of the methyl-ionone isomers 6-9 is described. The enantiomers of the γ-isomers 8 and 9 are prepared by enzyme-mediated resolution of the corresponding 4-hydroxy derivatives followed by reductive elimination of the hydroxy group. The absolute configuration of the latter compound is determined by chemical correlation with the known α-isomers. Since all the isomers obtained are components of the artificial violet odourants sold under the trade name of Iralia, their odour properties are evaluated by professional perfumers.
- Barakat, Assem,Brenna, Elisabetta,Fuganti, Claudio,Serra, Stefano
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experimental part
p. 2316 - 2322
(2009/04/11)
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- Synthesis of CD3-labeled 11-cis-retinals and application to solid-state deuterium NMR spectroscopy of rhodopsin
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Efficient synthesis of 11-Z-retinals labeled with 2H at the C5, C9, or C13 methyl groups is described. The 2H-labeled retinals were used to regenerate the visual pigment rhodopsin for structural investigations. Solid-state 2H NMR data provided the orientation of retinal within the rhodopsin binding pocket as well as its conformation. Extension of the approach to other membrane receptors can yield knowledge of their mechanisms of activation as a guide for ligand-based drug design.
- Tanaka, Katsunori,Struts, Andrey V.,Krane, Sonja,Fujioka, Naoko,Salgado, Gilmar F. J.,Martinez-Mayorga, Karina,Brown, Michael F.,Nakanishi, Koji
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body text
p. 2177 - 2184
(2009/08/08)
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- ANTINEOPLASTIC AND CURCUMIN DERIVATIVES AND METHODS OF PREPARATION AND USE
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This invention comprises antineoplastic curcumin derivatives and methods of preparation and use thereof. Note is made of the acylation product of the lithium enolate of β-ionone using the acid chloride, 2(E)-3-(2,6,6-trimethycyclohex-1-en-1-yl)propenoyl chloride derived from β-cyclocitral. Particular reference is made to the isomeric compound, 1-(2,6,6-trimethylcyclohex-2-en-1-yl)-7-(2,6,6-trimethylcyclohex-1-en-1-yl)- 1,6-heptadiene-3,5-dione.
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Page/Page column 10
(2010/11/28)
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- A short and efficient regioselective approach to the C-6 to C-19 segment of bifurcaranes and a formal total synthesis of β-microbiotene, microbiotol and cyclocuparanol
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Employing an epoxide rearrangement based ring contraction reaction, a short and efficient regioselective approach to the C-6 to C-19 segment of the toluquinol substituted diterpenes bifurcaranes, and its extension to a formal total synthesis of the sesquiterpenes (±)-β-microbiotene, (±)-microbiotol and (±)-cyclocuparanol are described. The Royal Society of Chemistry 1999.
- Srikrishna,Anitha Nagamani
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p. 3393 - 3394
(2007/10/03)
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- Retinoidal dienamides and related aromatic amides. Replacement of the 9-ene structure of retinoic acid with a trans- or cis-amide group
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Several retinoid candidates which possess an amide bond at the position corresponding to the 9-ene part of retinoic acid (1) were synthesized and their conformations and biological activities were investigated. N-(methoxycarbonyl)dienamines, prepared by t
- Shimasaki,Kagechika,Fukasawa,Kawachi,Shudo
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p. 100 - 107
(2007/10/02)
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- Improved Synthesis of 2,6,6-Trimethyl-1-cyclohexene-1-acetaldehyde, a Key Intermediate for Drimanerelated Sesquiterpenes
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The titel compound is conveniently prepared in 65percent overall yield by a two step synthesis starting from the comercially available β-ionone.
- Jong, Johannes C. de,Wildeman, Jurjen,Leusen, Albert M. van,Feringa, Ben L.
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p. 589 - 596
(2007/10/02)
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- 1,3,5-Hexatriene photochemistry. The photo-isomerization of (Z)-3-(6',6'-dimethyl-2'-methylenecyclohexylidene)-1-propene
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The photo-isomerization of (Z)-3-(6',6'-dimethyl-2'-methylenecyclohexylidene)-1-propene has been studied under conditions of triplet photosensitization, using benzophenone as sensitizer, and direct irradiation with λ 254 nm.Under the former condi
- Geenevasen, Jan A. J.,Cerfontain, Hans
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p. 631 - 634
(2007/10/02)
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- Isolation and Identification of the Polyenes Formed During the Thermal Degradation of β,β-Carotene
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It has been proposed that carotenoid natural products are the source of part of the aromatic fraction of petroleum.In order to understand the mechanisms by which carotenoids are converted to aromatic products, an investigation of the polyene intermediates formed in the thermal degradation of β,β-carotene was initiated.As a result of this investigation, four polyene intermediates have been isolated and identified: 1,12-bis(2,6,6-trimethylcyclohex-1-enyl)-3,6,10-trimethyldodeca-1,3,5,7,9,11-hexaene, 1,12-bis(2,6,6-trimethylcyclohex-1-enyl)-3,7-dimethyldodeca-1,3,5,7,9, 11-hexaene, 1,6-bis(2,6,6-trimethylcyclohex-1-enyl)-3-methylhexa-1,3,5-triene, and 1,6-bis(2,6,6-trimethylcyclohex-1-enyl)hexa-1,3,5-triene.Independent syntheses confirmed the structures of the polyene intermediates. 1H NMR established the type and number of methyl substituents.Mass spectra of the saturated analogues confirmed the positions of the in-chain methyl substituents.The structures of the polyene intermediates are consistent with proposals that β,β-carotene thermally degrades by a series of symmetry-allowed electrocyclic processes followed by a thermal elimination.However, not all of the degradation products arise from electrocyclic-type processes.The presence of 1,1,3-trimethylcyclohexane and long chain aromatics indicates that disproportionation reactions are occurring in the complex degradation reaction.
- Byers, Jim
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p. 1515 - 1522
(2007/10/02)
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- DOUBLE BOND CLEAVAGE REACTION OF SILYL ENOL ETHERS USING MoO2(acac)2-tBuOOH
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The double bond of various silyl enol ethers is smoothly cleaved to give carbonyl compounds by an oxidizing reagent MoO2(acac)2-tBuOOH.
- Kaneda, Kiyotomi,Kii, Nobuyoshi,Jitsukawa, Koichiro,Teranishi, Shiichiro
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p. 2595 - 2598
(2007/10/02)
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