Retinoid analogues

Vitamin A and its retinoid analogues have gained popularity in the treatment of acne and other dermatological diseases (see Chapter 41). 

Further sulfoxide elimination led to the formation of dienoate esters, including a novel retinoid analogue (Eq. 93) [271]. More recent chemistry involved 1,2-Stevens rearrangement to gain access to aminoacid analogues (Eq. 94) [272]. The second strategic use involves the addition of alcohols to the... 

Retinoids failed to activate NADPH oxidase in dibutyryl cAMP differentiated HL-60 cells (Seifert and SCHACHTELE 1988). In HL-60 cells retinoids have been found to potentiate formyl-methionyl-leucyl-phenylalanine-induced and phorbol myrist-ate acetate-induced 02 formation (Seifert and SchAchtele 1988). Using receptor specific retinoid analogues it was demonstrated that retinoid X receptor-retinoic acid receptor heterodimers mediate retinoid-induced differentiation of HL60 cells, while retinoid X receptor-retinoid X receptor homodimers mediate subsequent retinoid-mediated apoptosis (Nagy et al. 1995, Kizaki et al. 1996). 

In the preparation of trifluoromethyl retinoid analogues 1837 as anticancer agents [1328], a key intermediate, 3-trifluoromethylpropenal 1836 was synthesized by Swem oxidation of the corresponding alcohol 183S. 

The 9-ds-P-carotene gives rise to 9-cis-retinoic acid which has retinoid activity and 11-ds-P-carotene yields 11-ds-retinol which is central to the regeneration of rhodopsin in the eye. It is not known if other -carotene ds-isomers produce biologically active retinoids. There is currently some debate as to whether some of the other carotenoids can give rise to other biologically active retinoid analogues. 

Topical therapy is the initial drug treatment strategy for patients with mild to moderate psoriasis. It is estimated that approximately 70% to 80% of all patients with psoriasis can he treated adequately with use of topical therapy.1 Topical therapies include corticosteroids, coal tar products, anthralin, vitamin D3 analogues such as calcipotriol, retinoids such as tazarotene, and topical immunomodulators such as tacrolimus and pime-crolimus.18 Vitamin D3 analogues and topical retinoids all affect keratinocyte functions and the immune response. Currently, these are in wider use than is either anthralin or coal tar preparations. 

Retinoids are a family of naturally occurring and synthetic analogues of vitamin A. The skin of subjects deficient in vitamin A becomes hyperplastic and keratotic (phrynoderma, or toad skin). While natural vitamin A is occasionally employed therapeutically, synthetic retinoids are more effective and represent a major advance in dermatological pharmacotherapy. Retinoids have myriad effects on cellular differentiation and proliferation it is likely that nuclear retinoic acid receptors mediate these effects by activating gene expression in a manner analogous to receptors for steroid hormones and thyroid hormones. Despite a common mechanism of action, however, retinoids vary widely in their physiological effects. 

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. 

These researchers also described further syntheses of modified retinoids such as 9-demethyl- 14-carboxyretinoic acid [76], 9-methylene-13-demethyl analogues of natural retinoids [77], aromatic 9-methylene and 13-demethyl-retinol, retinal, and ethyl 13-demethy 1-9-methylene retinoate [78], Fig. (43). 

Retinoic Acid Receptor. Most of the biological effects of retinoids are mediated through the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). Both all-/ran.s-retinoic acid and 9-d.v-rctinoic acid serve as agonists of RAR, while only 9-d.v-rctinoic acid functions as an agonist of RXR. The functional RAR exists as a heterodimer with RXR, while functional RXR exists as a homodimer. Methoprene is a juvenile hormone III analogue that mimics the activity of this insect hormone. 

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. 

Interference with matrix production Proline analogues Prolyl hydroxylase inhibitors Interferon-y Retinoids... 

Griffiths, C.E.M. Retinoids vitamin D analogues action on nuclear transcription, Hasp. Med., 59,... 

Benzofurotriazoles 353 were prepared and their activity in the inhibition of CYP26A1 evaluated in a MCF-7 cell assay. These compounds are analogues of the advanced pharmaceutical candidate liarozole, 354 <2006MIP308-86>. CYP26A1 catalyzes the metabolism of all-/ra j retenoic acid (ATRA) and is believed to be principally responsible for controlling the levels of this retenoid. Elevated levels of ATRA are used to treat hormone refractory prostate cancer and psoriasis. It is hoped that inhibition of CYP26A1 will limit the development of resistance to these retinoid treatments. 

Silicon analogues 105b,d of known pan-RAR selective retinoid agonist TTNPB 105a were synthesized from ketones 106 by a Wittig reaction followed by hydrolysis (07CBC1688) (Scheme 19). 

The term vitamin A currently is applied to compounds posse.s.sing biological activity like that of retinol. The term vilamiii Ai refers to all-/ i .v-retinol. The term retinoid is applied to retinol and its naturally occurring derivatives plus synthetic analogues, which need not have vitamin A activity. 

Introduction.—This Report covers the literature published up to approximately the end of September, 1981. Few new carotenoid structures have been reported. The main advances in carotenoid chemistry have been in the stereospecific synthesis of carotenoids with chiral end-groups. Current interest in the possible use of retinoids in cancer chemotherapy has prompted the preparation of a considerable number of retinoic acid analogues. There has been no major new development in the use of physical methods but h.p.l.c. becomes more and more the method of choice for carotenoid separation, purification, and assay, and the increasing number of papers on resonance Raman spectroscopy emphasizes the potential value of this technique in the carotenoid field. 

Natural and synthetic compounds with vitamin A activity and inactive synthetic analogues of vitamin A are collectively termed retinoids. The most biologically active. 

Ito, M., Kodama, A., Hiroshima, T., and Tsukida, K., Retinoids and related compounds. Part 9. Synthesis and spectral characteristics of retinal analogues involving the ll- s-locked-cyclopentatrie-nyhdene structure, 7. Chem. Soc., Perkin Trans. 1, 905, 1986. 

---