Retinoids

Retinoids. The 9,11-di-cw-isomer of retinaldehyde (90) has been prepared in six steps from the C15 aldehyde (93) and used to form a 9,11-di-m-rhodopsin with cattle opsin.60 The 9,1 l-di-cw-isomer was also one of four di-cis forms obtained by irradiation of all-fra/w-retinaldehyde in acetonitrile.61 The sterically hindered 

I- cis- and 7,13-di-ciy-isomers of vitamin A [retinol (91)] have been prepared via the 1-cis photoisomerization product of the sulphone (94).62 Several isotopically labelled species of retinaldehyde and derivatives have been synthesized, including 

Broek and J. Lugtenburg, Reel. Trav. Chim. Pays-Bas, 1980, 99, 363. 

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 

A procedure for the preparation of 1-bromoacetylenes and conjugated enynes77 has been used to make the retinaldehyde derivative (126). Retro-aldol reaction of the retinylidenedimedone (127) with MeNHa gave all-Pms-retinaldehyde in 90% yield.78 Oxidation of (127) gave the 5,6- and 5,8-epoxides (128) and (130).79 The 4-acetoxy-, 4-hydroxy-, and 4-keto-derivatives (131) (X = H,OH, H,OAc, and O respectively) and the seco-compound (133) were also prepared. Compounds (128), (130 X = O), and (131) underwent retro-aldol reaction to give the aldehydes 

Retinoids play a major role in lung embryology and organogenesis, deficiencies of dietary retinoic acid 

Hind et al. (2002) described the temporal and spatial expression of the retinoid-synthesizing enzymes Aldh-1 and Raldh-2 in the postnatal mouse lung. Both enzymes are upregulated during the period of maximal alveolar wall cell proliferation. Aldh-1 is located in the bronchial epithehum and alveolar parenchyma, and Raldh-2 is restricted to the bronchial epithelium and pleural mesothelial cells. 

Retinoic acid modulated secretion of normal human tracheobronchial epithehal cells in air-hquid interface cultures (Yoon et al. 1997). 1.5 nM was re- 

The antioxidant activity of retinoids against hpid peroxidation has long been observed both in vitro (Nicotra et al. 1975, Halevy and Sklan 1987, Vile and Wintebourn 1988, Das 1989, Livrea et al. 1992) and in vivo (Kartha and Krishnamur-THY 1977, CiAccio et al. 1993). Samokyszyn and Marnett (1987) showed that 13-ris-retinoic acid may react with peroxyl radicals by addition but not H-atom abstraction. 

Retinoic acid 5,6-epoxidation was catalysed by human blood cells but not by human plasma, and purified human haemoglobin also catalysed the ep-oxidation of retinoic acid to 5,6-epoxyretinoic acid (Iwahashi et al. 1985). 

Retinoid acid is a transcription factor. Retinoids play significant roles in dermatology, in the prevention of some cancers, and in the chemistry of vision. Consequently, many works have been dedicated to fluorinated analogues of retinoids. 

By introducing fluorine atoms to the polyenic system of retinal, the geometry, electronic properties, hydrophobicity, and absorption properties of the molecule will be modified. Thus, fluoro derivatives of retinal are useful tools to understand the interactions between retinal and opsin, especially on the level of charge and hydrophobic effects at the protein site. Moreover, fluorine atoms are probes in NMR and allow studies on model molecules of visual pigments Consequently, syntheses of mono-, di-, and trifluoro derivatives of retinal have been the subject of many investigations. 

The presence of a CF3 group in 16,16,16-trifluororetinal provokes an hypsochrom effect, probably due to the torsion between the polyenic chain and the cycle. However, this effect is not necessarily accompanied by the translocation of a proton. Conversely, a CF3 group in the 13 position (20,20,20-F) maintains the proton pump 

The antitumor activities of mono-, di-, and trifluorinated analogues of retinoic acids on the polyenic chain, and also of some aromatic analogues, have been evaluated on mice papillomas. Some of these compounds exhibit superior activities to nonfluori-nated analogues.  

