Abstract
Splitomicin (1) and 41 analogues were prepared and evaluated in cell-based Sir2 inhibition and toxicity assays and an in vitro Sir2 inhibition assay. Lactone ring or naphthalene (positions 7-9) substituents decrease activity, but other naphthalene substitutions (positions 5 and 6) are well-tolerated. The hydrolytically unstable aromatic lactone is important for activity. Lactone hydrolysis rates were used as a measure of reactivity; hydrolysis rates correlate with inhibitory activity. The most potent Sir2 inhibitors were structurally similar to and had hydrolysis rates similar to 1.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Histone Deacetylase Inhibitors
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Lactones / chemistry
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Naphthalenes / chemical synthesis*
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Naphthalenes / chemistry
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Naphthalenes / pharmacology
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Pyrones / chemical synthesis*
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Pyrones / chemistry
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Pyrones / pharmacology
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Saccharomyces cerevisiae / drug effects
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Saccharomyces cerevisiae / enzymology
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Silent Information Regulator Proteins, Saccharomyces cerevisiae / antagonists & inhibitors
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Sirtuin 2
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Sirtuins / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Histone Deacetylase Inhibitors
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Lactones
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Naphthalenes
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Pyrones
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Silent Information Regulator Proteins, Saccharomyces cerevisiae
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naphthalene
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splitomicin
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SIR2 protein, S cerevisiae
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Sirtuin 2
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Sirtuins