Retinoic acid isomerization

Isomer interconversion due to assay manipulations could also be determined from the recovery experiment. Isomerization data was obtained from the radioactivity profile of the HPLC purification step. The amount of cis isomerizing to trans was 3%. The same amount of trans retinoic acid isomerized to cis. The assay causes a small amount of isomerization but to an equal extent for both isomers. 

Baillet, A., Corbeau, L., Rafidson, R, and Ferrier, D., Separation of isomeric compounds by reversed-phase high-performance liquid chromatography using Ag+ complexation. Application to cis-trans fatty acid methyl esters and retinoic acid photoisomers, /. Chromatogr., 634, 251, 1993. 

Babler and Schlidt [86] described a route to a versatile C15 phosphonate, used for a stereoselective synthesis of all E retinoic acid and p-carotene. Base-catalyzed isomerization of the vinyl-phosphonate afforded the corresponding allyl-phosphonate as the sole product. Homer-Emmons olefination with ethyl 3-methyl-4-oxo-2-butenoate concluded the facile synthesis of all E ethyl retinoate. The C15 phosphonate was synthesized starting from the epoxide of P-ionone. Subsequent isomerization with MgBr2, afforded the C14 aldehyde in 93%... 

Retinol can be oxidized to retinal (6.2) and further to retinoic acid (6.3). Cis-trans isomerization can also occur, e.g. the conversion of all trans-retinal to 11-cis-retinal (6.4), which is important for vision. 

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. 

Post-ingestion from a-, (3- y-carotene other carotenes Sir Douglas Mawson nobly denied himself but gave dog liver to his fellow Antarctic explorers who died of Vitamin A poisoning Post-ingestion from a-, (3- y-carotene other carotenes thence isomerization of all /rcm.s-Retinoic acid... 

With hydroxylamine, al -trans, ll-c/5-, and 13-cw-retinal gave a mixture of the syn- and anti-oximes, whereas 11,13-di-cw-retinal gave only the syn-oxime/ The synthesis of the dansyl-lysyl-lysine-N-retinylidene Schiff base has been described/ The products of a colour reaction of retinoic acid (121) in 74% H2SO4 have been identified as (122) and (123)/ The oxidation and isomerization of retinoic acid by I2 and light have been used to prepare the a -trans- and 13-CI5-isomers of 4-oxoretinoic acid (124) which were separated by h.p.l.c/ The photoisomerization of the retinoid (125) has been studied. The many isomers produced were separated by h.p.l.c. and characterized by H and n.m.r. ... 

A quantum chemical study of the mechanism of the cis-trans photochemical isomerization in retinal like protonated Schiff bases uses the model compound 1-imino-2.3-pentadiene23. The lowest excited state is B like but the second A like state is particularly labile photochemically. The photoisomerization of all trans-retinal has been studied in a variety of organic solvents and organized media232 The structure of the isomers involved in the photoisomerization of retinoic acid and photoprotective effects in model physiological solutions have been determined233. picosecond time-resolved absorption study of... 

Ci s-retinoic acid is a version of vitamin A that, along with all-trflMS-retinoic add, is used as a hormone. 9-OS KA binds to a protein called RXR, while albfra is-RA binds to RAR. 9-Cfs-RA can be formed by cleavage of dietary 9-cr S p Carotenc, or from the enzymatic isomeristation of all-fr HS-RA, at a singJe double bond, 9-Ci s-P-carotene is typically present in the diet, but since it is not a required nutrient and i.s not a vitamin, it is apparent that isomerization of a /M .s-RA may supply ali the 9-l j b-RA that is needed. 

Retinoic acid, an endogenous retinoid, is a potent inducer of cellular differentiation. Because cancer is fundamentally a loss of cellular differentiation, circulating levels of retinoic acid could play an important role in chemoprevention. However, physiological concentrations are typically below the limits of HPLC detection. Sensitive techniques, such as negative chemical ionization (NCI) GC/MS have been employed for quantification, but cause isomerization and also fail to resolve the cis and trans isomers of retinoic acid. Normal phase HPLC can resolve the cis and trans isomers of retinoic acid without isomerization, and mobile phase volatility makes it readily compatible with the mass spectrometer. Based on these considerations, a method combining microbore normal phase HPLC separation with NCI-MS detection was developed to quantify endogenous 13-cis and all-trans retinoic acid in human plasma. The limit of detection was 0.5 ng/ml, injecting only 8 pg of retinoic acid onto the column. The concentration of 13-cis retinoic acid in normal, fasted, human plasma (n=13) was 1.6 +/- 0.40 ng/ml. 

