Linked Life Data

12139461

Source:http://linkedlifedata.com/resource/pubmed/id/12139461

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
16
pubmed:dateCreated
2002-7-25
pubmed:abstractText
On the basis of the original lead neocryptolepine or 5-methyl-5H-indolo[2,3-b]quinoline, an alkaloid from Cryptolepis sanguinolenta, derivatives were prepared using a biradical cyclization methodology. Starting from easily accessible educts, this approach allowed the synthesis of hitherto unknown compounds with a varied substitution pattern. As a result of steric hindrance, preferential formation of the 3-substituted isomers over the 1-substituted isomers was observed when cyclizing N-(3-substituted-phenyl)-N'-[2-(2-trimethylsilylethynyl)phenyl]carbodiimides. All compounds were evaluated for their activity against chloroquine-sensitive as well as chloroquine-resistant Plasmodium falciparum strains, for their activity against Trypanosoma brucei and T. cruzi, and for their cytotoxicity on human MRC-5 cells. Mechanisms of action were investigated by testing heme complexation using ESI-MS, inhibition of beta-hematin formation, DNA interactions (DNA-methyl green assay and linear dichroism), and inhibition of human topoisomerase II. Neocryptolepine derivatives with a higher antiplasmodial activity and a lower cytotoxicity than the original lead have been obtained. This selective antiplasmodial activity was associated with inhibition of beta-hematin formation. 2-Bromoneocryptolepine was the most selective compound with an IC(50) value against chloroquine-resistant P. falciparum of 4.0 microM in the absence of cytotoxicity (IC(50) > 32 microM). Although cryptolepine, a known lead for antimalarials also originally isolated from Cryptolepis sanguinolenta, was more active (IC(50) = 2.0 microM), 2-bromoneocryptolepine showed a low affinity for DNA and no inhibition of human topoisomerase II, in contrast to cryptolepine. Although some neocryptolepine derivatives showed a higher antiplasmodial activity than 2-bromocryptolepine, these compounds also showed a higher affinity for DNA and/or a more pronounced cytotoxicity. Therefore, 2-bromoneocryptolepine is considered as the most promising lead from the present work for new antimalarial agents. In addition, 2-bromo-, 2-nitro-, and 2-methoxy-9-cyanoneocryptolepine exhibited antitrypanosomal activity in the micromolar range in the absence of obvious cytotoxicity.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
45
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3497-508
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:12139461-Alkaloids, pubmed-meshheading:12139461-Animals, pubmed-meshheading:12139461-Antimalarials, pubmed-meshheading:12139461-Cell Line, pubmed-meshheading:12139461-DNA, pubmed-meshheading:12139461-Heme, pubmed-meshheading:12139461-Hemin, pubmed-meshheading:12139461-Humans, pubmed-meshheading:12139461-Intercalating Agents, pubmed-meshheading:12139461-Plasmodium falciparum, pubmed-meshheading:12139461-Polymers, pubmed-meshheading:12139461-Quinolines, pubmed-meshheading:12139461-Spectrometry, Mass, Electrospray Ionization, pubmed-meshheading:12139461-Structure-Activity Relationship, pubmed-meshheading:12139461-Topoisomerase II Inhibitors, pubmed-meshheading:12139461-Trypanocidal Agents, pubmed-meshheading:12139461-Trypanosoma brucei brucei, pubmed-meshheading:12139461-Trypanosoma cruzi
pubmed:year
2002
pubmed:articleTitle
Synthesis, cytotoxicity, and antiplasmodial and antitrypanosomal activity of new neocryptolepine derivatives.
pubmed:affiliation
Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
pubmed:publicationType
Journal Article