Retinoic acid derivatives

The stmcture of vitamin A [11103-57-4] and some of the important derivatives are shown in Figure 1. The parent stmcture is aH-Zra/ j -retinol [68-26-8] and its lUPAC name is (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2,4,6,8-nonatetraen-l-ol (1). The numbering system for vitamin A derivatives parallels the system used for the carotenoids. In older Hterature, vitamin A compounds are named as derivatives of trimethyl cyclohexene and the side chain is named as a substituent. For retinoic acid derivatives, the carboxyl group is denoted as C-1 and the trimethyl cyclohexane ring as a substituent on C-9. The stmctures of vitamin A and -carotene were elucidated by Karrer in 1930 and several derivatives of the vitamin were prepared by this group (5,6). In 1935, Wald isolated a substance found in the visual pigments of the eye and was able to show that this material was identical with Karrer s retinaldehyde [116-31-4] (5) (7). 

Photoreactive aryl azide linked retinoic acid derivative (termed ADAM-3,55, Fig. 18) labeled efficiently the recombinant E-subunit and the covalent attachment was identified within residues 492 - 510 and 589 - 594, which correspond to similar sequences found in the human retinoic receptor [148]. 

The retinoids, a family of molecules that are related to retinol (vitamin A), are essential for vision, reproduction, growth, and maintenance of epithelial tissues. Retinoic acid, derived from oxidation of dietary retinol, mediates most of the actions of the retinoids, except for vision, which depends on retinal, the aldehyde derivative of retinol. 

E. Retinoic Acid Derivatives with a modified side chain and/or polar terminus... 

Topical applications of retinoic acid derivatives reduce the visible signs of aging and of photodamage,266 though there is little correlation between the histologic changes and the clinical appearance of the skin. Initial improvement in fine wrinkling and skin texture correlates with the deposition of HA in the epidermis. 

The alkylation of sulfur-stabilized anions has been the subject of an excellent recent review633. Anions adjacent to a wide range of sulfur functionalities may be alkylated readily, the most common being sulfoxide and sulfone a-anions. In the synthesis of retinoic acid derivatives and vitamin A634-636, a-sulfonyl anions have been alkylated with an co-acetoxy-containing allyl halide in good yield (equation 96). 

Retinoids (e.g. retinoic acid) are involved in development and in metabolic regulation (e.g. through induction of expression of PEPCK, the rate limiting enzyme in gluconeogenesis). Retinoic acid derives from retinol, which in turn derives from ingestion of plant a-, 3- and "/-carotenes and other carotenes. Retinoic acid acts via retinoic acid receptors and retinoid X receptors note that these receptors can heterodimerize in the nucleus with other related hormone receptors such as PPA-Rs. The developmental importance of retinoic acid is underscored by the teratogenicity of retinoic acid and other vitamin A related compounds, notably some compounds developed for anti-acne properties. 

Vitamin A (retinols) plays a role in epithelial function and the retinoic acid derivative, acitretin (Neotigason, orally), inhibits psoriatic hyperkeratosis over 4-6 weeks. Acitretin should be used in courses (6-9 months) with intervals (3-4 months). It is teratogenic, like the other vitamin A derivatives. Rigorous precautions for use in women of childbearing potential are laid down by the manufacturer and must be followed, including contraception for 2 years after cessation, because the drug is stored in the liver and in fat and released over many months. The plasma t) is 3 months. It can cause other serious toxicity (see Vitamin A, p. 739). Tazarotene, a topical retinoid, is of some benefit in mild psoriasis, but is irritant. 

Vitamin A (retinoic acid) derivatives reduce sebum production and keratmisation. Vitamin A is a teratogen. 

Balaban, A.T., Catana, C., Dawson, M. and Niculescu-Duvaz, I. (1990a). Applications of Weighted Topological Index J for QSAR of Carcinogenesis Inhibitors (Retinoic Acid Derivatives). Rev.Roum.Chim.,35, 997-1003. 

Many retinaldehyde, retinol, and retinoic acid derivatives and analogues have been synthesized. The (3i )-3-hydroxy-derivatives (98), (99), and (100) were prepared from the optically active C15 Wittig salt (31).68 9-Bromoretinaldehyde (101 trans and 9-cis), 13-bromoretinaIdehyde (102 trans and ll-cis), phenyl-retinaldehyde (103 trans and 9-cis), and p-dimethylami nophenyl retinaldehyde (104 trans) have been prepared and used to make bacteriorhodopsin analogues.69 5,6-Dihydroretinaldehyde (105) and its desmethyl analogue (106) also formed... 

Isotretinoin, a retinoic acid derivative with antiacne properties, is indicated in the treatment of severe cystic acne ume-sponsive to conventional therapy. In addition, it has been used in keratinization disorders resistant to conventional therapy. 

To this end, a small library of 29 compounds based on retinoic acid derivatives was designed and synthesized. Modifications at the C4 position at the hydrophobic ring were incorporated to prevent its oxidation. Derivatives were grouped in four major families aminonitrile retinoids (AmRs), boron-aminonitrile retinoids (BAmR), guanidine retinoids (GRs), and atypical retinoids (AR) (Figure 5.9). 

In summary, the selective activation of CMA achieved by the retinoic acid derivatives shows the potential selective targeting of autophagy processes using small molecules. 

M., Das, B.C., Gavathiotis, E., and Cuervo, A.M. (2013) Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives. 

Also based on the nomenclature rules for carotenoids is the use of the prefix nor for those retinoids that, compared with a standard structure, lack carbon atoms. The retinoic acid derivative (32) below is accordingly named 19,20-dinorretinoic acid methyl ester and retinoid (28) 5-acetyl-4,18-dinorretinoic acid. 

The base-catalyzed condensation reaction of the C15 aldehyde (4) with methyl P-methylglutaconate (536) gave the retinoic acid derivative (537), which is substituted in the tetraene side chain by an additional carboxyl group. 

Bhat and De Luca (1981) addressed this question by studying the effect of radioactively labeled retinoic acid on mannolipid formation in transformed mouse 3T12 cells. Using both thin-layer chromatography and HPLC, they were able to demonstrate the formation of a retinoic acid-derived mannolipid (MXP) with properties closely related to those of MRP. However, positive identification of MXP is still lacking. Although their results exclude the reduction of retinoic... 

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