Retinoids synthetic

Retinoids with Substituted Phenyl Rings and Miscellaneous Ring Systems 

A large number of retinoids in which the cyclogeranyl ring of the natural retinoids has been replaced by a different ring system have been prepared using the reaction sequences previously developed for the synthesis of retinol (1), 

The structure of retinaldehyde (2) was also modified by similarly substituted phenyl rings. 2-Chloro-6-fluorobenzaldehyde (219), was reacted with the C5 phosphonate (220) in the form of the PO-activated ylid, two steps being required to build the tetraene side chain (Matsumoto et al, 1980). In each case the nitrile group was reduced to a formyl group using diisobutyl aluminum hydride. 

Aldol condensation of 2,3,6-trimethylbenzaldehyde (224) with 4-(tert-butylthio)-but-3-en-2-one (225) gave (226), which was treated with methyl-lithium and finally treated under acidic conditions to give the Cj aldehyde 

4-Thiaretinoic acid (233) and 4-thiaretinol (234) were synthesized according to the (C 5 H- C3 + C2) method (Baas et al., 1966). Aldol condensation of the aldehyde (229) with acetone gave the ketone (230), which reacted with the metallized C2 phosphonate (231) to give the methyl ester (232). After hydrolysis of the ester (232), it proved possible to isolate all-trart5-4-thiaretinoic acid (233) 

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Synthetic Retinoid Receptor Selective Agonists/ Antagonists... 

These arotinoids, which were first introduced for the treatment of skin diseases, may also have potential as anticancer diugs. For example, the synthetic retinoid 6-[3-(l-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) has been shown to induce apoptosis in a variety of cancer cells including lung cancer cells in vitro, and studies concerning the use of this agent in vivo would be desirable. 

Kagechika H (2002) Novel synthetic retinoids and separation of the pleiotrophc retinoidal activities. Curr Med Chem 9(5) 591-608... 

Tazarotene is a synthetic retinoid that mediates cell differentiation and proliferation [19]. Tazarotene, a pro-drug of tazarotenic acid,has recently been proven effective as a treatment for photodamaged skin [11]. 

Pasquali, D, V Rossi, G Bellastella, A Ballastella, and AA Sinisi. 2006. Natural and synthetic retinoids in prostate cancer. Curr Pharm Des 12 1923-1929. 

Tazarotene (Tazorac) is a synthetic retinoid that is hydrolyzed to its active metabolite, tazarotenic acid, which modulates keratinocyte proliferation and differentiation. It is available as a 0.05% or 0.1% gel and cream and is applied once daily (usually in the evening) for mild to moderate plaque psoriasis. Adverse effects are dose- and frequency related and include mild to moderate pruritus, burning, stinging, and erythema. Application of the gel to eczematous skin or to more than 20% of body surface area is not recommended because this may lead to extensive systemic absorption. Tazarotene is often used with topical corticosteroids to decrease local adverse effects and increase efficacy. 

N. Krause, in Chemistry and Biology of Synthetic Retinoids, M. I. Dawson,... 

Isotretinoin, or 13-cis-retinoic acid, and etretinate are available for oral administration. Isotretinoin is a synthetic retinoid that is used for sever cystic acne, recalcitrant to standard therapies. Its mechanism of action is not well understood but involves the inhibition of sebaceous gland size and function. 

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. 

Isotretinoin is a synthetic retinoid which acts by inhibiting sebaceous gland size and function. 

Isotretinoin (Accutane) is a synthetic retinoid currently restricted to the oral treatment of severe cystic acne that is recalcitrant to standard therapies. The precise mechanism of action of isotretinoin in cystic acne is not known, although it appears to act by inhibiting sebaceous gland size and function. The drug is well absorbed, extensively bound to plasma albumin, and has an elimination half-life of 10-20 hours. 

