Aromatic retinoids

Likewise, retinoic acid (11) and its derivatives [40,41], as well as synthetic aromatic retinoids (arotinoids) [42,43], inhibited A23187-stimulated release... 

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. 

It is a metabolite of the aromatic retinoid, etretinate used in the treatment of psoriasis. 

Acitretin (Soriatane), a metabolite of the aromatic retinoid etretinate, is quite effective in the treatment of psoriasis, especially pustular forms. It is given orally at a dosage of 25-50 mg/d. Adverse effects attributable to acitretin therapy are similar to those seen with isotretinoin and resemble hypervitaminosis A. Elevations in cholesterol and triglycerides may be noted with acitretin, and hepatotoxicity with liver enzyme elevations has been reported. Acitretin is more teratogenic than isotretinoin in the animal species studied to date, which is of special concern in view of the drug s prolonged elimination time (more than 3 months) after chronic administration. In cases where etretinate is formed by concomitant administration of acitretin and ethanol, etretinate may be found in plasma and subcutaneous fat for many years. 

Fontan B, Bonafe JL, Moatti JP. Toxic effects of the aromatic retinoid etretinate. Arch Dermatol 1983 119(3) 187—8. 

A study of the sensitized photochemical behaviour of the aromatic retinoids (177) has shown that they undergo (4 + 2)-cyclodimerisations. The photo reactions of the pentaenals (178) has been reported. 

Directly (thalidomide, cytotoxic drugs, antithyroid drugs, aromatic retinoids, e.g. isotretinoin) any drug affecting cell division, enzymes, protein synthesis or DNA s)mthesis, is a potential teratogen, e.g. many antimicrobials. 

PUVA (liver function, antinuclear antibodies) Aromatic retinoids (liver function, plasma lipids). 

In 1990, etretinate (Tigason) was replaced by acitretin (Neo-Tigason), an aromatic retinoid, a carboxylic acid metabolite of etretinate (15). It is effective in pustular psoriasis and psoriatic palmoplantar keratoderma and in combination with PUVA or topical therapy (calci-potriol or glucocorticoids) in the treatment of other forms of psoriasis. It has also been used to treat disorders of keratinization (ichthyosis, palmoplantar keratoderma, Darier s disease) and severe cutaneous forms of lichen planus. It prevents new skin carcinomas in patients with xeroderma pigmentosum and those who are immunosuppressed. The main advantage of acitretin is its short half-life of 50 hours, compared with over 80 days for etretinate (16). 

Physical Methods.—Separation and Assay. A range of isomers of astaxanthin (8) diacetate (9-cis, 13-cis, 15-cis, 9,9 -di-cis, 9,13-di-cw, 9,13 -di-cw, 13,13 -di-cw, 13,15-di-cw), prepared by thermal and iodine-catalysed isomerization of irans-(S) have been separated by h.p.l.c.126 A procedure has been developed for separation of bean leaf etioplast pigments, including carotenoids,127 by h.p.l.c. H.p.l.c. separations of esters of all-trans-, 9-cis-, 11-cw-, and 13-cw-retinol,128-130 and determinations of retinol in serum,131 retinol and 13-cw-retinoic acid,132 and the aromatic retinoid (195)133 in plasma have been described. A reversed-phase ion-pair... 

Asato, A.E., Peng, A., Hossain, M.Z., Mirzadegan, T., and Bertram, J.S., Azulenic retinoids. Novel nonbenzenoid aromatic retinoids with anticancer activity, 7. Med. Chem., 36, 3137, 1993. Hashizume, H., Ito, H., Kanaya, N., Nagashima, H., Usui, H., Oshima, R., Kanao, M., Tomoda, H., Sunazuka, T., Nagamitsu, T., Kumagai, H., and Omura, S., Synthesis and biological activities of new HMG-CoA synthase inhibitors. 2-Oxetanones with a side chain containing biphenyl, terphenyl or phenylpyridine. Heterocycles, 38, 1551, 1994. 

Adtretin is a second-generation retinoid. Acitretin (Soriatane) is the major metabolite of etretinate, an aromatic retinoid that formerly was approved for psoriasis but withdrawn from the market because of its undesirable pharmacokinetics. Acitretin has an elimination half-Ufe of 2 to 3 days. 

Bun, H. al-Mallah, N.R. Aubert, C. Cano, J.P. High-performance liquid chromatography of aromatic retinoids and isotretinoin in biological fluids. Methods Enzymol., 1990, 189, 167-172... 

