Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Culture Road, Shenhe District, Shenyang, 110016, China.
College of Pharmacy, Qiqihar Medical University, Qiqihar, 161006, Heilongjiang, China.
Eur J Med Chem. 2022 Feb 5;229:114070. doi: 10.1016/j.ejmech.2021.114070. Epub 2021 Dec 23.
Celastrol, a quinone methide triterpenoid, possesses potential anti-glioma activity. However, its relatively low activity limit its application as an effective agent for glioma treatment. In search for effective anti-glioma agents, this work designed and synthesized two series of celastrol C-3 OH and C-20 COOH derivatives 4a-4o and 6a-6o containing 1, 2, 3-triazole moiety. Their anti-glioma activities against four human glioma cell lines (A172, LN229, U87, and U251) were then evaluated using MTT assay in vitro. Results showed that compound 6i (IC = 0.94 μM) exhibited substantial antiproliferative activity against U251 cell line, that was 4.7-fold more potent than that of celastrol (IC = 4.43 μM). In addition, compound 6i remarkably inhibited the colony formation and migration of U251 cells. Further transmission electron microscopy and mitochondrial depolarization assays in U251 cells indicated that the potent anti-glioma activity of 6i was attributed to necroptosis. Mechanism investigation revealed that compound 6i induced necroptosis mainly by activating the RIP1/RIP3/MLKL pathway. Additionally, compound 6i exerted acceptable BBB permeability in mice and inhibited U251 cell proliferation in an in vivo zebrafish xenograft model, obviously. In summary, compound 6i might be a promising lead compound for potent celastrol derivatives as anti-glioma agents.
三萜醌类化合物雷公藤红素具有潜在的抗神经胶质瘤活性。然而，其相对较低的活性限制了其作为治疗神经胶质瘤的有效药物的应用。为了寻找有效的抗神经胶质瘤药物，本工作设计并合成了两个系列的含有 1,2,3-三唑结构单元的雷公藤红素 C-3 OH 和 C-20 COOH 衍生物 4a-4o 和 6a-6o。然后，通过 MTT 法在体外评估了它们对四种人神经胶质瘤细胞系（A172、LN229、U87 和 U251）的抗神经胶质瘤活性。结果表明，化合物 6i（IC50=0.94μM）对 U251 细胞系表现出显著的增殖抑制活性，比雷公藤红素（IC50=4.43μM）强 4.7 倍。此外，化合物 6i 显著抑制了 U251 细胞的集落形成和迁移。进一步的透射电镜和线粒体去极化实验表明，6i 的强抗神经胶质瘤活性归因于坏死性凋亡。机制研究表明，化合物 6i 通过激活 RIP1/RIP3/MLKL 通路诱导坏死性凋亡。此外，化合物 6i 在小鼠中表现出可接受的 BBB 通透性，并在体内斑马鱼异种移植模型中明显抑制 U251 细胞的增殖。综上所述，化合物 6i 可能是一种有前途的先导化合物，可用于开发强效的雷公藤红素衍生物作为抗神经胶质瘤药物。
