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.authorBecker, Johnen_ZA
dc.contributor.authorvan der Merwe, Marinaen_ZA
dc.contributor.authorvan Brummelen, Annaen_ZA
dc.contributor.authorPillay, Pamishaen_ZA
dc.contributor.authorCrampton, Bridgeten_ZA
dc.contributor.authorMmutlane, Edwinen_ZA
dc.contributor.authorParkinson, Chrisen_ZA
dc.contributor.authorvan Heerden, Fanieen_ZA
dc.contributor.authorCrouch, Neilen_ZA
dc.contributor.authorSmith, Peteren_ZA
dc.contributor.authorMancama, Daluen_ZA
dc.contributor.authorMaharaj, Vineshen_ZA
dc.date.accessioned2015-11-11T12:02:06Z
dc.date.available2015-11-11T12:02:06Z
dc.date.issued2011en_ZA
dc.description.abstractBACKGROUND: 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.identifier.apacitationBecker, J., van der Merwe, M., van Brummelen, A., Pillay, P., Crampton, B., Mmutlane, E., ... Maharaj, V. (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. <i>Malaria Journal</i>, http://hdl.handle.net/11427/14890en_ZA
dc.identifier.chicagocitationBecker, John, Marina van der Merwe, Anna van Brummelen, Pamisha Pillay, Bridget Crampton, Edwin Mmutlane, Chris Parkinson, et al "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." <i>Malaria Journal</i> (2011) http://hdl.handle.net/11427/14890en_ZA
dc.identifier.citationBecker, 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.ris TY - Journal Article AU - Becker, John AU - van der Merwe, Marina AU - van Brummelen, Anna AU - Pillay, Pamisha AU - Crampton, Bridget AU - Mmutlane, Edwin AU - Parkinson, Chris AU - van Heerden, Fanie AU - Crouch, Neil AU - Smith, Peter AU - Mancama, Dalu AU - Maharaj, Vinesh AB - 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. DA - 2011 DB - OpenUCT DO - 10.1186/1475-2875-10-295 DP - University of Cape Town J1 - Malaria Journal LK - https://open.uct.ac.za PB - University of Cape Town PY - 2011 T1 - 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 TI - 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 UR - http://hdl.handle.net/11427/14890 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/14890
dc.identifier.urihttp://dx.doi.org/10.1186/1475-2875-10-295
dc.identifier.vancouvercitationBecker J, van der Merwe M, van Brummelen A, Pillay P, Crampton B, Mmutlane E, et al. 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. Malaria Journal. 2011; http://hdl.handle.net/11427/14890.en_ZA
dc.language.isoengen_ZA
dc.publisherBioMed Central Ltden_ZA
dc.publisher.departmentDivision of Clinical Pharmacologyen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Licenseen_ZA
dc.rights.holder2011 Becker et al; licensee BioMed Central Ltd.en_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/2.0en_ZA
dc.sourceMalaria Journalen_ZA
dc.source.urihttp://www.malariajournal.com/en_ZA
dc.subject.otherAnti-plasmodial Activityen_ZA
dc.subject.otherAnti-malarial Activityen_ZA
dc.subject.otherSesquiterpene Lactoneen_ZA
dc.subject.otherParasite Lactate Dehydrogenaseen_ZA
dc.subject.otherpLDH Assayen_ZA
dc.titleIn vitro anti-plasmodial activity of Dicoma anomala subsp. gerrardii (Asteraceae): identification of its main active constituent, structure-activity relationship studies and gene expression profilingen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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