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

Hamilton, Chris J., Saravanamuthu, Ahilan, Poupat, Christiane, Fairlamb, Alan H. and Eggleston, Ian M. (2006) Time-dependent inhibitors of trypanothione reductase: Analogues of the spermidine alkaloid lunarine and related natural products. Bioorganic & Medicinal Chemistry, 14 (7). pp. 2266-2278. ISSN 0968-0896

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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 I and the alkaloid itself have been synthesized in racemic form and evaluated against TryR in order to determine the key features of I 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. (c) 2005 Elsevier Ltd. All rights reserved.

Item Type: Article
Uncontrolled Keywords: disulfide reductase,conjugate addition,time-dependent inhibitors,natural products
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Rachel Smith
Date Deposited: 17 May 2011 15:47
Last Modified: 05 May 2020 23:45
URI: https://ueaeprints.uea.ac.uk/id/eprint/30704
DOI: 10.1016/j.bmc.2005.11.004

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