SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF STILBENE RETINOID ANALOGS SUBSTITUTED WITH HETEROAROMATIC CARBOXYLIC-ACIDS

Retinoids elicit biological responses by activating a series of nuclea r receptors. Six retinoid receptors belonging to two families are curr ently known: retinoic acid receptors (RAR(alpha,beta,and gamma)) and r etinoid X receptors (RXR(alpha,beta,and gamma)). Stilbene retinoid ana logs of retinoic acid (RA), such as 8,8-tetramethyl-2-naphthalenyl)pro pen-1-yl]benzoic acid (TTNPB, 1) and 8,8-pentamethyl-2-naphthalenyl)pr open-1-yl]benzoic acid (3-methyl-TTNPB, 2), display differential RAR a nd RXR activities, depending on the substituent at C3 of the naphthale ne ring. We report here structural modifications of the benzoate moiet y of 2 that result in analogs with greater RXR selectivity as well as those with pan-agonist (activate both RAR and RXR receptors) activitie s, analyze the structural features that impart receptor selectivity, a nd describe a stereoselective method for the synthesis of these analog s. The biological activities associated with the RAR and RXR receptors were examined by testing representative examples with different recep tor activation profiles for their ability to induce tissue transglutam inase (Tgase) activity in a human promyelocytic leukemia cell line (HL -60 cdm-1) and to inhibit tumor-promoter-induced ornithine decarboxyla se (ODC) activity in hairless mouse skin. These results suggest that R AR agonists and RXR agonists may have different therapeutic applicatio ns. Finally, we show that RXR agonists are significantly reduced in te ratogenic potency relative to RAR agonists and may therefore have sign ificant advantages in clinical practice.