Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitro growth of Plasmodium falciparum
Identifieur interne : 001350 ( Istex/Corpus ); précédent : 001349; suivant : 001351Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitro growth of Plasmodium falciparum
Auteurs : Leonie Harmse ; Robyn Van Zyl ; Nathanael Gray ; Peter Schultz ; Sophie Leclerc ; Laurent Meijer ; Christian Doerig ; Ivan HavlikSource :
- Biochemical Pharmacology [ 0006-2952 ] ; 2001.
English descriptors
- KwdEn :
- Teeft :
- Antimalarial, Antimalarial activity, Assay, Biochem, Biochemical pharmacology, Cdks, Compound, Cyclin, Derivative, Doerig, Enzyme, Enzyme system, Experimental details, Falciparum, Falciparum enzymes, Gametocyte, Gametocyte formation, Harmse, High activity, Inhibitor, Inhibitory effect, Isomer, Isopentenyladenine, Kinase, Kinase activity, Kinase inhibitors, Meijer, Olomoucine, Parasite, Parasite growth, Pharmacology, Plasmodium, Plasmodium falciparum, Plasmodium falciparum protein kinase, Protein kinase, Protein kinases, Purine, Purine derivatives, Purine ring, Purvalanol, Purvalanol series, Ring stage, Roscovitine, Structural comparison, Submicromolar, Substituent, Substitution, Unpublished observations, Various purine derivatives.
Abstract
Abstract: The development of novel chemotherapeutic agents has become an urgent task due to the development and rapid spread of drug resistance in Plasmodium falciparum, the protozoan parasite responsible for cerebral malaria. Cyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle, and several enzymes of this family have been identified in P. falciparum. In recent years, a number of purine-derived kinase inhibitors have been synthesised, some of which display selective activity against CDKs. This report describes a study in which various purine derivatives were screened for in vitro antimalarial activity. The erythrocytic asexual stages of the chloroquine-resistant P. falciparum strain (FCR-3) were cultivated in vitro in the presence of the various purines, and their effect on parasite proliferation was determined by the [3H]hypoxanthine incorporation assay. Our results show considerable variation in the sensitivity of P. falciparum to the different purines, as well as a general independence from their effect on purified starfish CDK1/cyclin B activity, which has been the standard assay used to identify CDK-specific inhibitors. Two subfamilies of purines with moderate to poor activity against CDK1/cyclin B activity showed submicromolar activity against P. falciparum. Structure-activity analysis indicates that certain structural features are associated with increased activity against P. falciparum. These features can be exploited to synthesise compounds with higher activity and specificity towards P. falciparum.
Url:
DOI: 10.1016/S0006-2952(01)00644-X
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ISTEX:9A5ACF2A691D8978BC3B7521E442FDE8D28344B2Le document en format XML
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Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa</mods:affiliation></affiliation></author><author><name sortKey="Van Zyl, Robyn" sort="Van Zyl, Robyn" uniqKey="Van Zyl R" first="Robyn" last="Van Zyl">Robyn Van Zyl</name><affiliation><mods:affiliation>Department of Experimental and Clinical Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa</mods:affiliation></affiliation></author><author><name sortKey="Gray, Nathanael" sort="Gray, Nathanael" uniqKey="Gray N" first="Nathanael" last="Gray">Nathanael Gray</name><affiliation><mods:affiliation>Genomics Institute of the Novartis Research Foundation, 3115 Merryfield Row, Suite 200, San Diego, CA 92121, USA</mods:affiliation></affiliation></author><author><name sortKey="Schultz, Peter" sort="Schultz, Peter" uniqKey="Schultz P" first="Peter" last="Schultz">Peter Schultz</name><affiliation><mods:affiliation>Genomics Institute of the Novartis Research Foundation, 3115 Merryfield Row, Suite 200, San Diego, CA 92121, USA</mods:affiliation></affiliation></author><author><name sortKey="Leclerc, Sophie" sort="Leclerc, Sophie" uniqKey="Leclerc S" first="Sophie" last="Leclerc">Sophie Leclerc</name><affiliation><mods:affiliation>Station Biologique de Roscoff, C.N.R.S., BP 74, 29682 Roscoff cedex, Bretagne, France</mods:affiliation></affiliation></author><author><name sortKey="Meijer, Laurent" sort="Meijer, Laurent" uniqKey="Meijer L" first="Laurent" last="Meijer">Laurent Meijer</name><affiliation><mods:affiliation>Station Biologique de Roscoff, C.N.R.S., BP 74, 29682 Roscoff cedex, Bretagne, France</mods:affiliation></affiliation></author><author><name sortKey="Doerig, Christian" sort="Doerig, Christian" uniqKey="Doerig C" first="Christian" last="Doerig">Christian