College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
School of Pharmaceutical Engineering, and Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Bioorg Chem. 2021 Nov;116:105330. doi: 10.1016/j.bioorg.2021.105330. Epub 2021 Sep 11.
A series of cyano-substituted 2,4-diarylaminopyrimidines was designed and synthesized as potent non-covalent JAK3 inhibitors. Among the derivatives synthesized, 9o (IC = 22.86 nM), 9 k (IC = 21.58 nM), and 9j (IC = 20.66 nM) demonstrated inhibitory potencies against JAK3 similar to the known JAK3 inhibitor tofacitinib (IC = 20.10 nM). Moreover, 9o displayed potent anti-proliferative activities against Raji and Ramos cells, with IC values of 0.9255 μM and 1.405 μM, respectively. In addition, 9o demonstrated low toxicity in normal HBE (human bronchial epithelial cells, IC > 10 μΜ) and L-02 (human liver cells, IC = 3.104 μΜ) cells. Analysis of the mode of action by flow cytometry indicated that 9o effectively arrested Raji cells at the G2/M phase. Taken together, these results suggested that 9o might be a promising candidate for development as a potential treatment for B-cell lymphoma.
一系列氰基取代的 2,4-二芳基氨基嘧啶被设计并合成为有效的非共价 JAK3 抑制剂。在所合成的衍生物中，9o（IC=22.86 nM）、9k（IC=21.58 nM）和 9j（IC=20.66 nM）对 JAK3 的抑制活性与已知的 JAK3 抑制剂托法替尼（IC=20.10 nM）相当。此外，9o 对 Raji 和 Ramos 细胞表现出强大的抗增殖活性，IC 值分别为 0.9255 μM 和 1.405 μM。此外，9o 在正常 HBE（人支气管上皮细胞，IC>10 μΜ）和 L-02（人肝细胞，IC=3.104 μΜ）细胞中表现出低毒性。流式细胞术分析作用模式表明，9o 能有效将 Raji 细胞阻滞在 G2/M 期。综上所述，这些结果表明 9o 可能是一种有前途的候选药物，可开发用于治疗 B 细胞淋巴瘤。
