Heteroarotinoids

The absolute configuration of the /r -4-dicyanovinylthiochroman derivative 49 has been confirmed as, V at C-3 and R at the adjacent side-chain C atom <2006CC1563> and the (/. (-geometry of the alkene moiety of the heteroarotinoid 50 was established from a single-crystal analysis <2005PS(180)67>. 

In a subsequent investigation by the author (3), heteroarotinoid derivatives, (III), containing urea or thiourea linker were prepared. 

Heteroarotinoids with a five-membered terminal ring 5... 

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. 

HETEROAROTINOIDS WITH A FIVE-MEMBERED TERMINAL RING... 

The preparation of heteroarotinoids (9) and (10) Schemes 1.1 and 1.2) [29,31] began with the conversion of the known amines (18) [71] and (19) [72] to the respective fluoroborate diazonium salts (20) and (21), respectively, by standard techniques. Generation of the aromatic free radical was accomplished in acetone in the presence of the stable free radical TEMPO. Cyclization of hetero-substituted aromatic free radicals generally occurs in a regiospecific manner with the formation of an exocyclic primary radical which then couples with a second molar equivalent of TEMPO [73-75]. However, both exo- and endo-cyclic free radicals were generated from salt... 

In order to evaluate the therapeutic efficacy of heteroarotinoids with reduced hydrocarbon character (and potentially diminished toxicity), other heteroarotinoids containing a five-membered ring have been synthesized [29-32,67]. In view of the high anti-cancer activities of heteroarotinoids (5)... 

Synthesis of diaryl heteroarotinoids (11) and (12) [27,30,31] began with a Lewis acid-catalyzed cyclization of tertiary alcohol (34) to give dihydroben-zothiophene (36) as the sole isolated product. The chemistry of the ensuing steps was similar to that used to prepare (9) and (10) and other diaryl heteroarotinoids and involved (a) Friedel-Crafts acylation of a fused aromatic-heterocyclic system, (b) reduction of the resulting ketone to a benzylic carbinol, (c) phosponium salt formation, and finally (d), Wittig coupling to methyl 4-formylbenzoate. The free acids (13) and (14) were obtained by saponification. 

Heteroarotinoids containing a terminal thiochroman system have shown excellent activity [27,28,31,65-67] and toxicity profiles [63,64]. In order to... 

Heteroarotinoids (63) and (64) containing a central triple bond were prepared for use in the treatment of epithelial disorders [26]. 

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... 

Replacement of the central double bond in the most potent stilbene-4-carboxylic acid (TTNPB, (3)) with either CONH or NHCO resulted in activity greater (10-fold in the case of CONH) than either TTNPB or retinoic acid as measured by the HL-60 assay [22,23]. Similar replacement of the central double bond in (5), a heteroarotinoid, eliminated activity as indicated by the TOC assay [79]. 

Gale, J.B. (1988) Heteroarotinoids with a Five-Membered A-Ring (Thesis), Oklahoma State University, Stillwater, OK (1990) Chem. Abstr. 112, 235633. 

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