Doerig</name><affiliation><mods:affiliation>Unité INSERM U511, La Pitié-Salpétrière, 91 Bd de l’Hôpital, 75643 Paris cedex 13, France</mods:affiliation></affiliation></author><author><name sortKey="Havlik, Ivan" sort="Havlik, Ivan" uniqKey="Havlik I" first="Ivan" last="Havlik">Ivan Havlik</name><affiliation><mods:affiliation>Department of Experimental and Clinical Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Biochemical Pharmacology</title><title level="j" type="abbrev">BCP</title><idno type="ISSN">0006-2952</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="2001">2001</date><biblScope unit="volume">62</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="341">341</biblScope><biblScope unit="page" to="348">348</biblScope></imprint><idno type="ISSN">0006-2952</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-2952</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cyclin-dependent kinases</term><term>Kinase inhibitors</term><term>Malaria</term><term>Olomoucine</term><term>Plasmodium falciparum</term><term>Purvalanol</term><term>Roscovitine</term></keywords><keywords scheme="Teeft" xml:lang="en"><term>Antimalarial</term><term>Antimalarial activity</term><term>Assay</term><term>Biochem</term><term>Biochemical pharmacology</term><term>Cdks</term><term>Compound</term><term>Cyclin</term><term>Derivative</term><term>Doerig</term><term>Enzyme</term><term>Enzyme system</term><term>Experimental details</term><term>Falciparum</term><term>Falciparum enzymes</term><term>Gametocyte</term><term>Gametocyte formation</term><term>Harmse</term><term>High activity</term><term>Inhibitor</term><term>Inhibitory effect</term><term>Isomer</term><term>Isopentenyladenine</term><term>Kinase</term><term>Kinase activity</term><term>Kinase inhibitors</term><term>Meijer</term><term>Olomoucine</term><term>Parasite</term><term>Parasite growth</term><term>Pharmacology</term><term>Plasmodium</term><term>Plasmodium falciparum</term><term>Plasmodium falciparum protein kinase</term><term>Protein kinase</term><term>Protein kinases</term><term>Purine</term><term>Purine derivatives</term><term>Purine ring</term><term>Purvalanol</term><term>Purvalanol series</term><term>Ring stage</term><term>Roscovitine</term><term>Structural comparison</term><term>Submicromolar</term><term>Substituent</term><term>Substitution</term><term>Unpublished observations</term><term>Various purine derivatives</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: The development of novel chemotherapeutic agents has become an urgent task due to the development and rapid spread of drug resistance in Plasmodium falciparum, the protozoan parasite responsible for cerebral malaria. Cyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle, and several enzymes of this family have been identified in P. falciparum. In recent years, a number of purine-derived kinase inhibitors have been synthesised, some of which display selective activity against CDKs. This report describes a study in which various purine derivatives were screened for in vitro antimalarial activity. The erythrocytic asexual stages of the chloroquine-resistant P. falciparum strain (FCR-3) were cultivated in vitro in the presence of the various purines, and their effect on parasite proliferation was determined by the [3H]hypoxanthine incorporation assay. Our results show considerable variation in the sensitivity of P. falciparum to the different purines, as well as a general independence from their effect on purified starfish CDK1/cyclin B activity, which has been the standard assay used to identify CDK-specific inhibitors. Two subfamilies of purines with moderate to poor activity against CDK1/cyclin B activity showed submicromolar activity against P. falciparum. Structure-activity analysis indicates that certain structural features are associated with increased activity against P. falciparum. These features can be exploited to synthesise compounds with higher activity and specificity towards P. falciparum.</div></front></TEI><istex><corpusName>elsevier</corpusName><keywords><teeft><json:string>falciparum</json:string><json:string>kinase</json:string><json:string>purine</json:string><json:string>purvalanol</json:string><json:string>antimalarial</json:string><json:string>roscovitine</json:string><json:string>plasmodium</json:string><json:string>olomoucine</json:string><json:string>parasite</json:string><json:string>antimalarial activity</json:string><json:string>cdks</json:string><json:string>isomer</json:string><json:string>meijer</json:string><json:string>gametocyte</json:string><json:string>harmse</json:string><json:string>doerig</json:string><json:string>pharmacology</json:string><json:string>cyclin</json:string><json:string>biochemical