Abstract
Celastrol, a friedelane-type triterpenoid isolated from the genus Triperygium, possesses antitumor, anti-inflammatory, and immunosuppressive activities. A total of 42 celastrol derivatives (1a-1t, 2a-2l, and 3a-3j) were synthesized and evaluated for their immunosuppressive activities. Compounds 2a-2e showed immunosuppressive effects, with IC50 values ranging from 25 to 83 nM, and weak cytotoxicity (CC50 > 1 μM). Compound 2a, with a selectivity index value 31 times higher than that of celastrol, was selected as a lead compound. Further research showed that 2a exerted its immunosuppressive effects by inducing apoptosis and inhibiting cytokine secretion via Lck- and ZAP-70-mediated signaling pathways.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Cytokines / antagonists & inhibitors
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Drug Screening Assays, Antitumor
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Humans
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Immunosuppressive Agents / chemical synthesis*
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Immunosuppressive Agents / pharmacology*
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Male
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Mice
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Mice, Inbred BALB C
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Pentacyclic Triterpenes / chemical synthesis*
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Pentacyclic Triterpenes / pharmacology*
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Signal Transduction / drug effects
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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ZAP-70 Protein-Tyrosine Kinase / drug effects
Substances
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Antineoplastic Agents
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Cytokines
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Immunosuppressive Agents
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Pentacyclic Triterpenes
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ZAP-70 Protein-Tyrosine Kinase
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Zap70 protein, mouse
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celastrol