Modulation of Mutagenesis by 3-carotene and 13-cis-Retinoic Acid. The provitamin 3-carotene, and a synthetic derivative of vitamin A, 13-cis-retinoic acid, were examined with respect to their capacity to modulate 2-fluorenamine-induced mutagenicity in Salmonella. These studies were carried out since dietary and serum levels of 3-carotene vary widely among humans. Also, there is considerable interest in the anti-tumor activity of 13-cis-retinoic acid and other synthetic retinoids. 

In no instance did the synthetic retinoid possess as great an inhibitory capacity as do retinol or retinyl acetate. In addition, the provitamin g-carotene had no effect on mutagenicity of 2-fluorenamine in Salmonella regardless of the carcinogen activation system (Tables III and IV). Thus, 3-carotene would apparently require enzymatic cleavage to vitamin A in order to have an effect in this ijri vitro bioassay and exerts no role by itself in modulating the metabolism of chemical carcinogens in the model system. 

Similar effects were observed with the synthetic retinoid 13-cis-retinoic acid, while 3-carotene was without effect in modulating the mutagenicity of aromatic amines in Salmonella. 

Dawson, M. Okamura, W. (1990) Chemistry and Biology of Synthetic Retinoids Boca Raton FI CRC Press fig. 2. 

During the 1980s, two drugs used to treat different types of skin diseases were found to be teratogenic. The drugs, generic names are isotretoin and etretinate, respectively, and they are synthetic retinoids (i.e., derivatives of vitamin A). Isotretoin (Accutane) was prescribed for the treatment of acne while etretinate was prescribed for psoriasis. 

Structurally, vitamin A and many synthetic retinoids consist of a (3-ionone ring, a polyunsaturated polyene chain, and a polar end group. The polar end group can exist in several oxidation states, as retinol, retinal, or retinoic acid. Retinol and retinyl esters are the most abundant vitamin A forms found in the body (Blaner and Olson, 1994). Retinol can be esterified with long-chain fatty acids (mainly palmitate, oleate, and stearate) to form retinyl esters, which are the body s storage form of vitamin A. Retinol also can undergo oxidation to retinal, which can be oxidized further to retinoic acid. The active... 

Natural variations in nuclear receptors reinforce the idea that nuclear receptors are good candidates for the creation of orthogonal ligand-receptor pairs. For example, the human retinoic acid receptor (RAR) has three subtypes RARa, RAR/ and RARy. These three subtypes differ at 87 amino acids but have only three divergent residues in the binding pocket [11] (Tab. 8.1). However, these three divergent residues are responsible for different binding profiles of synthetic retinoids... 

The doses of retinol that are protective in animals are in the toxic range (Section 2.5.1) and are unlikely to be useful in cancer therapy or prevention. A number of synthetic retinoids have been developed, in a search for compounds that show anticancer activity, but are metabolized, stored, and transported differently, or bind to different subtypes of retinoid receptor and are less toxic. RXR-selective ligands are less toxic and more active in animal cancer models than RAR ligands (Lippman and Lotan, 2000). Fenretinamide, and possibly other retinoids that have antitumor activity, exerts at least part of its action by induction of apoptosis by a receptor-independent mechanism (Wu et al., 2001). 

Synthetic retinoids, either specific for RAR or RXR, such as those introduced by Chen et could considerably enlarge therapeutic possibilities. 

Inhibition of dihydroceramide desaturase. The last enzyme in the de novo biosynthesis of ceramide is inhibited by GT-11, but at high concentrations this compound also inhibited SIP lyase and SPTase (147, 148). Fenretinide (4-HPR, Fig. 12) also inhibited dihydroceramide desaturase (147, 148). This synthetic retinoid and its analogs have apoptogenic activity, which elevates intracellular ceramide levels and induces cell death in a variety of cell types in vitro and in vivo by multiple mechanisms (117, 149, 150). 

Tretinoin (Retin-A) is applied topically (not in combination with other keratolytics). It may promote UV-induced skin cancer. Tretinoin should be avoided in sunny weather, and in pregnancy. Benefit is seen in about 10 weeks. Adapalene, a synthetic retinoid, may be better tolerated. 

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