Vitamin A acid

Retinoic acid (vitamin A acid). Retinol (vitamin A... 

Retinal (Vitamin A aldehyde). Retinoic acid (Vitamin A acid), Retinyl acetate, Retinyl palmitate see entries in Chapter 4. 

Common Name Vitamin A acid retinoic acid Structural Formula ... 

After stirring for 2 hours at room temperature, the mass of vitamin A acid has crystallized out. It is sharply filtered off by suction and washed with a little ice-cold isopropanol. From the filtrate, a further small amount of mainly all trans vitamin A acid crystallizes out upon the addition of water. The filter cake is suspended in 600 parts of water and stirred for 4 hours at room temperature it is filtered by suction and the product washed with water. It is dried in vacuo at 40° to 50°C and 115 parts of vitamin A acid are obtained. The melting point lies between 146° and 159°C. 

The mixture of the all trans and mainly 9,10-cis vitamin A acid may be separated by fractional crystallization from ethanol. All trans vitamin A acid has a melting point of 180° to 182°C and 9,10-cis vitamin A acid, which crystallized in the form of pale yellow fine needles collected into clusters, has a melting point of 189° to 190°C. 

Retinoic acid (RA) describes a group of vitamin A acid (synonym Vitamin A1 acid) derivatives such as all-irans-retinoic acid (tretinoin), 9-cis-retinoic acid and 13-cis retinoic acid (isotretinoin). Retinoic acids act through binding to retinoic acid and retinoid X response elements. 

Retinoids Vitamin A Carotinoids Retinylesters Retinol Retinal Retinoic acid Vitamin A acid... 

Analogously prepared are the / -D-glucosyl ester of 8 -apo-/ -carotene-8 -oic acid (as imidazolide and triazolide, obtained in 81 and 66% yield, respectively) and vitamin A acid (as triazolide, obtained in 87% yield) tl95]... 

Tretinoin (a retinoid topical vitamin A acid) is a comedolytic agent that increases cell turnover in the follicular wall and decreases cohesiveness of cells, leading to extrusion of comedones and inhibition of new comedo formation. It also decreases the number of cell layers in the stratum corneum from about 14 to about five. 

Tretinoin (Trans-Retinoic Acid Vitamin A Acid)... 

An interesting and fimctionally important aspect of transcriptional activators is that one and the same protein can act as both an activator and a repressor. The alternative functionality is determined by the sequence environment, the presence of other transcriptional activators (steroid receptors, see ch. 4), by specific repressors or by low molecular weight effectors. Examples are the receptors for vitamin A acid, which, in the absence of its ligand, represses the genes with cognate DNA elements. TTie repression is exerted in the DNA-bound form. In the presence of its hgand, vitamin A acid, the same receptor acts as a transcriptional activator (see ch. 4). 

A large number of proto-oncogenes code for transcription factors required for progression of the cell cycle and/or for the differentiation of the cell. The best known and investigated examples of oncogenic mutated transcription factors involve the jun, fos and myc genes and the genes for the T3 receptor and the vitamin A acid receptor. 

As shown in Scheme 1, isotretinoin (1) was first synthesized by Garbers et al. in 1968 utilizing a key Wittig condensation. Phosphonium salt 8 was prepared from direct treatment of vinyl p-ionol 7 with triphenylphosphonium bromide (PhsPaHBr) in ethanol. Subsequent addition of an excess of sodium ethoxide to 8 was followed by an ethanol solution of cij-3-formyl crotonic acid (9) to produce isotretinoin (1,2-cjs-vitamin A acid. 

In a 1985 patent by Hoffmann-La Roche, the Wittig condensation was also the crucial step in assembling isotretinoin (1, Scheme 2). Under the optimized conditions, 1.03 equivalents of phosphonium salt 8 was condensed with 1 equivalent of hydroxybutenolide 9 in the presence of 1.25 equivalents of 2 N KOH in isopropanol at -30°C for 1 to 1.5 h. The product (91.5% total yield) consisted of 75.9% of 2-cis-4-cis-vitamin A acid (10) and 16.7% of isotretinoin (1). Without separation, the mixture of 10 and 1 was subjected to palladium-catalyzed isomerization conditions the mixture was heated at 50°C for 1 h in acetonitrile in the presence of 0.10 mol% of palladium(n) nitrate, four equivalents (based on palladium nitrate) of triphenylphosphine and 2... 

Retinoic acid (vitamin A acid), in which the alcohol group has been oxidized, shares some but not all of the actions of retinol. Retinoic acid is ineffective in restoring visual or reproductive function in certain species in which retinol is effective. Flowever, retinoic acid is very potent in promoting growth and controlling differentiation and maintenance of epithelial tissue in vitamin A-deficient animals. Indeed, all-trans-retinoic acid (tretinoin) appears to be the active form of vitamin A in all tissues except the retina, and is 10- to 100-fold more potent than retinol in various systems in vitro. Isomerization of this compound in the body yields 13-n.v-rctinoic acid (isotretinoin), which is nearly as potent as tretinoin in many of its actions on epithelial tissues but may be as much as fivefold less potent in producing the toxic symptoms of hypervitaminosis A. 

Wohlrab, W., The influence of urea on the penetration kinetics of vitamin-A-acid into human skin, Z. Hautkr., 65, 803, 1990. 

Isotretinoin is a variant of tretinoin, which is better known as vitamin A acid, and has the chemical name 3,7-dimethyl-9-(2,6,6-trimethyl-i-cyclohexen-i-yl)-2,4,6,8-nonatetraenoic acid. Its structure contains a chain of 9 carbons with double bonds between alternative carbon pairs along the chain. Tretinoin has trans double bonds which means they... 

Vitamin A acid, especially used in the treatment of acne for some years, can also be obtained by Wittig reaction. Thus, olefination of phosphorane 506, with y-formyl-crotonic ester 509 as well as the reversed Wittig olefination, i.e. the conversion of aldehyde 511 and ylide 512 yields the ester 510 of vitamin A acid 255), according to Scheme 86. 

Cis- 13-Vitamin A acid was synthesized by Bestmann and Ermann 2565 starting from the aldehyde synthon 514, one endocyclic double bond of which already exhibits cw-configuration. Olefination of 514 with the ylide 513 affords the 2/7-pyran-2-one derivative 515, which is reduced and hydrolyzed to the cis-13-vitamin A acid 516. Applying the same synthetic technique also the aromatic analogs 517, 518 and 519 are obtained 256) (Scheme 87). 

The first synthesis of a vitamin A derivative was described by H. H. Inhoffen, D. A. von Dorp and J. F. Arens in 1944 for the vitamin A acid (retinoic acid 5)2). The first syntheses 3) of vitamin A (2), discovered independently of one another, became known in 1947, and were followed as early as 1948 by an industrial... 

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