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: Chris J Hamilton, Ahilan Saravanamuthu, Christiane Poupat, Alan H Fairlamb, Ian M Eggleston
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 14 Issue 7 Pg. 2266-78 (Apr 01 2006) ISSN: 0968-0896 [Print] England
• PMID: 16303308 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkaloids
• Biological Factors
• Enzyme Inhibitors
• Trypanocidal Agents
• lunarine
• NADH, NADPH Oxidoreductases
• trypanothione reductase
• Spermidine

Topics

• Alkaloids (chemical synthesis, chemistry, pharmacology)
• Animals
• Biological Factors (chemical synthesis, chemistry, pharmacology)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• In Vitro Techniques
• Kinetics
• Molecular Conformation
• NADH, NADPH Oxidoreductases (antagonists & inhibitors)
• Parasitic Sensitivity Tests
• Spermidine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship
• Time Factors
• Trypanocidal Agents (chemical synthesis, chemistry, pharmacology)
• Trypanosoma brucei brucei (drug effects)