Synthesis, Cytotoxicity, and Antiplasmodial and Antitrypanosomal Activity of New Neocryptolepine Derivatives
Identifieur interne : 000797 ( Istex/Curation ); précédent : 000796; suivant : 000798Synthesis, Cytotoxicity, and Antiplasmodial and Antitrypanosomal Activity of New Neocryptolepine Derivatives
Auteurs : Tim H. M. Jonckers [Belgique] ; Sabine Van Miert [Belgique] ; Kanyanga Cimanga [Belgique] ; Christian Bailly [Belgique] ; Pierre Colson [Belgique] ; Marie-Claire De Pauw-Gillet [Belgique] ; Hilde Van Den Heuvel [Belgique] ; Magda Claeys [Belgique] ; Filip Lemière [Belgique] ; Eddy L. Esmans [Belgique] ; Jef Rozenski [Belgique] ; Ludo Quirijnen [Belgique] ; Louis Maes [Belgique] ; Roger Dommisse [Belgique] ; Guy L. F. Lemière [Belgique] ; Arnold Vlietinck [Belgique] ; Luc Pieters [Belgique]Source :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 2002.
Abstract
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 β-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 β-hematin formation. 2-Bromoneocryptolepine was the most selective compound with an IC50 value against chloroquine-resistant P. falciparum of 4.0 μM in the absence of cytotoxicity (IC50 > 32 μM). Although cryptolepine, a known lead for antimalarials also originally isolated from Cryptolepis sanguinolenta, was more active (IC50 = 2.0 μM), 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.
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DOI: 10.1021/jm011102i
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<author><name sortKey="Van Miert, Sabine" sort="Van Miert, Sabine" uniqKey="Van Miert S" first="Sabine" last="Van Miert">Sabine Van Miert</name>
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<author><name sortKey="Colson, Pierre" sort="Colson, Pierre" uniqKey="Colson P" first="Pierre" last="Colson">Pierre Colson</name>
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<author><name sortKey="De Pauw Gillet, Marie Claire" sort="De Pauw Gillet, Marie Claire" uniqKey="De Pauw Gillet M" first="Marie-Claire" last="De Pauw-Gillet">Marie-Claire De Pauw-Gillet</name>
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<author><name sortKey="Van Den Heuvel, Hilde" sort="Van Den Heuvel, Hilde" uniqKey="Van Den Heuvel H" first="Hilde" last="Van Den Heuvel">Hilde Van Den Heuvel</name>
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<author><name sortKey="Claeys, Magda" sort="Claeys, Magda" uniqKey="Claeys M" first="Magda" last="Claeys">Magda Claeys</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
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<author><name sortKey="Lemiere, Filip" sort="Lemiere, Filip" uniqKey="Lemiere F" first="Filip" last="Lemière">Filip Lemière</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
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<affiliation wicri:level="4"><mods:affiliation> Department of Chemistry, University of Antwerp.</mods:affiliation>
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<author><name sortKey="Esmans, Eddy L" sort="Esmans, Eddy L" uniqKey="Esmans E" first="Eddy L." last="Esmans">Eddy L. Esmans</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
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<affiliation wicri:level="4"><mods:affiliation> Department of Chemistry, University of Antwerp.</mods:affiliation>
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<author><name sortKey="Rozenski, Jef" sort="Rozenski, Jef" uniqKey="Rozenski J" first="Jef" last="Rozenski">Jef Rozenski</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
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<affiliation><mods:affiliation> Rega Institute for Medical Research.</mods:affiliation>
<wicri:noCountry code="no comma"> Rega Institute for Medical Research.</wicri:noCountry>
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<author><name sortKey="Quirijnen, Ludo" sort="Quirijnen, Ludo" uniqKey="Quirijnen L" first="Ludo" last="Quirijnen">Ludo Quirijnen</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
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<affiliation><mods:affiliation> Tibotec-Virco NV.</mods:affiliation>
<wicri:noCountry code="no comma"> Tibotec-Virco NV.</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Maes, Louis" sort="Maes, Louis" uniqKey="Maes L" first="Louis" last="Maes">Louis Maes</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation><mods:affiliation> Tibotec-Virco NV.</mods:affiliation>
<wicri:noCountry code="no comma"> Tibotec-Virco NV.</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Dommisse, Roger" sort="Dommisse, Roger" uniqKey="Dommisse R" first="Roger" last="Dommisse">Roger Dommisse</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Department of Chemistry, University of Antwerp.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
<orgName type="university">Université d'Anvers</orgName>
</affiliation>
</author>
<author><name sortKey="Lemiere, Guy L F" sort="Lemiere, Guy L F" uniqKey="Lemiere G" first="Guy L. F." last="Lemière">Guy L. F. Lemière</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Department of Chemistry, University of Antwerp.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
<orgName type="university">Université d'Anvers</orgName>
</affiliation>
</author>
<author><name sortKey="Vlietinck, Arnold" sort="Vlietinck, Arnold" uniqKey="Vlietinck A" first="Arnold" last="Vlietinck">Arnold Vlietinck</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Department of Pharmaceutical Sciences, University of Antwerp.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
<orgName type="university">Université d'Anvers</orgName>
</affiliation>
</author>
<author><name sortKey="Pieters, Luc" sort="Pieters, Luc" uniqKey="Pieters L" first="Luc" last="Pieters">Luc Pieters</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Department of Pharmaceutical Sciences, University of Antwerp.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
<orgName type="university">Université d'Anvers</orgName>
</affiliation>
