SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF RETINOID-X RECEPTOR-SELECTIVE DIARYL SULFIDE ANALOGS OF RETINOIC ACID

Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to pro mote gene transcription, There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor ( RXR) family, which are each further divided into three subclasses: RAR (alpha,beta,gamma) and RXR(alpha,beta,gamma). Herein we describe the s ynthesis and structure-activity relationships of a new series of diary l sulfide retinoid analogs that specifically bind and transactivate th e RXRs. Furthermore, the sulfoxide and sulfone derivatives of these an alogs are partial agonists which activate the RXRs only at high concen trations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other c ompounds with arotinoid-like structures. We show also that these compo unds have activity in nontransfected cells as demonstrated by their ab ility to induce TGase activity in HL-60 Cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced ter atogenic toxicity compared to RAR-specific agonists since these compou nds are much less potent inhibitors of chondrogenesis than RAR-specifi c agonists such as TTNPB.