pharmacology</json:string><json:string>submicromolar</json:string><json:string>purine derivatives</json:string><json:string>plasmodium 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details</json:string><json:string>parasite growth</json:string><json:string>ring stage</json:string><json:string>compound</json:string><json:string>enzyme</json:string></teeft></keywords><author><json:item><name>Leonie Harmse</name><affiliations><json:string>E-mail: leoni@hixnet.co.za</json:string><json:string>Department of Experimental and Clinical Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa</json:string></affiliations></json:item><json:item><name>Robyn van Zyl</name><affiliations><json:string>Department of Experimental and Clinical Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa</json:string></affiliations></json:item><json:item><name>Nathanael Gray</name><affiliations><json:string>Genomics Institute of the Novartis Research Foundation, 3115 Merryfield Row, Suite 200, San Diego, CA 92121, USA</json:string></affiliations></json:item><json:item><name>Peter Schultz</name><affiliations><json:string>Genomics Institute of the Novartis Research Foundation, 3115 Merryfield Row, Suite 200, San Diego, CA 92121, USA</json:string></affiliations></json:item><json:item><name>Sophie Leclerc</name><affiliations><json:string>Station Biologique de Roscoff, C.N.R.S., BP 74, 29682 Roscoff cedex, Bretagne, France</json:string></affiliations></json:item><json:item><name>Laurent Meijer</name><affiliations><json:string>Station Biologique de Roscoff, C.N.R.S., BP 74, 29682 Roscoff cedex, Bretagne, France</json:string></affiliations></json:item><json:item><name>Christian Doerig</name><affiliations><json:string>Unité INSERM U511, La Pitié-Salpétrière, 91 Bd de l’Hôpital, 75643 Paris cedex 13, France</json:string></affiliations></json:item><json:item><name>Ivan Havlik</name><affiliations><json:string>Department of Experimental and Clinical Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Plasmodium falciparum</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Malaria</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Cyclin-dependent kinases</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Olomoucine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Roscovitine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Purvalanol</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Kinase inhibitors</value></json:item></subject><articleId><json:string>6834</json:string></articleId><arkIstex>ark:/67375/6H6-XMF89QKX-B</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>Full-length article</json:string></originalGenre><abstract>Abstract: The development of novel chemotherapeutic agents has become an urgent task due to the development and rapid spread of drug resistance in Plasmodium falciparum, the protozoan parasite responsible for cerebral malaria. Cyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle, and several enzymes of this family have been identified in P. falciparum. In recent years, a number of purine-derived kinase inhibitors have been synthesised, some of which display selective activity against CDKs. This report describes a study in which various purine derivatives were screened for in vitro antimalarial activity. The erythrocytic asexual stages of the chloroquine-resistant P. falciparum strain (FCR-3) were cultivated in vitro in the presence of the various purines, and their effect on parasite proliferation was determined by the [3H]hypoxanthine incorporation assay. Our results show considerable variation in the sensitivity of P. falciparum to the different purines, as well as a general independence from their effect on purified starfish CDK1/cyclin B activity, which has been the standard assay used to identify CDK-specific inhibitors. Two subfamilies of purines with moderate to poor activity against CDK1/cyclin B activity showed submicromolar activity against P. falciparum. Structure-activity analysis indicates that certain structural features are associated with increased activity against P. falciparum. These features can be exploited to synthesise compounds with higher activity and specificity towards P. falciparum.