Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid.
J Med Chem
; 39(18): 3556-63, 1996 Aug 30.
Article
em En
| MEDLINE
| ID: mdl-8784454
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sulfetos
/
Fatores de Transcrição
/
Tretinoína
/
Receptores do Ácido Retinoico
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
1996
Tipo de documento:
Article
País de afiliação:
Estados Unidos