Kochhar, D.M. Penner, J.D. Minutella, L.M. Biotransformation of etretinate and developmental toxicity of etretin and other aromatic retinoids in teratogenesis bioassays. Drug Metab.Dispos., 1989, 17, 618-624... 

Retinoids include natural compounds and synthetic derivatives of retinol that exhibit vitamin A activity. First-generation retinoids include retinol, tretinoin (aU-ironi-retinoic acid), isotretinoin (13-cu-retinoic acid), and alitretinoin (9-cw-retinoic acid). Second-generation retinoids, also known as aromatic retinoids, were created by alteration of the cyclic end group and include acitretin. Third-generation retinoids contain further modifications and are called arotinoids. Members of this generation include tazarotene and bexarotene. Adapalene, a derivative of naphthoic acid with retinoid-like properties, does not fit precisely into any of the three generations. 

Several retinoids have recently been reported which exhibit similar potency relative to retinoic acid but which may prove to be less toxic than RA and which may exhibit selective anti-cancer activity. These agents belong to the class of retinoids termed heteroarotinoids [27-31,63,65-67]. Heteroarotinoids are heterocyclic analogues of the arotinoids [11,63,68], which are potent aromatic retinoids that include the well-studied compound (3), TTNPB, [4-(( )-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl)benzoic acid], and compound (4), TTNN, 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-naphthanoic acid. The most recent developments in heteroarotinoid research will be addressed below. 

Additionally, Shudo and co-workers [20,22-24,69] have recently designed a series of retinoidal benzoic adds with promising anti-cancer activity, espedally as indicated by the HL-60 assay. The structure of these aromatic retinoids resemble that of TTNPB but contain a different conjugated group [that is, NHCO, CONH, SO NH, COCH=CH, N=N, or N=N(0)] in place of the central propenyl group. Although these compounds have been discussed in a previous review [16], the synthesis and anti-leukaemic activity... 

A new class of aromatic retinoids that are biologically very active has been described by Loeliger et al (1980). These compounds have been called arotinoids or in a more general way retinoidal benzoic acid derivatives. One of their important features is their greatly increased chemical stability, which is a result of the aromatization of the chromophoric system. Therefore, the stability of these compounds in a labeled form should also be increased, which would greatly enhance their utility in biological experimentation. 

A radioimmunoassay method has been developed for the measurement of retinol and its derivatives in plasma (Conrad and Wirtz, 1973 Westfall and Wirtz, 1980 Wirtz and Westfall, 1981). Antibodies to retinoids are produced by injecting a conjugate of retinoic acid and albumin into rabbits. The antisera produced reacted well (K = 2 x 10 L/M) with a -trans-rttinoic acid, reti-naldehyde, retinol, and retinyl phosphate, less well with cis isomers, and poorly with retinyl palmitate, 3-carotene, and aromatic retinoids. As little as 1-2 ng of retinol could be detected in serum by this procedure. 

Etretinate, a synthetic aromatic retinoid, has been used as an investigational drug in many thousands of patients throughout the world for various dermatologic disorders it is commercially available by prescription in several European countries for treatment of psoriasis and some disorders of keratinization. As with isotretinoin, the side effects manifested during therapy with etretinate are predominantly mucocutaneous. 

The aromatic retinoid etretinate is less effective than isotretinoin in the treatment of acne. In a double-blind study, 56 men received either isotretinoin or etretinate at a dosage of 1 mg/kg/day for 8 weeks. At 8 weeks posttreatment, there was a 69% reduction in the number of acne cysts and nodules in the isotretinoin group but only a 33% decrease in the etretinate group (Goldstein et al., 1982). 

Dawson MI, Hobbs PD, Derdzinski KA, Chao W-R, Frenking G, Loew GH, Jetten AM, Napoli JL, Williams JB, Sani BP et al (1989) Effect of structural modifications in the C7-C11 region of the retinoid skeleton on biological activity in a series of aromatic retinoids. J Med Ghent 32 1504-1517... 

Importantly, therapeutic efficacy of PUVA was drastically enhanced combining PUVA and oral administration of aromatic retinoid derivates such as etretinate 10 days before to starting PUVA therapy. This modality, called RePUVA, was able to reduce both the time and number of treatments necessary for complete clearance of psoriatic lesions (30%) and the UVA cumulative dose required to clear psoriasis (56%) [130,131]. Balneotherapy using 8-MOP and UVA radiation represents an alternative modality for the treatment of this skin disease [132]. 

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