SYNTHESIS AND CHARACTERIZATION OF HETEROAROTINOIDS DEMONSTRATE STRUCTURE SPECIFICITY RELATIONSHIPS

Heteroarotinoids are synthetic retinoids derived from trans-retinoic a cid and the arotinoid structures and include a heteroatom in a five- o r six-membered cyclic ring. This is the first systematic study of infl uences of the heteroatom, ring size, number of aryl groups, and termin al side chain on retinoid receptor specificity. Two new heteroarotinoi ds were synthesized and characterized. Although all heteroarotinoids a ctivated RAR receptors, two dominant associations between structure an d specificity were identified across all compounds. The six-membered r ing conferred increased RAR beta specificity over the five-membered ri ng. The sulfur atom conferred greater specificity for RAR gamma than t he oxygen atom. RAR alpha specificity was attenuated by a combination of influences from the heteroatom and aryl groups. In summary, the het eroatom and cyclic ring size exerted dominant effects, while the numbe r of aryl rings and terminal side chain had attenuating effects on ret inoid receptor specificity of heteroarotinoids.