Time-dependent inhibitors of trypanothione reductase: Analogues of the spermidine alkaloid lunarine and related natural products

Chris J. Hamilton, Ahilan Saravanamuthu, Christiane Poupat, Alan H. Fairlamb, Ian M. Eggleston (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    32 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)2266-2278
    Number of pages13
    JournalBioorganic and Medicinal Chemistry
    Volume14
    Issue number7
    DOIs
    Publication statusPublished - 1 Apr 2006

    Keywords

    • Conjugate addition
    • Disulfide reductase
    • Natural products
    • Time-dependent inhibitors

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