TY - JOUR
T1 - Time-dependent inhibitors of trypanothione reductase. Analogues of the spermidine alkaloid lunarine and related natural products
AU - Hamilton, C J
AU - Saravanamuthu, A
AU - Poupat, C
AU - Fairlamb, A H
AU - Eggleston, I M
PY - 2006
Y1 - 2006
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.
UR - http://dx.doi.org/10.1016/j.bmc.2005.11.004
U2 - 10.1016/j.bmc.2005.11.004
DO - 10.1016/j.bmc.2005.11.004
M3 - Article
SN - 0968-0896
VL - 14
SP - 2266
EP - 2278
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
ER -