In vitro anti-plasmodial activity of Dicoma anomala subsp. gerrardii (Asteraceae): identification of its main active constituent, structure-activity relationship studies and gene expression profiling

 

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dc.contributor.author Becker, John en_ZA
dc.contributor.author van der Merwe, Marina en_ZA
dc.contributor.author van Brummelen, Anna en_ZA
dc.contributor.author Pillay, Pamisha en_ZA
dc.contributor.author Crampton, Bridget en_ZA
dc.contributor.author Mmutlane, Edwin en_ZA
dc.contributor.author Parkinson, Chris en_ZA
dc.contributor.author van Heerden, Fanie en_ZA
dc.contributor.author Crouch, Neil en_ZA
dc.contributor.author Smith, Peter en_ZA
dc.contributor.author Mancama, Dalu en_ZA
dc.contributor.author Maharaj, Vinesh en_ZA
dc.date.accessioned 2015-11-11T12:02:06Z
dc.date.available 2015-11-11T12:02:06Z
dc.date.issued 2011 en_ZA
dc.identifier.citation Becker, J. V., Van der Merwe, M. M., Van Brummelen, A. C., Pillay, P., Crampton, B. G., Mmutlane, E. M., ... & Maharaj, V. J. (2011). In vitro anti-plasmodial activity of Dicoma anomala subsp. gerrardii (Asteraceae): identification of its main active constituent, structure-activity relationship studies and gene expression profiling. Malar J, 10(1), 1À11. en_ZA
dc.identifier.uri http://hdl.handle.net/11427/14890
dc.identifier.uri http://dx.doi.org/10.1186/1475-2875-10-295
dc.description.abstract BACKGROUND: Anti-malarial drug resistance threatens to undermine efforts to eliminate this deadly disease. The resulting omnipresent requirement for drugs with novel modes of action prompted a national consortium initiative to discover new anti-plasmodial agents from South African medicinal plants. One of the plants selected for investigation was Dicoma anomala subsp. gerrardii, based on its ethnomedicinal profile. METHODS: Standard phytochemical analysis techniques, including solvent-solvent extraction, thin-layer- and column chromatography, were used to isolate the main active constituent of Dicoma anomala subsp. gerrardii. The crystallized pure compound was identified using nuclear magnetic resonance spectroscopy, mass spectrometry and X-ray crystallography. The compound was tested in vitro on Plasmodium falciparum cultures using the parasite lactate dehydrogenase (pLDH) assay and was found to have anti-malarial activity. To determine the functional groups responsible for the activity, a small collection of synthetic analogues was generated - the aim being to vary features proposed as likely to be related to the anti-malarial activity and to quantify the effect of the modifications in vitro using the pLDH assay. The effects of the pure compound on the P. falciparum transcriptome were subsequently investigated by treating ring-stage parasites (alongside untreated controls), followed by oligonucleotide microarray- and data analysis. RESULTS: The main active constituent was identified as dehydrobrachylaenolide, a eudesmanolide-type sesquiterpene lactone. The compound demonstrated an in vitro IC50 of 1.865 muM against a chloroquine-sensitive strain (D10) of P. falciparum. Synthetic analogues of the compound confirmed an absolute requirement that the alpha-methylene lactone be present in the eudesmanolide before significant anti-malarial activity was observed. This feature is absent in the artemisinins and suggests a different mode of action. Microarray data analysis identified 572 unique genes that were differentially expressed as a result of the treatment and gene ontology analysis identified various biological processes and molecular functions that were significantly affected. Comparison of the dehydrobrachylaenolide treatment transcriptional dataset with a published artesunate (also a sesquiterpene lactone) dataset revealed little overlap. These results strengthen the notion that the isolated compound and the artemisinins have differentiated modes of action. CONCLUSIONS: The novel mode of action of dehydrobrachylaenolide, detected during these studies, will play an ongoing role in advancing anti-plasmodial drug discovery efforts. en_ZA
dc.language.iso eng en_ZA
dc.publisher BioMed Central Ltd en_ZA
dc.rights This is an Open Access article distributed under the terms of the Creative Commons Attribution License en_ZA
dc.rights.uri http://creativecommons.org/licenses/by/2.0 en_ZA
dc.source Malaria Journal en_ZA
dc.source.uri http://www.malariajournal.com/ en_ZA
dc.subject.other Anti-plasmodial Activity en_ZA
dc.subject.other Anti-malarial Activity en_ZA
dc.subject.other Sesquiterpene Lactone en_ZA
dc.subject.other Parasite Lactate Dehydrogenase en_ZA
dc.subject.other pLDH Assay en_ZA
dc.title In vitro anti-plasmodial activity of Dicoma anomala subsp. gerrardii (Asteraceae): identification of its main active constituent, structure-activity relationship studies and gene expression profiling en_ZA
dc.type Journal Article en_ZA
dc.rights.holder 2011 Becker et al; licensee BioMed Central Ltd. en_ZA
uct.type.publication Research en_ZA
uct.type.resource Article en_ZA
dc.publisher.institution University of Cape Town
dc.publisher.faculty Faculty of Health Sciences en_ZA
dc.publisher.department Division of Clinical Pharmacology en_ZA
uct.type.filetype Text
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This is an Open Access article distributed under the terms of the Creative Commons Attribution License Except where otherwise noted, this item's license is described as This is an Open Access article distributed under the terms of the Creative Commons Attribution License