Retinoic

Brent et al., 1989] Brent, G. A., Dunn, M. K., Harney, J. W., Gulick, T., and Larsen, P. R. Thyroid hormone aporeceptor represses Ta inducible promoters and blocks activity of the retinoic acid receptor. New Biol. 1 (1989) 329-336 [Cevc and Marsh, 1987] Cevc, G., and Marsh, D. Phospholipid Bilayers Physical Principles and Models. John Wiley Sons, New York, 1987. 

Retinal trans-Retinal [116-31-4] Retinaldehyde [116-31-4] Retinitis pigmentosa Retinoblastoma Retinoic acid... 

Table 16. Retinoic Acids, Vitamin D, and Type II Receptor Agonists and Antagonists...

Tretinoin, the - -trans isomer of retinoic acid [302-79-4] was shown in the 1960s to be useful for the treatment of disorders associated with abnormal epithehal differentiation. 

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). 

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. 

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). 

Retinoic acid (vitamin A acid). Retinol (vitamin A... 

Retinal (Vitamin A aldehyde). Retinoic acid (Vitamin A acid), Retinyl acetate, Retinyl palmitate see entries in Chapter 4. 

CPR can be used to find continuous paths for complex transitions that might have hundreds of saddle points and need to be described by thousands of path points. Examples of such transitions include the quaternary transition between the R and T states of hemoglobin [57] and the reorganization of the retinoic acid receptor upon substrate entry [58]. Because CPR yields the exact saddle points as part of the path, it can also be used in conjunction with nonnal mode analysis to estimate the vibrational entropy of activation... 

Figure 10.12 Response elements for heterodimers of the nuclear receptor for ds-retinoic acid (RXR) with the receptors for vitamin D (VDR), thyroid hormone (TR) and trans-retinoic acid (RAR). The half-sites of these response elements have identical nucleotide sequences and are organized as direct repeats. They differ in the number of base pairs in the spacer region between the half-sites. This difference forms the basis for the ability of the heterodimers to discriminate between the different response elements.

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). 

H. E. Ang, E. Deltour, T. E. Hayamizu, M. Zgombic-Knight and G. Duester, Retinoic acid synthesis in mouse embiyos during gasti ulation and craniofacial development linked to class IV alcohol dehydrogenase gene expression , /. Biol. Chem. 271 9526-9534(1996). 

H. M. M. Arafa, E. M. A. Hamada, M. M. A. Elzamai and H. Nau, Eully automated detemination of selective retinoic acid receptor ligands in mouse plasma and tissue by reversed-phase liquid chi omatography coupled on-line with solid-phase extraction , 7. Chromatogr. A 729 125-136 (1996). 

Common Name Vitamin A acid retinoic acid Structural Formula ... 

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. 

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