Synthesis and characterization of heteroarotinoids demonstrate structure specificity relationships

Heteroarotinoids are synthetic retinoids derived from trans-retinoic acid and the arotinoid structures and include a heteroatom in a five- or six-membered cyclic ring. This is the first systematic study of influences of the heteroatom, ring size, number of aryl groups, and terminal side chain on retinoid receptor specificity. Two new heteroarotinoids were synthesized and characterized. Although all heteroarotinoids activated RAR receptors, two dominant associations between structure and specificity were identified across all compounds. The six-membered ring conferred increased RAR beta specificity over the five-membered ring. The sulfur atom conferred greater specificity for RAR gamma than the oxygen atom. RAR alpha specificity was attenuated by a combination of influences from the heteroatom and aryl groups. In summary, the heteroatom and cyclic ring size exerted dominant effects, while the number of aryl rings and terminal side chain had attenuating effects on retinoid receptor specificity of heteroarotinoids.