The synthesis and inhibitory activity of dethiotrypanothione and analogues against trypanothione reductase

Josephine A. Czechowicz; April K. Wilhelm; Maroya D. Spalding; Anna M. Larson; Linnea K. Engel; David G. Alberg

doi:10.1021/jo062597s

The synthesis and inhibitory activity of dethiotrypanothione and analogues against trypanothione reductase

Josephine A. Czechowicz, April K. Wilhelm, Maroya D. Spalding, Anna M. Larson, Linnea K. Engel, David G. Alberg

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Abstract

(Chemical Equation Presented) 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 K_i = 16 μM.

Original language	English (US)
Pages (from-to)	3689-3693
Number of pages	5
Journal	Journal of Organic Chemistry
Volume	72
Issue number	10
DOIs	https://doi.org/10.1021/jo062597s
State	Published - May 11 2007
Externally published	Yes

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T1 - The synthesis and inhibitory activity of dethiotrypanothione and analogues against trypanothione reductase

AU - Czechowicz, Josephine A.

AU - Wilhelm, April K.

AU - Spalding, Maroya D.

AU - Larson, Anna M.

AU - Engel, Linnea K.

AU - Alberg, David G.

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AB - (Chemical Equation Presented) 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 μM.

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The synthesis and inhibitory activity of dethiotrypanothione and analogues against trypanothione reductase

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