Abstract
Trypanothione reductase (TR) catalyzes the NADPH-dependent reduction of trypanothione disulfide (1). TR plays a central role in the trypanosomatid parasite's defense against oxidative stress and has emerged as a promising target for antitrypanosomal drugs. We describe the synthesis and activity of dethiotrypanothione and analogues (2-4) as inhibitors of Trypanosoma cruzi TR. The syntheses of these macrocycles feature ring-closing olefin metathesis (RCM) reactions catalyzed by ruthenium catalyst 17. Derivative 4 is our most potent inhibitor with a Ki=16 microM.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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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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Glutathione / analogs & derivatives*
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Glutathione / chemical synthesis
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Glutathione / chemistry
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Glutathione / pharmacology
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Molecular Structure
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NADH, NADPH Oxidoreductases / antagonists & inhibitors*
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NADH, NADPH Oxidoreductases / metabolism*
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Spermidine / analogs & derivatives*
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Spermidine / chemical synthesis
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Spermidine / chemistry
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Spermidine / pharmacology
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Trypanosoma cruzi / enzymology
Substances
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Enzyme Inhibitors
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trypanothione
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NADH, NADPH Oxidoreductases
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trypanothione reductase
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Glutathione
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Spermidine