Retinoic acid analogues

A. Synthesis of Tritium-labelled Retinol and Retinoic Acid Analogues... 

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. 

The reaction of ethyl 4-(bromofluoromethyl)benzoate with triethyl phosphite at 200°C produces the corresponding a-fluorobenzylphosphonate in 68% yield. After Homer-Wadsworth-Emmons olefination, this gives fiuorinated aromatic retinoic acid analogues. - ... 

Many retinal and retinoic acid analogues have been synthesized. Many of the seven aromatic analogues of retinal (97)—(101), (103), and (104) and their geometrical isomers form stable complexes with cattle opsin, as does the allenic adamantyl retinal analogue (105) synthesized from adamantan-2-one. 5,6-Dihydro-, 7,8-dihydro, 9,10-dihydro-, 11,12-dihydro, and 9,10,11,12-tetra-hydro-retinals (106)—(110) have been synthesized from carbonyl intermediates, e.g. (Ill) prepared by selective reduction of the a,jS-unsaturation with... 

Dawson MI, Chan R, Hobbs PD, Chao W and Schiff LJ (1983) Aromatic retinoic acid analogues. 2. Synthesis and pharmacological activity. J Med Chem 26 1282-1293... 

Muccio DD, Brouillette WJ, Breitman TR, Taimi M, Emanuel PD, Zhang X, Chen G, Sani BP, Venepally P, Reddy L et al (1998) Conformationally defined retinoic acid analogues. 4. Potential new agents for acute promyelocytic and juvenile myelomonocytic leukemias. / MeJ Chem 41 1679-1687... 

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. 

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. ... 

In a comparable approach, Valla et al. [73] described the synthesis of 9-methylene analogues of retinol, retinal, retinonitrile and retinoic acid, using the p-methylenealdehyde derived from P-ionone. Homer-Emmons condensation with ethyl 4-(diethoxyphosphoryl)-3-methylbut-2-enoate carbanion afforded the ester in 55% yield, as a mixture of 13E/13Z isomers (50/50). This ethyl 9-methylene-retinoate was saponified with ethanolic NaOH to give the corresponding 9-methylene-retinoic acid in 55% yield (13 /13Z 50/50). The retinol analogue was obtained by DIBAL-H reduction of the ethyl ester (75%, 132T/13Z isomers 65/35). 

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. 

Vitamin A and its analogues, in particular retinoic acid, are involved in the proliferation and differentiation of epithelial tissues and have continued to be used in the treatment of dermatological disorders such as acne, psoriasis and hyperkeratosis [133, 134]. Currently, much effort is being focused on... 

An analogue of vitamin A, isotretinoin (Accutane), or 13-cfs-retinoic acid, is used for control of severe recalcitrant cystic acne and other keratinizing dermatoses. Oral administration of 1 to 2 mg/kg body weight daily temporarily suppresses sebaceous gland activity, changes surfece lipid composition of the skin, and inhibits kera-tinization. The therapeutic effect is resolution of lesions and, in most patients, prolonged remission of the disease. 

Tretinoin (a//-frans-retinoic acid), a natural metabolite of vitamin A, was the first vitamin A analogue to be used orally, with some success, but its general therapeutic ratio did not differ markedly from that of vitamin A itself. 

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... 

X-Ray Structures. The X-ray structure of the 9-ethyl analogue (168) of retinoic acid has been determined." The polyene chain is slightly more curved than that of retinoic acid itself, and the cyclohexene ring is rotated 64° out of the s-cis conformation. 

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. 

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... 

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