Time-dependent inhibitors of trypanothione reductase. Analogues of the spermidine alkaloid lunarine and related natural products
Hamilton, C. J., Saravanamuthu, A., Poupat, C., Fairlamb, A. H. and Eggleston, I. M., 2006. Time-dependent inhibitors of trypanothione reductase. Analogues of the spermidine alkaloid lunarine and related natural products. Bioorganic and Medicinal Chemistry, 14, pp. 2266-2278.
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The macrocyclic spermidine alkaloid lunarine 1 from Lunaria biennis is a competitive, time-dependent inhibitor of the protozoan oxidoreductase trypanothione reductase (TryR), a promising target in drug design against tropical parasitic diseases. Various molecules related to 1 and the alkaloid itself have been synthesized in racemic form and evaluated against TryR in order to determine the key features of 1 that are associated with time-dependent inhibition. Kinetic data are consistent with an inactivation mechanism involving a conjugate addition of an active site cysteine residue onto the C-24–C-25 double bond of the tricyclic nucleus of 1. Comparison of data for synthetic (±)-1, the natural product, and other derivatives 7–10 from L. biennis confirms the importance of the unique structure of the tricyclic core as a motif for inhibitor design and reveals that the non-natural enantiomer may be a more suitable scaffold upon which thiophilic groups may be presented.
|Creators||Hamilton, C. J., Saravanamuthu, A., Poupat, C., Fairlamb, A. H. and Eggleston, I. M.|
|Departments||Faculty of Science > Pharmacy & Pharmacology|
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