title: Time-dependent inhibitors of trypanothione reductase: analogues of the spermidine alkaloid lunarine and related natural products.
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.
authors.affiliation: Division of Biological Chemistry and Molecular Microbiology, School of Life Sciences, Carnelley Building, University of Dundee, Dundee DD1 4HN, UK.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Hamilton
authors.forename: Ahilan
authors.initials: A
authors.lastname: Saravanamuthu
authors.forename: Christiane
authors.initials: C
authors.lastname: Poupat
authors.forename: Alan H
authors.initials: AH
authors.lastname: Fairlamb
authors.forename: Ian M
authors.initials: IM
authors.lastname: Eggleston
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001685:Biological Factors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008968:Molecular Conformation; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D021261:Parasitic Sensitivity Tests; D013095:Spermidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects
chemical_list: D000470:Alkaloids; D001685:Biological Factors; D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; C511148:lunarine; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D013095:Spermidine