Retinoid-related compounds

It is known that retinoid-related compounds (Fig. 7) represent classes of promising antioxidative potential. A series of melatonin retinoids was synthesized using the condensation reaction sequence involving tetrahydrote-... 

Other promising retinoid-related compounds are the atypical or non-classical retinoid, N-(4-hydroxyphenyl)retinamide (fenretinide) [114,115], and the second- and third-generation RAMBAs [17]. As discussions of these promising clinical agents are beyond the scope of this chapter, readers are advised to consult recent reviews on these classes of compounds [17,114,115]. 

The invention [87] relates to the discovery that specific adamantyl or adamantyl group derivatives containing retinoid-related compounds induce apoptosis of cancer cells and therefore may be used for the treatment of cancer, including advanced cancer. It has been shown that such adamantyl compounds, e.g., 2-[3-(l-adamantyl)-4-methoxyphenyl]-5-benzimidazole carboxylic acid 135), can be used to treat or prevent cervical cancers. 

Vitamin A (retinol) and retinoic acid are carotenoid oxidation compounds that are very important for human health. The main functions of retinoids relate to vision and cellular differentiation. With the exception of retinoids, it was only about 10 years ago that other carotenoid oxidation products were first thought to possibly exert biological effects in humans and were implicated in the prevention - or promotion of degenerative diseases. A review on this subject was recently published. ... 

Although the term vitamin A has been used to denote specific chemical compounds, such as retinol or its esters, this term now is used more as a generic descriptor for compounds that exhibit the biological properties of retinol. Retinoid refers to the chemical entity retinol or other closely related naturally occurring derivatives. Retinoids also include structurally related synthetic analogues, which need not have retinol-like (vitamin A) activity. The structural formulas for the vitamin A family of retinoids are shown in Figure 66.3. Retinol (vitamin Aj), a primary alcohol, is present in esterihed form in the tissues of animals and saltwater fish, mainly in the liver. A closely related compound, 3-dehydroretinol (vitamin A2), is obtained from the tissues of freshwater fish and usually occurs mixed with retinol. 

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. 

Retinoids. A new procedure has been described for the synthesis of vitamin A [retinol (95)] and related compounds via ir-allyl Pd complexes. Thus prenyl acetate (96) with PdCl2 gave the complex (97), the structure of which was... 

Vitamin A is essential for life, and although humans and other animals are capable of modifying retinoid compounds, these species are incapable of the de novo synthesis of retinoids. Thus, dietary intake of the retinoids is crucial for the maintenance of health and prevention of vitamin A deficiency. Dietary retinoids consist of two general types (i) carotenoids, including principally jS-carotene as well as potentially hundreds of other related compounds... 

Kodama, A., Ito, M., and Tsukida, K., Retinoids and related compounds. Part 4. Synthesis of bicychc retinoates, Chem. Pharm. Bull., 30, 4205, 1982. 

Retinoids are compounds structurally related to retinol, more commonly known as vitamin A. The basic structure of vitamin A is that of a ditherpene with a hydrophobic ring on one end and an isoprenic side chain containing a polar hydroxyl group on the other. It has long been known that vitamin A has at least three distinct functions in supporting mammalian life systemic, optic and reproductive ones. 

Figure 12.1 Chemical structures of retinoids and related compounds.

Wolf G (1996) A history of vitamin A and retinoids. FASEB J 10 1102-1107 Hicks RJ (1867) Night blindness in the Confederate army. Richmond Med J 3 34-38 Moore T (1957) Vitamin A. Part I. Historical introduction. Elsevier, Amsterdam, 3-29 American Institute of Nutrition (1990) Nomenclature policy generic descriptors and trivial names for vitamins and related compounds. J Nutr 120 12-19... 

Eyrolles L, Kawachi E, Kagechika H, Hashimoto Y, Shudo K (1994) Synthesis and biological activity of car-boxyphenylquinolines and related compounds as new potent retinoids. Retinobenzoic acids. VII. Chem Pharm Bull 42 2575-2581... 

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. 

This class includes both vitamin A and the provitamin A carotenoids. All the compounds related to all-trani-retinol (Figure 19.11) are known as vitamin A. These compounds, together with their metabolites and synthetic derivatives, exhibiting the same properties are called retinoids. Vitamin A is found in animal products as retinyl esters (mainly palmitate). 

The past twenty years have witnessed considerable progress in the synthesis and use of other retinoid-like molecules related to vitamin A. The aromatic retinoid etretin (8.54) and its ester etretinate (8.55) had some effectiveness in the treatment of psoriasis, a disorder of skin. 13-cA-Retinoic acid (isotretinoin) produces sebaceous gland atrophy and could prove useful in the treatment of severe acne vulgaris. Although these compounds have toxic side effects and are not in regular use, they have opened up new therapeutic possibilities. Retinoic acid (tretinoin, 8.56) has been employed in the treatment of acne. 

Spom, Roberts and Goodman81 have recently provided a broad overview of the field of the retinoids, based on the IUPAC-IUB Joint commission definition that Retinoids are a class of compounds consisting of four isoprenoid units joined in a head-to-tail manner. (The work was updated in 1994) Whereas there is only a handful of naturally occurring retinoids using this definition, more than a thousand man-made retinoids are known. The IUPAC-IUB bulletin recommended that the term, retinal, not be used as a chemical designation but be reserved as an adjective referring to the retina. They suggested that retinaldehyde be used instead in scientific literature as the name of chemical related to vision. 

Widespread use of tretinoin and related naturally occurring retinoids is limited by undesirable side effects, which probably arise from their activation of multiple receptors. Recently, compounds selective for the retinoid X receptors... 

Although retinoic acid and other retinoids are not very useful as vitamin A substitutes in the diet, they have been found to posses therapeutic value in treating dermatologic conditions. Nevertheless, an important side effect has been found in these compounds, they have teratogenic effects [16]. In view of this, It is important to determine which structural features in retinoids are related to teratogenicity in order to design a useful retinoid without this side effect. Some studies in this direction have been seen performed in another theoretical context [15],... 

Retinoids, a group of compounds related to vitamin A which have profound effects on DNA transcription, have an inhibitory effect on cellular proliferation and have been implicated in cellular differentiation (35-37). It has been suggested that depletion of retinoic acid (RA) secondary to retinal detachment may result in morphologic and proliferative changes in RPE that ultimately lead to PVR (38). RA also markedly... 

Niunerous retinoids are now known and these cannot be represented by a single generic structure. Generic stucture types I, II, and III, however, represent the structure of most retinoids synthesized to date Figure LI). Compounds represented by structure type I include isomers and closely related analogues of retinoic acid (1), acitretin (2) and its ethyl ester (etretinate), and mono-aromatic heteroarotinoids such as (6), (15)-(17), and (54)-(57). Retinoids type II include substituted naphthalene, stilbene, azobenzene, and diaromatic amides, and other hetero-substituted analogues... 

Limb bud development is a good system in which to study the role of retinoids as morphogens. Retinoids are natural and synthetic compounds related to retinol and retinoic acid. Retinoic acid is formed by the oxidation of retinol (see Section 2.4.1), and both retinoic acid and the related metabolite 3,4-didehyd-roretinoic acid are present in the normal limb buds of chick embryos (Scholfield, Rowe Brickell, 1992),... 

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