Retinoids structures

Attractive alternative to oral retinoid therapy in psoriasis (e.g., etretinate), primarily due to less toxicity. Structural changes to the basic retinoid structure (e.g., conformational rigidity) are claimed to enhance therapeutic efficacy and reduce the local toxicity associated with topical tretinoin (retinoic acid). However, place in therapy should await direct comparisons vs standard regimens in terms of efficacy, toxicity, and cost... 

Drug Based on the Retinoid Structure Used to Treat Psoriasis (Fig. 8.8), 373... 

Drug Based on the Retinoid Structure Used to Treat Psoriasis (Fig. 8.8). Etrinate is the ethyl ester of acitretin and is active after hydrolysis to the acidic drug. The terminal" half-life after 6 months of etrinate therapy is 120 days. In contrast, the terminal" half-life of acitretin is only 33-96 h. Both drugs are... 

Figure 8.8. Drug based on the retinoid structure used to treat psoriasis.

Several other assays of retinoid activity exist [83] and include evaluations of the ability of a retinoid to inhibit the exponential growth of S91 murine melanoma cells or to induce terminal differentiation of the fully neoplastic F9 teratocarcinoma cells. These and other assays of retinoid activity have been useful but the TOC, ODC, and HL-60 assays have been used most comprehensively in establishing retinoid structure-activity relationships, which are discussed below. 

The relationship between retinoid structure and retinoid activity has been extensively studied. Because of the large number of geometric isomers and conformers possible with the conjugated retinoid skeleton, a multitude of isomeric and/or conformationally-locked retinoids have been synthesized to determine the shape and size of the binding site of the putative retinoid receptor. Several methods exist for evaluation of retinoid activity. A fair... 

Maintenance of a cisoid restricted conformation about bonds C-6—C-7 and C-12—C-13 (structures types II and III) can provide activity equal to or better than that exhibited by all-rra/w-retinoic acid in most assays. TTNPB (3), TTNN (4), and (R12) (see Table 1.1) are marked by these restrictions and are parents to other type-II retinoids. In the induction of terminal differentiation of HL-60 and U-937 cells, however, removal of the latter conformational restriction results in enhanced activity. The tetramethyl-tetrahydronaphthyl-octatrienoic retinoid (structure type I, X=CMc2, aromatic ring B) is more potent than TTNPB, especially when either retinoid is administered in combination with cytokines (see POTENTIATIVE AND SYNERGISTIC EFFECTS USING RETINOIDS IN COMBINATION WITH CYTOKINES AND OTHER HORMONES below). 

The presence of a carboxyl terminal group is necessary for binding to CRABP and for retinoid activity [2]. However, comparison of other retinoid structural features shows a lack of correlation between retinoid potency and affinity for CRABP. Some potent retinoids do not bind to CRABP but do bind to nuclear retinoid receptors such as the RARs [146-149]. One such retinoid has been reported to be equally or more potent than RA but has lower affinity for RARs than RA [149]. It has been suggested that the reason for this apparent anomaly may be that the potency of RA is reduced because of its ability to bind to endogenous CRABP. It appears, therefore, that one of the functions of CRABP may be to regulate the amount of intracellular-active RA and thus control quantitatively the intensity of biological effects [149]. ... 

The prefix retro stated together with two positions of a retinoid structure indicates a shift in the conjugated polyene system. The first position gives the carbon atom from which a proton has been formally transferred to the carbon atom at the second position, e.g., 14-hydroxy-4,14-retroretinoic acid methyl ester (30) and 4,14-retroretinyl acetate (31). 

A number of interesting observations may be derived from the electronic spectra of novel retinoid structures. Table III shows the absorption data of isomeric retinaldehydes. 

The substitution pattern in the tetraene side chain of retinoids has been varied in a number of ways. In most cases, this structural variation was effected with a view to obtaining molecules with particular biological properties. Extensive investigations into the syntheses of retinoid structures substituted in the olefinic region by fluorine have been carried out. To synthesize these compounds, the well-tested reactions with phosphoranes or PO-activated ylids were carried out usihg fluorine-substituted building blocks. 

In the structure (553), the C-5-C-8 diene moiety of a typical retinoid structure is incorporated in a phenyl ring. As a result, the C-6—C-7 single bond is fixed in the cisoid configuration. Thus (553a) was prepared by reacting the phosphonium bromide (552a) with the formylcarboxylate (169) in the presence of butylene... 

The silylenol ether formed from (47) and trimethylchlorosilane was cyclized in situ, and the reaction mixture was worked up under acidic conditions to give the ketone (558). This was subjected to reduction with sodium borohydride, acid-catalyzed elimination of water, and oxidation with dichlorodicyanobenzoquinone (DDQ) to give the bicyclic ester (560). Introduction of a methoxy substituent into the retinoid structure (560) was likewise effected via the ketone (558). When this ketone was ketalized with methyl o-formate, methanol was eliminated and the product was oxidized, its six-membered ring system undergoing aromatization to form a substituted phenyl group. 

Retinoid structures have been synthesized in which the terminal functional group is formally incorporated in a heterocyclic ring system. (all- )-Retinonitrile (156) reacted with aluminum azide to give the acidic tetrazole (635) (Dawson et aL, 1980). 

The aryltetraene compounds (660) and (661) have been regarded as 13-cis retinoid structures that incorporate a phenyl ring in a manner such that isomerization to the all-trans form is impossible. Thus, (660) and (661) can be regarded as analogs of (13Z)-retinoic acid (17) and (1IZ, 13Z)-retinoic acid, respectively, in which the double bond is fixed in a cis position in the phenyl ring. 

Old. A large number of H-NMR and C-NMR spectra of geometric isomers of the naturally occurring retinoids and of their synthetic derivatives have been published (8-13). By recording H-NMR and C-NMR spectra and comparing the spectra with the data available m the data banks, it is possible in most cases to determine the configuration of a novel retinoid structure rapidly and reliably. (For a more detailed description, see Frickel in ref. 1.)... 

Kleywegt, G J, Bergfors, T., Senn, H., Le Motte, P, Gsell, B., Shudo K., and Jones, T. A. (1994) Crystal structures of cellular retinoic acid binding proteins I and II in complex with all-trans-retinoic acid and a synthetic retinoid. Structure 2, 1241-1258... 

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