</abstract><qualityIndicators><score>9.59</score><pdfWordCount>4950</pdfWordCount><pdfCharCount>30609</pdfCharCount><pdfVersion>1.2</pdfVersion><pdfPageCount>8</pdfPageCount><pdfPageSize>596 x 792 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractWordCount>220</abstractWordCount><abstractCharCount>1575</abstractCharCount><keywordCount>7</keywordCount></qualityIndicators><title>Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitro growth of Plasmodium falciparum</title><pmid><json:string>11434907</json:string></pmid><pii><json:string>S0006-2952(01)00644-X</json:string></pii><genre><json:string>research-article</json:string></genre><host><title>Biochemical Pharmacology</title><language><json:string>unknown</json:string></language><publicationDate>2001</publicationDate><issn><json:string>0006-2952</json:string></issn><pii><json:string>S0006-2952(00)X0160-8</json:string></pii><volume>62</volume><issue>3</issue><pages><first>341</first><last>348</last></pages><genre><json:string>journal</json:string></genre></host><namedEntities><unitex><date><json:string>2001</json:string></date><geogName></geogName><orgName><json:string>Research and Foreign Affairs</json:string><json:string>University of the Witwatersrand</json:string><json:string>Elsevier Science Inc.</json:string><json:string>European Commission</json:string><json:string>Research Institute for Diseases</json:string><json:string>INCO-DC</json:string></orgName><orgName_funder><json:string>INCO-DC</json:string></orgName_funder><orgName_provider></orgName_provider><persName><json:string>La Pitie-Salpetriere</json:string><json:string>Janet Freese</json:string><json:string>L. Harmse</json:string><json:string>M. Roscovitine</json:string><json:string>Ministeries</json:string><json:string>Nathanael Grayb</json:string><json:string>Christian Doerigd</json:string><json:string>Laurent Meijerc</json:string><json:string>Olomoucine</json:string><json:string>Sophie Leclercc</json:string><json:string>Robyn van Zyla</json:string><json:string>Peter Schultzb</json:string><json:string>L. Meijer</json:string></persName><placeName><json:string>San Diego</json:string><json:string>Durban</json:string><json:string>UK</json:string><json:string>Parktown</json:string><json:string>South Africa</json:string><json:string>CA</json:string><json:string>France</json:string></placeName><ref_url></ref_url><ref_bibl><json:string>[23]</json:string><json:string>[15,16]</json:string><json:string>[18]</json:string><json:string>[6,13]</json:string><json:string>[22]</json:string><json:string>[8]</json:string><json:string>[17]</json:string><json:string>L. Harmse et al.</json:string><json:string>[21]</json:string><json:string>[3]</json:string><json:string>[20]</json:string><json:string>[12,13]</json:string><json:string>[7]</json:string><json:string>[14,21]</json:string><json:string>[1,2]</json:string><json:string>[24]</json:string><json:string>[4,5]</json:string><json:string>Genomics Institute of the Novartis Research Foundation, 3115</json:string><json:string>[19]</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/6H6-XMF89QKX-B</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - pharmacology & pharmacy</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - clinical medicine</json:string><json:string>3 - pharmacology & pharmacy</json:string></scienceMetrix><scopus><json:string>1 - Life Sciences</json:string><json:string>2 - Pharmacology, Toxicology and Pharmaceutics</json:string><json:string>3 - Pharmacology</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Biochemistry, Genetics and Molecular Biology</json:string><json:string>3 - Biochemistry</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences biologiques fondamentales et appliquees. psychologie</json:string></inist></categories><publicationDate>2001</publicationDate><copyrightDate>2001</copyrightDate><doi><json:string>10.1016/S0006-2952(01)00644-X</json:string></doi><id>9A5ACF2A691D8978BC3B7521E442FDE8D28344B2</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-XMF89QKX-B/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-XMF89QKX-B/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/6H6-XMF89QKX-B/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitro growth of Plasmodium falciparum</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://scientific-publisher.data.istex.fr">ELSEVIER</publisher><availability><licence><p>©2001 Elsevier Science Inc.</p></licence><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M">elsevier</p></availability><date>2001</date></publicationStmt><notesStmt><note type="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note><note>Abbreviations: CDK, cyclin-dependent kinase; CDK1, cyclin-dependent kinase 1; and PfPK, Plasmodium falciparum protein kinase.</note><note type="content">Fig. 1: Structural comparison and dose-response curves with ic50 values showing the similar inhibitory effect of olomoucine, roscovitine, and isopentenyladenine on the proliferation of P. falciparum. Parasites synchronised in the ring stage (200 μL) were plated in microtiter plates at a parasitaemia of 0.5% and a haematocrit of 1% and incubated for 76 hrs in the presence of various concentrations of purines. Each point represents the percentage of [3H]hypoxanthine incorporation into nucleic acid relative to the untreated control and is the mean ± SD of triplicate samples. The curves and the ic50 values were obtained by analysis with the Prizm®, program. This curve represents the results of one representative experiment out of a series of four similar experiments performed.