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

• Published in: European journal of medicinal chemistry Vol. 229; p. 114070
• Main Authors: Feng, Yao, Wang, Wenbao, Zhang, Yan, Fu, Xuefeng, Ping, Kunqi, Zhao, Jiaxing, Lei, Yu, Mou, Yanhua, Wang, Shaojie
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.02.2022; Elsevier
• Subjects: Animals; Anti-glioma; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Blood-Brain Barrier - metabolism; Celastrol derivatives; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Glioma - drug therapy; Heterografts; Humans; Life Sciences & Biomedicine; Male; Mice; Necroptosis; Necroptosis - drug effects; Nuclear Pore Complex Proteins - metabolism; Pentacyclic Triterpenes - chemical synthesis; Pentacyclic Triterpenes - pharmacology; Pharmacology & Pharmacy; Protein Kinases - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; RIP1/RIP3/MLKL pathway; RNA-Binding Proteins - metabolism; Science & Technology; Signal Transduction; Structure-Activity Relationship; Wound Healing - drug effects; Zebrafish; Celastrol derivatives; Necroptosis; Anti-glioma; RIP1/RIP3/MLKL pathway; APOPTOSIS; DESIGN; ANTITUMOR-ACTIVITY; TRIAZOLYL DERIVATIVES; CELL-DEATH; TRITERPENE; INHIBITION; PROTEASOME; SELECTIVITY; HYBRIDS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.114070

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. [Display omitted] •Thirty celastrol-1, 2, 3-triazole derivatives with amide linker were designed and synthesized.•The derivatives were evaluated for their anti-glioma activities.•The structure-activity relationships were investigated.•Compound 6i exhibited remarkable growth inhibition in U251 cells through inducing necroptosis.•Compound 6i induced U251 cells necroptosis via activation of the RIP1/RIP3/MLKL pathway.