Gabr Moustafa T, Abdel-Raziq Mohammed S
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
Chem Biodivers. 2018 Sep;15(9):e1800244. doi: 10.1002/cbdv.201800244. Epub 2018 Aug 1.
A new series of fluorene derivatives was designed and synthesized as novel retinoic acid receptor-related orphan receptor gamma t (RORγt) inverse agonists utilizing a molecular hybridization approach. The new compounds 10 - 15 were evaluated for their RORγt activity using biochemical FRET and cellular reporter gene assays. Moreover, the inhibitory activity of the fluorene derivatives 10 - 15 in mouse Th17 cell differentiation assay was assessed. The hybrid compound 15 that combines both fluorene and arylsulfone moieties displayed promising RORγt activity with IC values of 68.6 and 99.5 nm in FRET and cellular assays, respectively. In addition, molecular modeling studies were employed to investigate potential binding mode of 15 to RORγt. These results render 15 a potential lead compound for development of therapeutics for Th17-driven autoimmune diseases.
利用分子杂交方法，设计并合成了一系列新型芴衍生物，作为新型视黄酸受体相关孤儿受体γt（RORγt）反向激动剂。使用生化荧光共振能量转移（FRET）和细胞报告基因测定法评估了新化合物10 - 15的RORγt活性。此外，还评估了芴衍生物10 - 15在小鼠Th17细胞分化测定中的抑制活性。结合芴和芳基砜部分的杂合化合物15在FRET和细胞测定中分别显示出有前景的RORγt活性，IC值分别为68.6和99.5纳米。此外，采用分子建模研究来研究15与RORγt的潜在结合模式。这些结果使15成为开发用于治疗Th17驱动的自身免疫性疾病的潜在先导化合物。
