6980-79-6Relevant academic research and scientific papers
Synthesis of one double bond-inserted retinal analogs and their binding experiments with opsins: Preparation of novel red-shifted channelrhodopsin variants
Okitsu, Takashi,Yamano, Yumiko,Shen, Yi-Chung,Sasaki, Toshikazu,Kobayashi, Yuka,Morisawa, Shoko,Yamashita, Takahiro,Imamoto, Yasushi,Shichida, Yoshinori,Wada, Akimori
, p. 265 - 272 (2020/11/26)
In optogenetics, red-shifted channelrhodopsins (ChRs) are eagerly sought. We prepared six kinds of new chromophores with one double bond inserted into the polyene side chain of retinal (A1) or 3,4-didehy-droretinal (A2), and examined their binding efficie
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.
, 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.
Polyenylidene thiazolidine derivatives with retinoidal activities
Tashima, Toshihiko,Kagechika, Hiroyuki,Tsuji, Motonori,Fukasawa, Hiroshi,Kawachi, Emiko,Hashimoto, Yuichi,Shudo, Koichi
, p. 1805 - 1813 (2007/10/03)
Several polyenylidene thiazolidinedione or 2-thioxo-4-thiazolidinone derivatives were synthesized and their retinoidal activities were examined in terms of the differentiation-inducing ability towards human promyelocytic leukemia HL-60 cells and inhibitory effect on interleukin (IL)-1α-induced IL-6 production in MC3T3-E1 cells. Compounds containing a trimethylcyclohexenyl ring induced HL-60 cell differentiation with weaker activity than retinoic acid (1a) by one or two orders of magnitude. The thiazolidinedione derivatives (2, 5, 7) showed stronger activity than the corresponding 2-thioxo-4-thiazolidinone derivatives (3, 6, 8). The effects of a retinoid antagonist (LE540) and synergists (retinoid X receptor (RXR) agonists, HX600 or HX630) on the activities of thiazolidine derivatives indicate that these compounds elicit their activities through the nuclear retinoic acid receptors (RARs). All the thiazolidines examined also inhibited IL-1α-induced IL-6 production with IC50 values of 10nM order. The retinoidal activities of the thiazolidines are significant, considering that replacement of the carboxylic acid in retinoid structures with bioisosteric functional groups is generally ineffective, as seen in the structure-activity relationships of retinoidal benzoic acids.
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
Dependence of the Triplet Potential of Retinal Homologues on the Chain Length: Resonance Raman Spectroscopy and Analysis of Triplet-Sensitized Isomerization
Mukai, Yumiko,Hashimoto, Hideki,Koyama, Yasushi
, p. 4042 - 4051 (2007/10/02)
The Raman spectra of triplet species produced from the all-trans, 7-cis and 9-cis isomers of β-ionylideneacetaldehyde (C15 aldehyde) and of β-ionylidenecrotonaldehyde (C17 aldehyde) were recorded.Each isomer of C15 aldehyde showed its own triplet Raman spectrum, while all the isomers of C17 aldehyde showed an identical triplet spectrum.The results were compared with those of isomeric retinal (C20 aldehyde) and retinylideneacetaldehyde (C22 aldehyde) obtained previously.Triplet-sensitized isomerization as well as direct photoisomerization of the all-trans isomer and the complete set of mono-cis isomers of C15, C17, C20, and C22 aldehydes were analyzed by HPLC.Mutual isomerization among the all-trans was seen for C17, C20, and C22 aldehydes.The quantum yield of triplet-sensitized isomerization for each isomer of the above aldehydes was determined. all the results are discussed in terms of triplet potentials with minima at cis and trans positions, the relative stability being dependent on the length of the polyene chain; the cis minima are as stable as the trans minimum for C15 aldehyde, while the cis minima are far less stable than the trans minimum for C17, C20, and C22 aldehydes.
Synthesis of 8-, 9-, 12-, and 13-mono-13C-retinal
Pardoen, J. A.,Mulder, P. P. J.,Berg, E. M. M. van den,Lugtenburg, J.
, p. 1431 - 1435 (2007/10/02)
The 8-, 9-, 12-, and 13-mono-13C-retinals were synthesized with >98percent chemical purity and 93percent 13C incorporation from 13C-labelled acetonitrile.Their 13C-13C and 13C-1H nmr coupling constants were determined.
Synthesis of 10-, 11-, 19- and 20-mono-13C-retinal
Pardoen, J. A.,Neijenesch, H. N.,Mulder, P. P. J.,Lugtenburg, J.
, p. 341 - 347 (2007/10/02)
The 10-, 11-, 19- and 20-mono-13C-all-trans-retinals were synthesized with >98percent chemical purity and 92percent 13C incorporation from 13C-labelled acetonitrile and 13C-labelled methyl iodide.Their 13C-13C and 13C-1H NMR coupling constants were measur
