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

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 7; pp. 2266 - 2278
• Main Authors: Hamilton, Chris J., Saravanamuthu, Ahilan, Poupat, Christiane, Fairlamb, Alan H., Eggleston, Ian M.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.04.2006; Elsevier Science; Elsevier
• Subjects: Alkaloids - chemical synthesis; Alkaloids - chemistry; Alkaloids - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Biological Factors - chemical synthesis; Biological Factors - chemistry; Biological Factors - pharmacology; Chemical Sciences; Conjugate addition; Disulfide reductase; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; In Vitro Techniques; Kinetics; Lunaria; Medical sciences; Molecular Conformation; NADH, NADPH Oxidoreductases - antagonists & inhibitors; Natural products; Organic chemistry; Parasitic Sensitivity Tests; Pharmacology. Drug treatments; Spermidine - analogs & derivatives; Spermidine - chemical synthesis; Spermidine - chemistry; Spermidine - pharmacology; Stereoisomerism; Structure-Activity Relationship; Time Factors; Time-dependent inhibitors; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma brucei brucei - drug effects; Conjugate addition; Time-dependent inhibitors; Natural products; Disulfide reductase; Lactam; Oxygen heterocycle; Macrocycle; Antiprotozoal agent; Alkaloid; Aromatic compound; Chemical synthesis; Trypanosoma brucei; Oxygen nitrogen heterocycle; Kinetoplastida; Protozoa; Enzyme; Enzyme inhibitor; Natural compound; Tetracyclic compound; Tricyclic compound; Competitive inhibition; Ketone; In vitro; Synthetic product; Parasiticide; Carboxamide; Oxidoreductases; Trypanothione reductase
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.11.004

The molecular mechanism and minimal structural requirements for time-dependent inactivation of trypanothione reductase by the spermidine alkaloid lunarine and other natural product-derived compounds are described. 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.