4808-00-8Relevant 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
, 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.
Vinyltin acetals in terpenic and nor-terpenic synthesis
Launay, Valerie,Beaudet, Isabelle,Quintard, Jean-Paul
, p. 937 - 946 (2007/10/03)
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
First synthesis of 9-Demethyl-14-Carboxyretinoic Acid
Giraud, Michel,Andriamialisoa, Zo,Valla, Alain,Zennache, Sakina,Potier, Pierre
, p. 3077 - 3080 (2007/10/02)
A short synthesis of 9-demethyl-14-carboxyretinoic acid from β-ionone via 9-demethyl-β-ionyldeneacetaldehyde is reported (48percent overal yield).
Synthesis of specifically deuteriated 9- and 13-demethylretinals
Berg, Ellen M. M. van den,Bent, Arie van der,Lugtenburg, Johan
, p. 160 - 167 (2007/10/02)
(13-2H)13-Demethylretinal, (11,12,13-2H3)13-demethylretinal, (9-2H)9-demethylretinal and (9,10-2H2)9-demethylretinal were prepared in all-E, 9Z, 11Z and 13Z isomeric form with high deuterium incorporation.In the
Preparation of 11,14-epoxy-bridged and isomeric chain-demethylated retinals. 13-Demethyl-11,14-epoxy-, 9-demethyl-, 13-demethyl- and 9,13-bisdemethyl-retinals
Broek, A. D.,Muradin-Szweykowska, M.,Courtin, J. M. L.,Lugtenburg, J.
, p. 46 - 51 (2007/10/02)
9-Cis- and all-trans-13-demethyl-11,14-epoxyretinyl acetate were prepared via a Wittig coupling between β-ionylidenetriphenylphosphonium bromide (1) and 5-(acetoxymethyl)furfural.Saponification of these acetates, subsequent oxidation and HPLC separation a
