Retinoic acid active isomers

The physiological hormone for the RARs is all-frans-retinoic acid RA 221 and that for the RXRs is its geometric isomer, 9-czs-retinoic acid (9-czs-RA 222) [320]. However, these polyolefinic hormones are of only limited use in elucidating the precise biological roles of each receptor family. Synthetic ligands that specifically activate only the RXR or RAR hormonal pathway and which cannot be converted into forms that activate the other pathway would be of much greater use in this regard. 

Retinyl esters and the P-carotene are incorporated into chylomicrons and taken up mainly by hepatocytes. In the liver retinol may be stored in stellate cells as retinyl esters, oxidized to retinoic acid or liberated into cells bound to retinol-binding proteins (RBP). All E retinoic acid and its 9Z isomer have an affinity for nuclear receptors. They activate the transcription and bind as dimers to specific nucleotide sequences, present in promoters of target genes. 

Another study45 used the 2H 7jz anisotropy of CD3 groups in 6-5-civ-retinoic acid, in 6-5-frans-retinoic acid (Fig. 16a) and in the membrane protein bacteriorhodopsin regenerated with CD3-labelled retinal (Fig. 16b) to examine the motion of the CD3 groups. It was found that for both forms of retinoic acid, a three-site hopping model fitted the experimental data, but with the difference that the activation energy for the cis isomer was 14.5 1 kJmol-1 whereas for the... 

Idres, N., J. Marill, M.A. Flexor and G.G. Chabot. Activation of retinoic acid receptor-dependent transcription by all- rauw-retinoic acid metabolites and isomers. J. Biol. Chem. 277 31491-31498, 2002. 

In 1982 the Food and Drug Administration (FDA) approved the oral use of isotretinoin (Accutane) for the treatment of severe nodulocystic acne that has not responded to antibiotics. This drug is not active topically. As the name suggests, isotretinoin is an isomer of tretinoin. The only structural difference between the two molecules lies in the spatial arrangement of the atoms around one carbon-carbon double bond. Isotretinoin has the chemical name 13-cA-retinoic acid. Through mechanisms not well understood, it decreases the size of the sebaceous glands and inhibits closure of the pore. These actions may diminish the ultimate formation of cysts. As is... 

AA - 861) inhibited the biosynthesis of LTD, LTB, and 5-HETE in RBL-1 extracts at a concentration of 1 pM (70-80% inh.). Bay 0 8278 (14)inhibits the formation of LO products 5-HETE, 12-HETE, 15-HETE, LTB, and its isomer in rabbit and human PMN s. LC-6 (15) has the ability to inhibit AA 5-LO activity. A correlation was observed between known antipsoriatic drugs (resorcinol, salicyclic acid, anthralin, AA, ETYA, mycophenolic acid, trans-retinoic acid and etretinate) and their inhibitory activity with soybean LO. Calmodulin (CM) antagonists trifluoroperamine, chlorpromazlne and dlphenylbutlamlne inhibited 5-LO from RBL-1 cells with potencies (IC-q 5.6, 9.6 and 8.3 pM, respectively) similar to those reported for their CM antagonism. 13-cis retinoic acid (Ro 4-3780) is a selective inhibitor of 5-LO with an of 9 pM. ... 

Although it appears that the isomerization of all-rra s-retinoic acid to the 13-cis isomer is a physiological event, the importance of this step is not known. The 13-cw-retinoic acid is equivalent in biological activity to all-rrans-retinoic acid, both in vivo (Zile and DeLuca, 1968) and in vitro (Newton et al., 1980). More work is needed, however, before it can be determined whether isomerization of retinoids might be an important event in the control of epithelial differentiation as has already been shown to be the case for the visual cycle. 

The 9-ds-P-carotene gives rise to 9-cis-retinoic acid which has retinoid activity and 11-ds-P-carotene yields 11-ds-retinol which is central to the regeneration of rhodopsin in the eye. It is not known if other -carotene ds-isomers produce biologically active retinoids. There is currently some debate as to whether some of the other carotenoids can give rise to other biologically active retinoid analogues. 

Embryos depend on the maternal uptake of retinol which must be metabolized to active retinoic acid isomers in order to fulfill all of its roles in vertebrate development. During vertebrate embryogenesis RA is detected in distinct spatiotemporal patterns (32, 37) suggesting that... 

The Matsui condensation of p-ionylideneacetaldehyde (I) and methyl senecio-ate-2,3- " C2 (XV), carried out in anhydrous ether (Manchand et al, 1965) with potassium amide, furnished a crude product in 76% yield containing dXVtrans-retinoic-13,14- " 2 acid (Vllb) and its 13-cis isomer in a ratio of about 2 1. The pure all-trans acid, with a specific activity of 51 mCi/mmol, was obtained by crystallization. 

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