5299-98-9Relevant academic research and scientific papers
Expansion of first-in-class drug candidates that sequester toxic all-trans-retinal and prevent light-induced retinal degeneration
Zhang, Jianye,Dong, Zhiqian,Mundla, Sreenivasa Reddy,Hu, X. Eric,Seibel, William,Papoian, Ruben,Palczewski, Krzysztof,Golczak, Marcin
supporting information, p. 477 - 491 (2015/01/30)
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.
Synthetic control of retinal photochemistry and photophysics in solution
Bassolino, Giovanni,Sovdat, Tina,Liebel, Matz,Schnedermann, Christoph,Odell, Barbara,Claridge, Timothy D.W.,Kukura, Philipp,Fletcher, Stephen P.
supporting information, p. 2650 - 2658 (2014/03/21)
Understanding how molecular structure and environment control energy flow in molecules is a requirement for the efficient design of tailor-made photochemistry. Here, we investigate the tunability of the photochemical and photophysical properties of the retinal-protonated Schiff base chromophore in solution. Replacing the n-butylamine Schiff base normally chosen to mimic the saturated linkage found in nature by aromatic amines results in the reproduction of the opsin shift and complete suppression of all isomerization channels. Modification of retinal by directed addition or removal of backbone substituents tunes the overall photoisomerization yield from 0 to 0.55 and the excited state lifetime from 0.4 to 7 ps and activates previously inaccessible reaction channels to form 7-cis and 13-cis products. We observed a clear correlation between the presence of polarizable backbone substituents and photochemical reactivity. Structural changes that increase reaction speed were found to decrease quantum yields, and vice versa, so that excited state lifetime and efficiency are inversely correlated in contrast to the trends observed when comparing retinal photochemistry in protein and solution environments. Our results suggest a simple model where backbone modifications and Schiff base substituents control barrier heights on the excited-state potential energy surface and therefore determine speed, product distribution, and overall yield of the photochemical process.
Azetidinone-retinoid hybrids: Synthesis and differentiative effects
Pori, Matteo,Galletti, Paola,Soldati, Roberto,Calzà, Laura,Mangano, Chiara,Giacomini, Daria
, p. 857 - 863 (2013/12/04)
As a part of a systematic investigation on the synthesis and biological activities of new β-lactam compounds, we examined β-lactam candidates 1, 2E and 2Z and their ability to induce cell proliferation or differentiation. Azetidinone 1 was chosen for its
Base-induced decarboxylation of polyunsaturated α-cyano acids derived from malonic acid: Synthesis of sesquiterpene nitriles and aldehydes with β-, φ-, and ψ-end groups
Dufossé, Laurent,Cartier, Dominique,Valla, Benoist,Fouillaud, Mireille,Labia, Roger,Valla, Alain
, p. 259 - 265 (2013/03/28)
Catalytic base-induced decarboxylation of polyunsaturated α-cyano-β-methyl acids derived from malonic acid led to the corresponding nitriles 3 (Schemes 2 and 3), 6 (Scheme 5), and 9 (Scheme 6). This decarboxylation occurred with previous deconjugation of
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
Valla, Alain,Valla, Benoist,Le Guillou, Regis,Cartier, Dominique,Dufosse, Laurent,Labia, Roger
, p. 512 - 520 (2008/02/07)
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.
9-Demethyl-9-haloretinals by Wadsworth-Emmons coupling - Easy preparation of pure (all-E), (9Z) and (11Z) isomers
Wang, Yajie,Woo, Wei Sein,Van Der Hoef, Ineke,Lugtenburg, Johan
, p. 2166 - 2175 (2007/10/03)
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.
Simple and efficient preparation of [10,20-13C2]- and [10-CH3,13-13C2]-10-methylretinal: Introduction of substituents at the 2-position of 2,3-unsaturated nitriles
Verdegem,Monnee,Lugtenburg
, p. 1269 - 1282 (2007/10/03)
In this paper, we present the synthesis of [10,20-13C2]-10-methylretinal and [10-CH3,13-13C2]-10-methylretinal, two doubly 13C-labeled chemically modified retinals that have been recently used to study the structural and functional details behind the photocascade of bovine rhodopsin (Verdegem et al. Biochemistry 1999, 38, 11316; de Lange et al. Biochemistry 1998, 37, 1411). To obtain both doubly 13C-labeled compounds, we developed a novel synthetic method to directly and regiospecifically introduce a methyl substituent on the 2-position of 3-methyl-5-(2′,6′,6′-trimethyl-1′ -cyclohexen-1′-yl)-2,4-pentadienenitrile. Encouraged by these results, we investigated the scope of this novel reaction by developing a general method for the introduction of a variety of substituents to the 2-position of 3-methyl-2,3-unsaturated nitriles, paving the way for simple and efficient synthesis of a wide variety of 10-, 14-, and 10,14-substituted chemically modified retinals, and other biologically important compounds.
A Novel Method for a Stereoselective Synthesis of Trisubstituted Olefin Using Tricarbonyliron Complex: A Highly Stereoselective Synthesis of (all-E)- and (9Z)-Retinoic Acids
Wada, Akimori,Hiraishi, Saeko,Takamura, Norio,Date, Tadamasa,Aoe, Keiichi,Ito, Masayoshi
, p. 4343 - 4348 (2007/10/03)
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).
New preparation of an important synthon for vitamin A synthesis
Andriamialisoa, Zo,Valla, Alain,Zennache, Sakina,Giraud, Michel,Potier, Pierre
, p. 8091 - 8092 (2007/10/02)
The "C-18 ketone" 1, key intermediate for vitamin A synthesis, is prepared in a few steps from β-ionone 3 via β-ionylidene acetonitrile 2 (32% overall yield).
