Structural characterization of 1,3-bis-tert-butyl monocyclic benzene derivatives with agonistic activity towards retinoid X receptor alpha

Retinoid X receptor alpha (RXR alpha) plays pivotal roles in multiple biological processes, but limited information is available on the structural features of chemicals that show low affinity for RXR alpha, but nevertheless cause sig-nificant activation, though these may represent a human health hazard. We recently discovered that several industrial chemicals having 1,3-bis-tert-butylbenzene as a common chemical structure exhibit agonistic activity towards rat RXR alpha. In this study, we explored the structure-activity relationship of 1,3-bis-tert-butyl monocyclic benzene derivatives for RXR alpha activation by means of in vitro and in silico analyses. The results indicate that a bulky substituent at the 5-position is favorable for agonistic activity towards human RXR alpha. Since 1,3-bis-tert- butyl monocyclic benzene derivatives with bulky hydrophobic moieties differ structurally from known RXR alpha ligands such as 9-cis-retinoic acid and bexarotene, our findings may be helpful for the development of structural alerts in the safety evaluation of industrial chemicals for RXR alpha-based toxicity to living organisms.

Automated summary

This study explored the structure-activity relationship of 1,3-bis-tert-butyl monocyclic benzene derivatives for RXR alpha activation and found that a bulky substituent at the 5-position is favorable for agonistic activity towards human RXR alpha.