Retinoids acetylenic

Tazarotene (Tazorac) is a synthetic acetylenic retinoid that is converted to its active form, tazarotenic acid, after topical application. 

It is an acetylenic retinoid prodrug which is hydrolysed to active metabolite tazarotenic acid, binds to retinoic acid receptors resulting in modified gene expression. 

Tazarotene (Tazorac) is an acetylenic retinoid that is available as a 0.1% gel and cream for the treatment of mild to moderately severe facial acne. Topical tazarotene should be used by women of childbearing age only after contraceptive counseling. It is recommended that tazarotene should not be used by pregnant women. 

Tazarotene (Tazorac) is an acetylenic retinoid prodrug that is hydrolyzed to its active form by an esterase. The active metabolite, tazarotenic acid, binds to retinoic acid receptors, resulting in modified gene expression. The precise mechanism of action in psoriasis is unknown but may relate to both anti-inflammatory and antiproliferative actions. Tazarotene is absorbed percutaneously, and teratogenic systemic concentrations may be achieved if applied to more than 20% of total body surface area. Women of childbearing potential must therefore be advised of the risk prior to initiating therapy, and adequate birth control measures must be utilized while on therapy. 

Much of the new chemistry on the coupling of alkynyl halides has dealt mostly with applications of known methods. The Cadiot-Chodkiewicz-type coupling reactions (i.e. terminal acetylene coupling with alkynyl halides) have formed the cornerstone of synthesis of acetylenic retinoids (i.e. 9)58. 

Tazarotene, a prodrug and a synthetic acetylenic retinoid, is converted to its active form, tazarotenic acid, after topical application. This new-generation retinoid also selectively binds to RARs and can alter expression of genes involved in cell proliferation, cell differentiation, and inflammation." " ... 

Although the yields tend to be modest, coupling of alkynyl, alkenyl, and allylic halides to terminal alkynes in the presence of a cuprous halide and an amine (e.g. Et N, pyridine) by the Cadiot-Chodkiewicz reaction provides a direct route to acetylenic derivatives that are of interest in the construction of vitamin A (1) and carotenoids. For example, heating the acetylenes 104, 95 or 105 with the bromides 106 and 107 in the presence of cuprous chloride and an amine in methanol provides a convenient route to the corresponding acetylenic retinoids 108, 109 and 110 [53,54]. Similarly, heating 3-bromobut-2-en-2-ol with the acetylene 105 gives 11,12-didehydrovitamin A (108) [53] (Scheme 26). 

In studying the linking of (401) with (402), it was recognized that when tetrahydrofuran was used as a solvent, the coupling reaction was suppressed. It is probably for this reason that the reaction of (401) with (407) in tetrahydrofuran gives (408) instead of the desired allene. However, the cuprate (407) cannot be prepared in other solvents. Allenic retinoids have also been postulated as reaction products in the elimination and isomerization of acetylenic retinoids (Sueiras and Okamura, 1980). 

Since the discovery of the elegant coupling techniques of the Wittig reactions, novel retinoid syntheses with acetylenic building blocks have been employed only for the design of specific synthetic retinoids, for example, in the synthesis of the acetylenic retinoids (427), (429), and (430) (Chauhan et al, 1982). 

Acetylenic retinoids (439) with a cyclogeranyl ring containing a functional group were prepared and used as building blocks in the synthesis of the carotenoid canthaxanthin (Rosenberger et al., 1979). 

Kraemer KH, Di Giovanna JJ, Moshell AN, Tarone RE, Peck GL (1988) Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 318 1633-1637 Krueger GG, Drake LA, Elias PM, Lowe NJ, Guzzo C, Weinstein GD, Lew-Kaya DA, Lue JC, Sefton J, Chandraratna RA (1998) The safety and efficacy of tazarotene gel, a topical acetylenic retinoid, in the treatment of psoriasis. Arch Dermatol 134 57-60... 

Tazarotene (Table 1) is an acetylenic third generation retinoid derivative. It is a poorly absorbed, nonisome-risable arotinoid, which is rapidly metabolized to its free carboxylic acid, tazarotenic acid, binding with high affinity to RARs, with the rank order of affinity being... 

A coupling reaction long used in acetylene chemistry is the Cadiot-Chodkiewicz coupling [112] its use in retinoid synthesis is demonstrated by the transformations depicted in Scheme 2-19 [113], The enyne precursor 169, on Cadiot-Chodkiewicz coupling with 3-bromo-2-propyn-l-ol (170) yields the diyne 171 which, by methodology long established in retinoid chemistry [114], may either be chain-elongated to dehydroretinal 172 or — via the diynal 173 — to the bis-acetylenic retinal 174. 

A general procedure has been published for the synthesis of retinoids, including vitamin A, by direct condensation of the side-chain, as ethyl 3,7-dimethylnona-2,4,6-trien-8-ynoate (80) to the appropriate cyclic ketone, e.g. 2,2,6-trimethyl-cyclohexanone (81). The acetylenic intermediate (82) is readily converted into vitamin A and derivatives. The side-chain reagent (80) is prepared in high yield by Emmons reaction between the acetylenic aldehyde (83) and the phospho-senecioate (84). In another synthesis of trans- tamm A, jS-ionylideneacetal-... 

In the 1950s, acetylenic compounds were employed in a variety of ways for building the carbon skeleton of natural retinoids. The reason for this is that acetylenes, after metalation with a Grignard reagent, can be employed for a very large variety of carbon-carbon coupling reactions (see Section V, A) (Isler et al., 1956 Isler and Schudel, 1963). 

---