Abstract
Chaetocin (1), a structurally complex epidithiodiketopiperazine (ETP) alkaloid produced by Chaetomium minutum, is a potent inhibitor of protein lysine methyltransferase G9a, which plays important roles in many biological processes. Here we present our synthetic investigations to identify a simple prototype G9a inhibitor structure based on structure-activity relationship (SAR) studies on chaetocin derivatives. The simple derivative PS-ETP-1 (14) was found to be a potent G9a inhibitor with greatly reduced cytotoxicity.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Survival / drug effects
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Chaetomium / chemistry*
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Diketopiperazines / chemical synthesis*
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Diketopiperazines / chemistry
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Diketopiperazines / pharmacology*
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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HL-60 Cells
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Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
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Humans
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Molecular Structure
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Piperazines / chemical synthesis
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Piperazines / chemistry
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Piperazines / pharmacology
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Structure-Activity Relationship
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Thioredoxin-Disulfide Reductase / metabolism
Substances
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Diketopiperazines
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Enzyme Inhibitors
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Piperazines
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chaetocin
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Thioredoxin-Disulfide Reductase
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Histone-Lysine N-Methyltransferase