The majority of pubhshed syntheses of tretinoin start with readily available (3-ionone (38-1), a compound that already incorporates the highly substituted cyclohexene ring as well as four of the side chain atoms. Condensation with the carbanion from acetonitrile followed by dehydration of the initially formed carbinol gives the intermediate (38-2). Reduction of the cyano group by diisobutylaluminum hydride leads to the 

Activity is largely retained in a compound in which one of the terminal double bonds in the side chain of tretinoin is replaced by an aromatic ring. The key reaction in the constmction of this compound consists in Wittig condensation of the ylide from 

For a detailed account see CRC Handbook of Eicosanoids Prostaglandins and Related Lipids, Lewis, A. L. ed CRC Press, Boca Raton, FL, 1987. 

Murcko, M. A. Bhisetti, G. R. U.S. Patent 1996, 5,558,397. The scheme shown here is partly conjectural due to difficulty in deciphering the patent. 

Cainelli, G. Cardillo, G. Contento, M. Grasseli, R Ronchi, A. U. Gazz. Chim. Ital. 

Preformed vitamin A is found only in animals and a small number of bacteria. A number of the carotenoid pigments in plants can be cleaved oxidatively to yield retinol /S-carotene is quantitatively the most important of these provitamin A carotenoids. Although preformed retinol is both acutely and chronically toxic in excess, carotene is not, because there is only a limited capacity to cleave it to retinol. 

In addition to its provitamin A role, p - carotene is a radical trapping antioxidant and may be nutritionally important in its own right both as an antioxidant and possibly also through direct actions that are independent of retinoids. Other carotenoids that occur in foods, and circulate in the bloodstream, also have free radical trapping activity, and, hence, potential metabolic significance, whether or not they are metabolic precursors of vitamin A. 

The term vitamin A can include any compound with the biological activity of the vitamin provitamin A carotenoids, retinol, and its active metabolites. 

Free retinol is chemically unstable and does not occur to any significant extent in foods or tissues. Rather, it is present as a variety of esters, mainly retinyl palmitate. Retinyl acetate is generally used as an analytical standard and in pharmaceutical preparations. Dehydroretinol (vitamin A2) is found in freshwater fishes and amphibians it has about half the biological activity of retinol. 

Retinoic acid occurs in foods in only small amounts. In conventional biological assays, it has lower potency than retinol or retinyl esters because it is not stored, but is metabolized rapidly. Furthermore, because retinoic acid 

Anhydroretinol binds to plasma tmd intracellultn RBPs, but not to the cellular retinoic acid binding proteins (CRABPs) or retinoid receptors. In experimental animals, it protects against the development of chemicedly induced tumors while showing none of the toxic effects of other retinoids. 

---

Vitamin A constitutes the most significant sector of the commercial retinoid market and is used primarily in the feed area. In the pharmaceutical area, there are several important therapeutic dermatologic agents which stmcturaHy resemble vitamin A and they are depicted in Figure 2 (see Pharmaceuticals). The carotenoids as provitamin A compounds also represent an important commercial class of compounds with P-carotene [7235-40-7] (10) occupying the central role (Fig. 3) (9). 

Because of the presence of an extended polyene chain, the chemical and physical properties of the retinoids and carotenoids are dominated by this feature. Vitamin A and related substances are yellow compounds which are unstable in the presence of oxygen and light. This decay can be accelerated by heat and trace metals. Retinol is stable to base but is subject to acid-cataly2ed dehydration in the presence of dilute acids to yield anhydrovitamin A [1224-18-8] (16). Retro-vitamin A [16729-22-9] (17) is obtained by treatment of retinol in the presence of concentrated hydrobromic acid. In the case of retinoic acid and retinal, reisomerization is possible after conversion to appropriate derivatives such as the acid chloride or the hydroquinone adduct. Table 1 Hsts the physical properties of -carotene [7235-40-7] and vitamin A. 

