Linked Life Data

11170645

Source:http://linkedlifedata.com/resource/pubmed/id/11170645

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2001-2-22
pubmed:abstractText
Trypanothione reductase (TR) is both a valid and an attractive target for the design of new trypanocidal drugs. Starting from menadione, plumbagin, and juglone, three distinct series of 1,4-naphthoquinones (NQ) were synthesized as potential inhibitors of TR from Trypanosoma cruzi (TcTR). The three parent molecules were functionalized at carbons 2 and/or 3 by various polyamine chains. Optimization of TcTR inhibition and TcTR specificity versus human disulfide reductases was achieved with the 3,3'-[polyaminobis(carbonylalkyl)]bis(1,4-NQ) series 19-20, in which an optimum chain length was determined for inhibition of the trypanothione disulfide reduction. The most active derivatives against trypanosomes in cultures were also studied as subversive substrates of TcTR and lipoamide dehydrogenase (TcLipDH). The activities were measured by following NAD(P)H oxidation as well as coupling the reactions to the reduction of cytochrome c which permits the detection of one-electron transfer. For TcTR, 20(4-c) proved to be a potent subversive substrate and an effective uncompetitive inhibitor versus trypanothione disulfide and NADPH. Molecular modeling studies based on the known X-ray structures of TcTR and hGR were conducted in order to compare the structural features, dimensions, and accessibility of the cavity at the dimer interface of TcTR with that of hGR, as one of the putative NQ binding sites. TcLipDH reduced the plumbagin derivatives by an order of magnitude faster than the corresponding menadione derivatives. Such differences were not observed with the pig heart enzyme. The most efficient and specific subversive substrates of TcTR and TcLipDH exhibited potent antitrypanosomal activity in in vitro T. brucei and T. cruzi cultures. The results obtained here confirm that reduction of NQs by parasitic flavoenzymes is a promising strategy for the development of new trypanocidal drugs.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
44
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
548-65
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:11170645-Animals, pubmed-meshheading:11170645-Cells, Cultured, pubmed-meshheading:11170645-Crystallography, X-Ray, pubmed-meshheading:11170645-Dihydrolipoamide Dehydrogenase, pubmed-meshheading:11170645-Enzyme Inhibitors, pubmed-meshheading:11170645-Female, pubmed-meshheading:11170645-Humans, pubmed-meshheading:11170645-Macrophages, Peritoneal, pubmed-meshheading:11170645-Mice, pubmed-meshheading:11170645-Models, Molecular, pubmed-meshheading:11170645-Myocardium, pubmed-meshheading:11170645-NADH, NADPH Oxidoreductases, pubmed-meshheading:11170645-Naphthoquinones, pubmed-meshheading:11170645-Oxidation-Reduction, pubmed-meshheading:11170645-Structure-Activity Relationship, pubmed-meshheading:11170645-Swine, pubmed-meshheading:11170645-Trypanocidal Agents, pubmed-meshheading:11170645-Trypanosoma cruzi
pubmed:year
2001
pubmed:articleTitle
2- and 3-substituted 1,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: synthesis and correlation between redox cycling activities and in vitro cytotoxicity.
pubmed:affiliation
UMR 8525 CNRS - Université Lille II, Institut de Biologie de Lille et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP447, 59021 Lille Cedex, France.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't