Most assays for the quantification of endogenous levels of 13-cis and all trans retinoic acid utilize GC/MS. This technique is highly sensitive, but GC isomer resolution is an inherent problem (22). Therefore, unequivocal quantification of cis and trans retinoic acid levels is impossible. The use of HPLC can eliminate isomerization, but lacks sensitivity. Therefore, HPLC in combination with MS should provide a highly sensitive method of quantification without isomerization. In this report, we describe the use of microbore normal phase HPLC/NCI-MS to quantify endogenous levels of 13-cis and all trans retinoic acid in human plasma. 

Physical Methods.—Separation and Assay. A range of isomers of astaxanthin (8) diacetate (9-cis, 13-cis, 15-cis, 9,9 -di-cis, 9,13-di-cw, 9,13 -di-cw, 13,13 -di-cw, 13,15-di-cw), prepared by thermal and iodine-catalysed isomerization of irans-(S) have been separated by h.p.l.c.126 A procedure has been developed for separation of bean leaf etioplast pigments, including carotenoids,127 by h.p.l.c. H.p.l.c. separations of esters of all-trans-, 9-cis-, 11-cw-, and 13-cw-retinol,128-130 and determinations of retinol in serum,131 retinol and 13-cw-retinoic acid,132 and the aromatic retinoid (195)133 in plasma have been described. A reversed-phase ion-pair... 

Chemical structure of a -tmns retinol (vitamin Ai), the most active form of vitamin A. Oxidation of C15 to an aldehyde or an acid produces, respectively, retinaldehyde (retinal) and retinoic acid. The cis-trans isomerization of the double bond between Ci i and C12 occurs during functioning of retinaldehyde in vision. 

Tsukada, M., Schroder, M., Roos, T.C., Chandraratna, R.A., Reichert, U., Merk, H.F., Orfanos, C.E. and Zouboulis, C.C. (2000) 13-cis retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoid acid receptors. The Journal of Investigative Dermatology, 115, 321-327. 

Creech Kraft, J. Juchau, M.R. Xenopus laevis A model system for the study of embryonic retinoid metabolism. III. Isomerization and metabolism of all-trares-retinoic acid and 9-cis-retinoic acid and their dysmorphogenic effects in embryos during neurulation. Drug Metab.Dispos., 1995, 23, 1058-1071... 

A group of compounds described as vitamin A (retinol) includes those that, within their molecules, possess the characteristic (3-ionone ring and the isoprene chain. They are capable of forming molecules of polyene alcohol, aldehyde, acid, and ester (retinal, retinoic acid, and retinyl palmitate, respectively) (Figure 7.1). They can occur in many isomeric forms as groups of compounds possessing diversified prop-... 

Chemical structure (Figure 1). Molecules formally composed of four isoprene units they naturally occur as an alcohol (retinol), an aldehyde (retinal), or as an acid (retinoic acid). From each of the three basic forms two variants exist vitamin A, with a jS-ionone ring and vitamin A2 with a dehydrated S-ionone ring. Native retinoids show cis-trans isomerism of the double bonds. Carotenoids are proforms of vitamin A (Figure 2). 

Cisoid retinoids have been isomerized to give the corresponding trans compounds by catalysis with iodine (Cainelli etal, 1973 Reif and Grassner, 1973). Methyl (13Z)-retinoate (176) has been converted to (all- )-retinoic acid (3) by being treated at room temperature with potassium amide in toluene and hydrolysis of the product obtained (Matsui, 1962). Homogeneous catalysis of a mixture of (9Z)-retinyl acetate (366) and (all- )-retinyl acetate (9) in the presence of palladium(II) chloride/acetonitrile adducts gave, by isomerization, a mixture more concentrated in (9), and pure (all- )-retinyl acetate (9) was then isolated in crystalline form from the latter mixture (Stoller and Wagner, 1975 Fischli et al., 1976). 

Another direct method of converting (all- )-retinoic acid (3) to the two isomeric 4-oxoretinoic acids (188) and (193) consisted in irradiating (3) in the presence of iodine. It was possible to separate (188) and (193) by HPLC (McKenzie et al., 1978b). 

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