Diphenylamine-based retinoid antagonists: regulation of RAR and RXR function depending on the N-substituent.

Abstract Based upon the structure–activity relationships of diphenylamine derivatives with retinoid synergistic activity (RXR agonists), novel diphenylamine derivatives with a long alkyl chain ( 9a and 9b ) or a benzyl group ( 10a – f ) as the N-substituent were designed and synthesized. All the synthesized compounds dose-dependently inhibited HL-60 cell differentiation induced by 3.3 × 10 −10  M Am80. Among them, compound 10f showed the most potent inhibitory activity, and the mechanism was shown, by means of transactivation assay for RARs and RXRs, to involve antagonism against RARs. The N-substituent of the diphenylamine skeleton plays an important role in determining the receptor selectivity for RARs or RXRs, as well as the agonist or antagonist nature of the activity.