TY - JOUR
T1 - Time-dependent inhibitors of trypanothione reductase
T2 - Analogues of the spermidine alkaloid lunarine and related natural products
AU - Hamilton, Chris J.
AU - Saravanamuthu, Ahilan
AU - Poupat, Christiane
AU - Fairlamb, Alan H.
AU - Eggleston, Ian M.
N1 - Funding Information:
We thank the UNDP/WORLD BANK/WHO (Special Programme for Research and Training in Tropical Diseases) for financial support (I.M.E.) and the Wellcome Trust (A.H.F.). We are also grateful to Dr. I. Fleet (UMIST) and Mr. D. Lamont (University of Dundee) for mass spectrometric analyses.
PY - 2006/4/1
Y1 - 2006/4/1
N2 - 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.
AB - 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.
KW - Conjugate addition
KW - Disulfide reductase
KW - Natural products
KW - Time-dependent inhibitors
UR - http://www.scopus.com/inward/record.url?scp=32844472788&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2005.11.004
DO - 10.1016/j.bmc.2005.11.004
M3 - Article
C2 - 16303308
AN - SCOPUS:32844472788
SN - 0968-0896
VL - 14
SP - 2266
EP - 2278
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 7
ER -