孤儿核受体RORγ拮抗剂的合成及其初步活性研究

Synthesis and preliminary bioactivities evaluation of retinoic acid-related orphan receptor γ inhibitors

目的设计合成新型维甲酸受体相关孤儿受体γ(RORγ)小分子拮抗剂,并检测其在细胞水平上对蛋白活性的影响。方法 2-氟苯胺与六氟丙酮发生取代反应,再经重氮化反应,叠氮化钠亲核进攻生成叠氮化合物,最终与炔基官能团发生分子间环加成反应生成三唑类氮杂环,共合成两类柔性不同的连接基团组成的目标化合物。采用荧光素酶报告基因实验(luciferase reporter gene assay)测定目标化合物对RORγ细胞水平的抑制活性。结果与结论合成了15个未见文献报道的新化合物,其结构经1H-NMR和ESI-MS谱确证。活性评价结果显示,多个化合物在细胞水平上对RORγ有抑制活性,其中化合物8a表现出最强的抑制活性,其抑制活性略优于阳性对照化合物,由此推论此类化合物可能具有潜在的抗炎作用。

The retinoic acid receptor-related orphan receptor 3γ （RORγ） has been shown to be essential for the expression of interleukin 17（IL-17） and the differentiation of T helper 17 ceUs（Thl7）. Thl7 cells have been implicated in the pathology of several autoimmune diseases including multiple sclerosis and rheumatoid arthritis. Therefore, ROR3/is a promising therapeutic target for treating Thl7-mediated autoimmune diseases. In this study, known RORγinhibitor SR2211 was used as template to develop new series of RORγ inhibitors using a modular chemistry approach. Fifteen target compounds were designed, synthesized and characterized by MS and ^1H-NMR. These compounds were assessed for RORγinhibitory activity using cell-based lucife- rase reporter gene assay. The data demonstrated that some compounds exhibited good biological activities, such as Ia and lie with the inhibitory rates of 56% and 33% ,respectively. It suggests that the new struc- tures have potential activities for the treatment of autoimmune diseases.