Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen 518036, China; Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Shenzhen 518036, China.
Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen 518036, China; Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Shenzhen 518036, China.
Bioorg Chem. 2022 Nov;128:106063. doi: 10.1016/j.bioorg.2022.106063. Epub 2022 Jul 29.
Rheumatoid arthritis (RA) is an autoimmune disease accompanied with serious symptoms, such as joint destruction and chronic synovitis. Though many anti-RA drugs could improve the outcome of RA patients to a certain extent, about 40% inefficient rate, severe side effects, and high costs have become urgent problems. Therefore, exploring new alternative drugs for RA therapy is still an urgent need so far. Isatin is an important structural motif found in numerous biologically active compounds and therapeutic agents. Herein, we aim to synthesize several novel isatin analogues for RA therapy and further explore the mechanism of the most potential anti-RA drug candidate in suppressing the pathological progress of RA in vitro and in vivo. We found that the most therapeutic potential compound, a novel small molecule isatin-honokiol hybrid named CT5-2 inhibited the viability of RA-fibroblast-like synoviocytes (FLSs), an effector cell of synovial hyperplasia in the RA synovial tissue with IC ranging from 8.54 to 10.66 μM. In addition, CT5-2 reduced the DNA replication and triggered cell cycle arrest and apoptosis of RA-FLSs. Moreover, differential analyses of RNA-sequencing and the mechanistic studies demonstrated that CDCA7 is a key gene correlated with RA progression, and CT5-2 could inhibit the c-Myc/CDCA7/p65 pathway to regulate CDK1, Bcl-2, and vimentin in RA-FLSs. Furthermore, CT5-2 relieved collagen-induced arthritis (CIA) and reduced the level of CDCA7, CDK1, Bcl-2, and vimentin of synovial tissue in CIA mice. Taken together, the novel small molecule isatin-honokiol hybrid CT5-2 exhibits a potential anti-RA drug candidate that inhibits proliferation and triggers cell cycle arrest and apoptosis of RA-FLSs by regulating the c-Myc/CDCA7/p65 pathway. Our study lays a good foundation for further clinical research and structuralmodification of CT5-2.
类风湿关节炎（RA）是一种伴有严重症状的自身免疫性疾病，如关节破坏和慢性滑膜炎。虽然许多抗 RA 药物可以在一定程度上改善 RA 患者的预后，但约 40%的无效率、严重的副作用和高成本已经成为迫切需要解决的问题。因此，到目前为止，探索 RA 治疗的新替代药物仍然是当务之急。靛红是许多生物活性化合物和治疗剂中发现的重要结构基序。在此，我们旨在合成几种新型的靛红类似物用于 RA 治疗，并进一步探讨最有潜力的抗 RA 药物候选物在体外和体内抑制 RA 病理进展的机制。我们发现，最具治疗潜力的化合物，一种新型小分子靛红-厚朴酚杂合体 CT5-2，以 IC 范围为 8.54-10.66μM 抑制 RA 成纤维样滑膜细胞（FLSs）的活力，RA 滑膜组织中滑膜过度增生的效应细胞。此外，CT5-2 降低 DNA 复制并触发 RA-FLSs 的细胞周期停滞和细胞凋亡。此外，RNA 测序的差异分析和机制研究表明，CDCA7 是与 RA 进展相关的关键基因，CT5-2 可以抑制 c-Myc/CDCA7/p65 通路来调节 RA-FLSs 中的 CDK1、Bcl-2 和波形蛋白。此外，CT5-2 缓解胶原诱导性关节炎（CIA）并降低 CIA 小鼠滑膜组织中 CDCA7、CDK1、Bcl-2 和波形蛋白的水平。总之，新型小分子靛红-厚朴酚杂合体 CT5-2 具有抑制 RA-FLSs 增殖并通过调节 c-Myc/CDCA7/p65 通路触发细胞周期停滞和细胞凋亡的潜力，为进一步的临床研究和 CT5-2 的结构修饰奠定了良好的基础。