</note><note type="content">Fig. 2: Structural comparison and dose-response curves of the purvalanol series of compounds showing the variation in activity against P. falciparum. Experimental details were as described in the legend of Fig. 1.</note><note type="content">Fig. 3: Structural comparison and dose-response curves of compounds 99 and 101 showing their submicromolar inhibitory effect on the proliferation of P. falciparum. Experimental details were as described in the legend of Fig. 1.</note><note type="content">Fig. 4: Structural comparison and dose-response curves showing the effect of the substitutions on C2 and C6 of the purine ring. Experimental details were as described in the legend of Fig. 1.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitro growth of Plasmodium falciparum</title><author xml:id="author-0000"><persName><forename type="first">Leonie</forename><surname>Harmse</surname></persName><email>leoni@hixnet.co.za</email><note type="correspondence"><p>Corresponding author. Tel.: +27-11-717-2271; fax: +1-27-11-643-5415</p></note><affiliation>Department of Experimental and Clinical Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Robyn</forename><surname>van Zyl</surname></persName><affiliation>Department of Experimental and Clinical Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Nathanael</forename><surname>Gray</surname></persName><affiliation>Genomics Institute of the Novartis Research Foundation, 3115 Merryfield Row, Suite 200, San Diego, CA 92121, USA</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Peter</forename><surname>Schultz</surname></persName><affiliation>Genomics Institute of the Novartis Research Foundation, 3115 Merryfield Row, Suite 200, San Diego, CA 92121, USA</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Sophie</forename><surname>Leclerc</surname></persName><affiliation>Station Biologique de Roscoff, C.N.R.S., BP 74, 29682 Roscoff cedex, Bretagne, France</affiliation></author><author xml:id="author-0005"><persName><forename type="first">Laurent</forename><surname>Meijer</surname></persName><affiliation>Station Biologique de Roscoff, C.N.R.S., BP 74, 29682 Roscoff cedex, Bretagne, France</affiliation></author><author xml:id="author-0006"><persName><forename type="first">Christian</forename><surname>Doerig</surname></persName><affiliation>Unité INSERM U511, La Pitié-Salpétrière, 91 Bd de l’Hôpital, 75643 Paris cedex 13, France</affiliation></author><author xml:id="author-0007"><persName><forename type="first">Ivan</forename><surname>Havlik</surname></persName><affiliation>Department of Experimental and Clinical Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa</affiliation></author><idno type="istex">9A5ACF2A691D8978BC3B7521E442FDE8D28344B2</idno><idno type="ark">ark:/67375/6H6-XMF89QKX-B</idno><idno type="DOI">10.1016/S0006-2952(01)00644-X</idno><idno type="PII">S0006-2952(01)00644-X</idno><idno type="article-id">6834</idno></analytic><monogr><title level="j">Biochemical Pharmacology</title><title level="j" type="abbrev">BCP</title><idno type="pISSN">0006-2952</idno><idno type="PII">S0006-2952(00)X0160-8</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="2001"></date><biblScope unit="volume">62</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="341">341</biblScope><biblScope unit="page" to="348">348</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2001</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Abstract: The development of novel chemotherapeutic agents has become an urgent task due to the development and rapid spread of drug resistance in Plasmodium falciparum, the protozoan parasite responsible for cerebral malaria. Cyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle, and several enzymes of this family have been identified in P. falciparum. In recent years, a number of purine-derived kinase inhibitors have been synthesised, some of which display selective activity against CDKs. This report describes a study in which various purine derivatives were screened for in vitro antimalarial activity. The erythrocytic asexual stages of the chloroquine-resistant P. falciparum strain (FCR-3) were cultivated in vitro in the presence of the various purines, and their effect on parasite proliferation was determined by the [3H]hypoxanthine incorporation assay. Our results show considerable variation in the sensitivity of P. falciparum to the different purines, as well as a general independence from their effect on purified starfish CDK1/cyclin B activity, which has been the standard assay used to identify CDK-specific inhibitors. Two subfamilies of purines with moderate to poor activity against CDK1/cyclin B activity showed submicromolar activity against P. falciparum. Structure-activity analysis indicates that certain structural features are associated with increased activity against P. falciparum. These features can be exploited to synthesise compounds with higher activity and specificity towards P. falciparum.