200720-67-8Relevant academic research and scientific papers
Retinal-chitosan conjugates effectively deliver active chromophores to retinal photoreceptor cells in blind mice and dogs
Gao, Songqi,Kahremany, Shirin,Zhang, Jianye,Jastrzebska, Beata,Querubin, Janice,Petersen-Jones, Simon M.,Palczewski, Krzysztof
, p. 438 - 452 (2018)
The retinoid (visual) cycle consists of a series of biochemical reactions needed to regenerate the visual chromophore 11-cis-retinal and sustain vision. Genetic or environmental factors affecting chromophore production can lead to blindness. Using animal models that mimic human retinal diseases, we previously demonstrated that mechanism-based pharmacological interventions can maintain vision in otherwise incurable genetic diseases of the retina. Here, we report that after 9-cis-retinal administration to lecithin:retinol acyltransferase-deficient (Lrat2/2) mice, the drug was rapidly absorbed and then cleared within 1 to 2 hours. However, when conjugated to form chitosan-9-cis-retinal, this prodrug was slowly absorbed from the gastrointestinal tract, resulting in sustainable plasma levels of 9-cis-retinol and recovery of visual function without causing elevated levels, as occurs with unconjugated drug treatment. Administration of chitosan-9-cis-retinal conjugate intravitreally in retinal pigment epithelium-specific 65 retinoid isomerase (RPE65)-deficient dogs improved photoreceptor function as assessed by electroretinography. Functional rescue was dose dependent and maintained for several weeks. Dosing via the gastrointestinal tract in canines was found ineffective, most likely due to peculiarities of vitamin A blood transport in canines. Use of the chitosan conjugate in combination with 11-cis-6-ring-retinal, a locked ring analog of 11-cis-retinal that selectively blocks rod opsin consumption of chromophore while largely sparing cone opsins, was found to prolong cone vision in Lrat2/2 mice. Development of such combination low-dose regimens to selectively prolong useful cone vision could not only expand retinal disease treatments to include Leber congenital amaurosis but also the age-related decline in human dark adaptation from progressive retinoid cycle deficiency.
P(CH3NCH2CH2)3N as a dehydrobromination reagent: Synthesis of vitamin A derivatives revisited
Wroblewski, Andrzej E.,Verkade, John G.
, p. 420 - 425 (2007/10/03)
Although P(CH3NCH2CH2)3N (1) was found to be less effective than 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in the removal of hydrogen bromide from vitamin A intermediates 13-cis-10-bromo-9,10-dihydroretinyl acetates (6) and 14-bromo-9,14-dihydroretinyl acetate (11) when the reaction was carried out in refluxing benzene, in acetonitrile at room temperature it was superior to DBN and DBU. A 31P NMR study of this reaction suggests that the carbanion generated from acetonitrile-d3 in the presence of 1 is the basic species that initiates the elimination step. Diastereoselectivity of the nucleophilic addition of (Z)-HC≡ C(CH3)=CHCH20H to the carbonyl group of (E)-2-methyl-4-(2′,6′,6′-trimethyl-1′-cyclohexen- 1′-yl)-3-butenal (2) was only moderate (20%), and (9R*, 10S*)-13-cis-11,12 -didehydro-9,10-dihydro-10-hydroxyretinol (3b) predominated. The LiAlH4 reduction of the C≡C bond in the diastereoisomeric diols 3 afforded 13-cis-9,10-dihydro-10-hydroxyretinols 4a and 4b as major products together with 11-cis-13-cis-isomers and the deoxygenated compound (3EZ,5EZ,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)- 1,3,5,8-nonatetraene (9). Reaction of 15-acetates of the pure diastereoisomeric allylic alcohols 4a and 4b with PBr3 occurred with significant but not identical retention of configuration, and with concomitant formation of the rearranged bromide 11.