More specific methods involve chromatographic separation of the retinoids and carotenoids followed by an appropriate detection method. This subject has been reviewed (57). Typically, hplc techniques are used and are coupled with detection by uv. For the retinoids, fluorescent detection is possible and picogram quantities of retinol in plasma have been measured (58—62). These techniques are particularly powerful for the separation of isomers. Owing to the thermal lability of these compounds, gc methods have also been used but to a lesser extent. Recently, the utiUty of cool-on-column injection methods for these materials has been demonstrated (63). 

Owing to the light and air sensitivity of the carotenoids and retinoids, sample handling is a critical issue. It is recommended to conduct extraction of these materials with peroxide-free solvents, to store biological samples at —70° C under argon and in the dark, to perform the analysis under yellow light, and to use reference compounds of high purity (57). 

The specific role of vitamin A in tissue differentiation has been an active area of research. The current thinking, developed in 1979, involves initial dehvery of retinol by holo-B >V (retinol-binding protein) to the cell cytosol (66). Retinol is then ultimately oxidized to retinoic acid and binds to a specific cellular retinoid-binding protein and is transported to the nucleus. Retinoic acid is then transferred to a nuclear retinoic acid receptor (RAR), which enhances the expression of a specific region of the genome. Transcription occurs and new proteins appear during the retinoic acid-induced differentiation of cells (56). 

A. P. De Leenheer, W. F. Lambert, and H. J. NeHs, eds.. Retinoids and Carotenoids iu Modem Chromatographic Ana/ysis of the Vitamins, Marcel Dekker, New York, 1992. 

M. A. Livrea and G. VidaU, eds.. Retinoids From Basic Science to C/inica/App/ications, Birkhauser Vedag, Germany, 1994. 

The retinoid isotretinoin (68) has been found to reduce the incidence of secondary malignancies in patients treated for head and neck cancer. In addition, the use of trans-m m.oic acid in patients having M3 leukemia has been reported to induce complete, although temporary, remissions (32). 

The retinoid X receptor forms heterodimers that recognize tandem repeats with variable spacings... 

Benzimidazole and benzodiazepines derivatives as retinoid antagonists 96YZ928. 

The retinoids share with certain steroid hormones the dis-I inetion of belonging to the few classes of substances capable 111 powerful positive influence on cell growth and differentia-... 

Retinoids are needed for cellular differentiation and skin growth. Some retinoids even exert a prophylactic effect on preneoplastic and malignant skin lesions. Fenretlnide (54) is somewhat more selective and less toxic than retinyl acetate (vitamin A acetate) for this purpose. It is synthesized by reaction of all trans-retinoic acid (53), via its acid chloride, with g-aminophe-nol to give ester 54 (13). 

Figure 5.2 Schematic representation of the final column-switching system (a) foi ward-flush position (b) back-flush position (further details are given in the text). Reprinted from Journal of Chromatography, A 828, A. K. Sakhi et al. Quantitative determination of endogenous retinoids in mouse embiyos by high-performance liquid cliromatography with on-line solid-phase exti action, column switcliing and electi ochemical detection , pp. 451 -460, copyright 1998, with permission from Elsevier Science.

Agents which enhance the host s response against neoplasias or force them to differentiate are termed biological response modifiers. Examples include interleukin 2 which is used to treat renal cell carcinoma, interferon a which is active against hematologic neoplasias, and tretinoin (all-trans retinoic acid) which is a powerful inducer of differentiation in certain leukemia cells by acting on retinoid receptors. Side effects include influenza like symptoms, changes in blood pressure and edema. 

The antagonist-induced conformation of nuclear hormone receptors attracts co-repressors like Nco/SMRT (nuclear hormone receptor co-repressor/silencing mediator of retinoid and thyroid receptors) which further recruit other nuclear proteins with histone deacetylase activity. Their action leads to chromatin condensation, thus preventing the general transcription apparatus from binding to promoter regions. 

CYP1B1 (chromosome 5) has been linked to primary congenital glaucoma. CYP1B1 is not regularly expressed in liver but is often found in various kinds of tumours. It metabolizes retinoids and many aromatic amines and PAHs to potentially carcinogenic products. 

Cell Cycle Control Diabetes Mellitus Retinoids... 

---