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>Plasmodium falciparum</term></item><item><term>Malaria</term></item><item><term>Cyclin-dependent kinases</term></item><item><term>Olomoucine</term></item><item><term>Roscovitine</term></item><item><term>Purvalanol</term></item><item><term>Kinase inhibitors</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2001">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-XMF89QKX-B/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: ce:floats; body; tail"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"><istex:entity SYSTEM="gr1" NDATA="IMAGE" name="GR1"></istex:entity><istex:entity SYSTEM="gr2" NDATA="IMAGE" name="GR2"></istex:entity><istex:entity SYSTEM="gr3" NDATA="IMAGE" name="GR3"></istex:entity><istex:entity SYSTEM="gr4" NDATA="IMAGE" name="GR4"></istex:entity></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="fla" xml:lang="en"><item-info><jid>BCP</jid><aid>6834</aid><ce:pii>S0006-2952(01)00644-X</ce:pii><ce:doi>10.1016/S0006-2952(01)00644-X</ce:doi><ce:copyright type="full-transfer" year="2001">Elsevier Science Inc.</ce:copyright></item-info><head><ce:title>Structure-activity relationships and inhibitory effects of various purine derivatives on the <ce:italic>in vitro</ce:italic> growth of <ce:italic>Plasmodium falciparum</ce:italic><ce:cross-ref refid="FN1"><ce:sup loc="post">1</ce:sup></ce:cross-ref><ce:footnote id="FN1"><ce:label>1</ce:label><ce:note-para><ce:italic>Abbreviations:</ce:italic> CDK, cyclin-dependent kinase; CDK1, cyclin-dependent kinase 1; and PfPK, <ce:italic>Plasmodium falciparum</ce:italic> protein kinase.</ce:note-para></ce:footnote></ce:title><ce:author-group><ce:author><ce:given-name>Leonie</ce:given-name><ce:surname>Harmse</ce:surname><ce:cross-ref refid="AFF1"><ce:sup loc="post">a</ce:sup></ce:cross-ref><ce:cross-ref refid="CORR1">*</ce:cross-ref><ce:e-address type="email">leoni@hixnet.co.za</ce:e-address></ce:author><ce:author><ce:given-name>Robyn</ce:given-name><ce:surname>van Zyl</ce:surname><ce:cross-ref refid="AFF1"><ce:sup loc="post">a</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Nathanael</ce:given-name><ce:surname>Gray</ce:surname><ce:cross-ref refid="AFF2"><ce:sup loc="post">b</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Peter</ce:given-name><ce:surname>Schultz</ce:surname><ce:cross-ref refid="AFF2"><ce:sup loc="post">b</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Sophie</ce:given-name><ce:surname>Leclerc</ce:surname><ce:cross-ref refid="AFF3"><ce:sup loc="post">c</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Laurent</ce:given-name><ce:surname>Meijer</ce:surname><ce:cross-ref refid="AFF3"><ce:sup loc="post">c</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Christian</ce:given-name><ce:surname>Doerig</ce:surname><ce:cross-ref refid="AFF4"><ce:sup loc="post">d</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Ivan</ce:given-name><ce:surname>Havlik</ce:surname><ce:cross-ref refid="AFF1"><ce:sup loc="post">a</ce:sup></ce:cross-ref></ce:author><ce:affiliation id="AFF1"><ce:label>a</ce:label><ce:textfn>Department of Experimental and Clinical Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa</ce:textfn></ce:affiliation><ce:affiliation id="AFF2"><ce:label>b</ce:label><ce:textfn>Genomics Institute of the Novartis Research Foundation, 3115 Merryfield Row, Suite 200, San Diego, CA 92121, USA</ce:textfn></ce:affiliation><ce:affiliation id="AFF3"><ce:label>c</ce:label><ce:textfn>Station Biologique de Roscoff, C.N.R.S., BP 74, 29682 Roscoff cedex, Bretagne, France</ce:textfn></ce:affiliation><ce:affiliation id="AFF4"><ce:label>d</ce:label><ce:textfn>Unité INSERM U511, La Pitié-Salpétrière, 91 Bd de l’Hôpital, 75643 Paris cedex 13, France</ce:textfn></ce:affiliation><ce:correspondence id="CORR1"><ce:label>*</ce:label><ce:text>Corresponding author. Tel.: +27-11-717-2271; fax: +1-27-11-643-5415</ce:text></ce:correspondence></ce:author-group><ce:date-received day="20" month="9" year="2000"></ce:date-received><ce:date-accepted day="29" month="1" year="2001"></ce:date-accepted><ce:abstract