title: Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
abstract: Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote 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 synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.
authors.affiliation: Department of Chemistry, Allergan, Incorporated, Irvine, California 92715-1599, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Beard
authors.forename: D F
authors.initials: DF
authors.lastname: Colon
authors.forename: T K
authors.initials: TK
authors.lastname: Song
authors.forename: P J
authors.initials: PJ
authors.lastname: Davies
authors.forename: D M
authors.initials: DM
authors.lastname: Kochhar
authors.forename: R A
authors.initials: RA
authors.lastname: Chandraratna
mesh_terms: D000818:Animals; D002356:Cartilage / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D018922:HL-60 Cells; D006801:Humans; D018168:Receptors, Retinoic Acid / Q000187:drug effects*; D047488:Retinoid X Receptors; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects*; D015533:Transcriptional Activation; D014162:Transfection; D014212:Tretinoin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013440:Sulfides; D014157:Transcription Factors; D014212:Tretinoin