Synthesis and biological evaluation of celastrol derivatives as potential anti-glioma agents by activating RIP1/RIP3/MLKL pathway to induce necroptosis

  • Eur J Med Chem. 2022 Feb 5;229:114070. doi: 10.1016/j.ejmech.2021.114070.
Yao Feng  1 ,  Wenbao Wang  2 ,  Yan Zhang  3 ,  Xuefeng Fu  1 ,  Kunqi Ping  1 ,  Jiaxing Zhao  1 ,  Yu Lei  1 ,  Yanhua Mou  4 ,  Shaojie Wang  5
Affiliations
  • 1. 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.
  • 2. College of Pharmacy, Qiqihar Medical University, Qiqihar, 161006, Heilongjiang, China.
  • 3. Department of Pharmacology, Shenyang Pharmaceutical University, 103 Culture Road, Shenhe District, Shenyang, 110016, China.
  • 4. Department of Pharmacology, Shenyang Pharmaceutical University, 103 Culture Road, Shenhe District, Shenyang, 110016, China. Electronic address: [email protected].
  • 5. 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. Electronic address: [email protected].
PMID: 34968902 DOI: 10.1016/j.ejmech.2021.114070
Abstract

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 (IC50 = 0.94 μM) exhibited substantial antiproliferative activity against U251 cell line, that was 4.7-fold more potent than that of celastrol (IC50 = 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.

Keywords
Anti-glioma; Celastrol derivatives; Necroptosis; RIP1/RIP3/MLKL pathway.
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