class="author"><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para view="all" id="simple-para.0030">The development of novel chemotherapeutic agents has become an urgent task due to the development and rapid spread of drug resistance in <ce:italic>Plasmodium falciparum</ce:italic>, the protozoan parasite responsible for cerebral malaria. Cyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle, and several enzymes of this family have been identified in <ce:italic>P. falciparum</ce:italic>. In recent years, a number of purine-derived kinase inhibitors have been synthesised, some of which display selective activity against CDKs. This report describes a study in which various purine derivatives were screened for <ce:italic>in vitro</ce:italic> antimalarial activity. The erythrocytic asexual stages of the chloroquine-resistant <ce:italic>P. falciparum</ce:italic> strain (FCR-3) were cultivated <ce:italic>in vitro</ce:italic> in the presence of the various purines, and their effect on parasite proliferation was determined by the [<ce:sup loc="pre">3</ce:sup>H]hypoxanthine incorporation assay. Our results show considerable variation in the sensitivity of <ce:italic>P. falciparum</ce:italic> to the different purines, as well as a general independence from their effect on purified starfish CDK1/cyclin B activity, which has been the standard assay used to identify CDK-specific inhibitors. Two subfamilies of purines with moderate to poor activity against CDK1/cyclin B activity showed submicromolar activity against <ce:italic>P. falciparum</ce:italic>. Structure-activity analysis indicates that certain structural features are associated with increased activity against <ce:italic>P. falciparum</ce:italic>. These features can be exploited to synthesise compounds with higher activity and specificity towards <ce:italic>P. falciparum</ce:italic>.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords class="keyword"><ce:section-title>Keywords</ce:section-title><ce:keyword><ce:text><ce:italic>Plasmodium falciparum</ce:italic></ce:text></ce:keyword><ce:keyword><ce:text>Malaria</ce:text></ce:keyword><ce:keyword><ce:text>Cyclin-dependent kinases</ce:text></ce:keyword><ce:keyword><ce:text>Olomoucine</ce:text></ce:keyword><ce:keyword><ce:text>Roscovitine</ce:text></ce:keyword><ce:keyword><ce:text>Purvalanol</ce:text></ce:keyword><ce:keyword><ce:text>Kinase inhibitors</ce:text></ce:keyword></ce:keywords></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitro growth of Plasmodium falciparum</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Structure-activity relationships and inhibitory effects of various purine derivatives on the</title></titleInfo><name type="personal"><namePart type="given">Leonie</namePart><namePart type="family">Harmse</namePart><affiliation>E-mail: leoni@hixnet.co.za</affiliation><affiliation>Department of Experimental and Clinical Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa</affiliation><description>Corresponding author. Tel.: +27-11-717-2271; fax: +1-27-11-643-5415</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Robyn</namePart><namePart type="family">van Zyl</namePart><affiliation>Department of Experimental and Clinical Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nathanael</namePart><namePart type="family">Gray</namePart><affiliation>Genomics Institute of the Novartis Research Foundation, 3115 Merryfield Row, Suite 200, San Diego, CA 92121, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">Schultz</namePart><affiliation>Genomics Institute of the Novartis Research Foundation, 3115 Merryfield Row, Suite 200, San Diego, CA 92121, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sophie</namePart><namePart type="family">Leclerc</namePart><affiliation>Station Biologique de Roscoff, C.N.R.S., BP 74, 29682 Roscoff cedex, Bretagne, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Laurent</namePart><namePart type="family">Meijer</namePart><affiliation>Station Biologique de Roscoff, C.N.R.S., BP 74, 29682 Roscoff cedex, Bretagne, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christian</namePart><namePart type="family">Doerig</namePart><affiliation>Unité INSERM U511, La Pitié-Salpétrière, 91 Bd de l’Hôpital, 75643 Paris cedex 13, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ivan</namePart><namePart type="family">Havlik</namePart><affiliation>Department of Experimental and Clinical Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">2001</dateIssued><copyrightDate encoding="w3cdtf">2001</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><abstract lang="en">Abstract: The development of novel chemotherapeutic agents has become an urgent task due to the development