Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Aoba-ku, Sendai, Japan.
Bioorg Med Chem. 2011 Apr 15;19(8):2501-7. doi: 10.1016/j.bmc.2011.03.026. Epub 2011 Mar 15.
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.
基于具有维甲酸协同活性（RXR 激动剂）的二苯胺衍生物的结构-活性关系，设计并合成了具有长烷基链（9a 和 9b）或苄基（10a-f）作为 N-取代基的新型二苯胺衍生物。所有合成的化合物均剂量依赖性地抑制了 3.3×10(-10)M Am80 诱导的 HL-60 细胞分化。其中，化合物 10f 表现出最强的抑制活性，通过 RARs 和 RXRs 的转激活测定表明，其作用机制涉及对 RARs 的拮抗作用。二苯胺骨架的 N-取代基在确定对 RARs 或 RXRs 的受体选择性以及活性的激动剂或拮抗剂性质方面起着重要作用。