and rapid spread of drug resistance in Plasmodium falciparum, the protozoan parasite responsible for cerebral malaria. Cyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle, and several enzymes of this family have been identified in P. falciparum. In recent years, a number of purine-derived kinase inhibitors have been synthesised, some of which display selective activity against CDKs. This report describes a study in which various purine derivatives were screened for in vitro antimalarial activity. The erythrocytic asexual stages of the chloroquine-resistant P. falciparum strain (FCR-3) were cultivated in vitro in the presence of the various purines, and their effect on parasite proliferation was determined by the [3H]hypoxanthine incorporation assay. Our results show considerable variation in the sensitivity of P. falciparum to the different purines, as well as a general independence from their effect on purified starfish CDK1/cyclin B activity, which has been the standard assay used to identify CDK-specific inhibitors. Two subfamilies of purines with moderate to poor activity against CDK1/cyclin B activity showed submicromolar activity against P. falciparum. Structure-activity analysis indicates that certain structural features are associated with increased activity against P. falciparum. These features can be exploited to synthesise compounds with higher activity and specificity towards P. falciparum.</abstract><note type="footnote">Abbreviations: CDK, cyclin-dependent kinase; CDK1, cyclin-dependent kinase 1; and PfPK, Plasmodium falciparum protein kinase.</note><note type="content">Fig. 1: Structural comparison and dose-response curves with ic50 values showing the similar inhibitory effect of olomoucine, roscovitine, and isopentenyladenine on the proliferation of P. falciparum. Parasites synchronised in the ring stage (200 μL) were plated in microtiter plates at a parasitaemia of 0.5% and a haematocrit of 1% and incubated for 76 hrs in the presence of various concentrations of purines. Each point represents the percentage of [3H]hypoxanthine incorporation into nucleic acid relative to the untreated control and is the mean ± SD of triplicate samples. The curves and the ic50 values were obtained by analysis with the Prizm®, program. This curve represents the results of one representative experiment out of a series of four similar experiments performed.</note><note type="content">Fig. 2: Structural comparison and dose-response curves of the purvalanol series of compounds showing the variation in activity against P. falciparum. Experimental details were as described in the legend of Fig. 1.</note><note type="content">Fig. 3: Structural comparison and dose-response curves of compounds 99 and 101 showing their submicromolar inhibitory effect on the proliferation of P. falciparum. Experimental details were as described in the legend of Fig. 1.</note><note type="content">Fig. 4: Structural comparison and dose-response curves showing the effect of the substitutions on C2 and C6 of the purine ring. Experimental details were as described in the legend of Fig. 1.</note><subject lang="en"><genre>Keywords</genre><topic>Plasmodium falciparum</topic><topic>Malaria</topic><topic>Cyclin-dependent kinases</topic><topic>Olomoucine</topic><topic>Roscovitine</topic><topic>Purvalanol</topic><topic>Kinase inhibitors</topic></subject><relatedItem type="host"><titleInfo><title>Biochemical Pharmacology</title></titleInfo><titleInfo type="abbreviated"><title>BCP</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">2001</dateIssued></originInfo><identifier type="ISSN">0006-2952</identifier><identifier type="PII">S0006-2952(00)X0160-8</identifier><part><date>2001</date><detail type="volume"><number>62</number><caption>vol.</caption></detail><detail type="issue"><number>3</number><caption>no.</caption></detail><extent unit="issue-pages"><start>261</start><end>400</end></extent><extent unit="pages"><start>341</start><end>348</end></extent></part></relatedItem><identifier type="istex">9A5ACF2A691D8978BC3B7521E442FDE8D28344B2</identifier><identifier type="ark">ark:/67375/6H6-XMF89QKX-B</identifier><identifier type="DOI">10.1016/S0006-2952(01)00644-X</identifier><identifier type="PII">S0006-2952(01)00644-X</identifier><identifier type="ArticleID">6834</identifier><accessCondition type="use and reproduction" contentType="copyright">©2001 Elsevier Science Inc.</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M">elsevier</recordContentSource><recordOrigin>Elsevier Science Inc., ©2001</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-XMF89QKX-B/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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