<affiliation wicri:level="1"><mods:affiliation> To whom correspondence should be addressed. Phone and fax: (32)3 820 27 09. E-mail pieters@uia.ua.ac.be.</mods:affiliation>
<country wicri:rule="url">Belgique</country>
</affiliation>
</author>
</titleStmt>
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<idno type="doi">10.1021/jm011102i</idno>
<idno type="url">https://api.istex.fr/ark:/67375/TPS-05PG9VCQ-8/fulltext.pdf</idno>
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<sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Synthesis, Cytotoxicity, and Antiplasmodial and Antitrypanosomal Activity of
New Neocryptolepine Derivatives</title>
<author><name sortKey="Jonckers, Tim H M" sort="Jonckers, Tim H M" uniqKey="Jonckers T" first="Tim H. M." last="Jonckers">Tim H. M. Jonckers</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Department of Chemistry, University of Antwerp.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
<orgName type="university">Université d'Anvers</orgName>
</affiliation>
<affiliation><mods:affiliation> These authors contributed equally to this work.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Van Miert, Sabine" sort="Van Miert, Sabine" uniqKey="Van Miert S" first="Sabine" last="Van Miert">Sabine Van Miert</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation><mods:affiliation> These authors contributed equally to this work.</mods:affiliation>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Department of Pharmaceutical Sciences, University of Antwerp.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
<orgName type="university">Université d'Anvers</orgName>
</affiliation>
</author>
<author><name sortKey="Cimanga, Kanyanga" sort="Cimanga, Kanyanga" uniqKey="Cimanga K" first="Kanyanga" last="Cimanga">Kanyanga Cimanga</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Department of Pharmaceutical Sciences, University of Antwerp.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
<orgName type="university">Université d'Anvers</orgName>
</affiliation>
</author>
<author><name sortKey="Bailly, Christian" sort="Bailly, Christian" uniqKey="Bailly C" first="Christian" last="Bailly">Christian Bailly</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation><mods:affiliation> INSERM U-524, Lille.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Colson, Pierre" sort="Colson, Pierre" uniqKey="Colson P" first="Pierre" last="Colson">Pierre Colson</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Institute of Chemistry, University of Liège.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Liège</settlement>
<region type="region" nuts="1">Région wallonne</region>
<region type="province" nuts="1">Province de Liège</region>
</placeName>
<orgName type="university">Université de Liège</orgName>
</affiliation>
</author>
<author><name sortKey="De Pauw Gillet, Marie Claire" sort="De Pauw Gillet, Marie Claire" uniqKey="De Pauw Gillet M" first="Marie-Claire" last="De Pauw-Gillet">Marie-Claire De Pauw-Gillet</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Institute of Anatomy, University of Liège.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Liège</settlement>
<region type="region" nuts="1">Région wallonne</region>
<region type="province" nuts="1">Province de Liège</region>
</placeName>
<orgName type="university">Université de Liège</orgName>
</affiliation>
</author>
<author><name sortKey="Van Den Heuvel, Hilde" sort="Van Den Heuvel, Hilde" uniqKey="Van Den Heuvel H" first="Hilde" last="Van Den Heuvel">Hilde Van Den Heuvel</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Department of Pharmaceutical Sciences, University of Antwerp.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
<orgName type="university">Université d'Anvers</orgName>
</affiliation>
</author>
<author><name sortKey="Claeys, Magda" sort="Claeys, Magda" uniqKey="Claeys M" first="Magda" last="Claeys">Magda Claeys</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Department of Pharmaceutical Sciences, University of Antwerp.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
<orgName type="university">Université d'Anvers</orgName>
</affiliation>
</author>
<author><name sortKey="Lemiere, Filip" sort="Lemiere, Filip" uniqKey="Lemiere F" first="Filip" last="Lemière">Filip Lemière</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Department of Chemistry, University of Antwerp.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
<orgName type="university">Université d'Anvers</orgName>
</affiliation>
</author>
<author><name sortKey="Esmans, Eddy L" sort="Esmans, Eddy L" uniqKey="Esmans E" first="Eddy L." last="Esmans">Eddy L. Esmans</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Department of Chemistry, University of Antwerp.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
<orgName type="university">Université d'Anvers</orgName>
</affiliation>
</author>
<author><name sortKey="Rozenski, Jef" sort="Rozenski, Jef" uniqKey="Rozenski J" first="Jef" last="Rozenski">Jef Rozenski</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation><mods:affiliation> Rega Institute for Medical Research.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Quirijnen, Ludo" sort="Quirijnen, Ludo" uniqKey="Quirijnen L" first="Ludo" last="Quirijnen">Ludo Quirijnen</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation><mods:affiliation> Tibotec-Virco NV.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Maes, Louis" sort="Maes, Louis" uniqKey="Maes L" first="Louis" last="Maes">Louis Maes</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation><mods:affiliation> Tibotec-Virco NV.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Dommisse, Roger" sort="Dommisse, Roger" uniqKey="Dommisse R" first="Roger" last="Dommisse">Roger Dommisse</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Department of Chemistry, University of Antwerp.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
<orgName type="university">Université d'Anvers</orgName>
</affiliation>
</author>
<author><name sortKey="Lemiere, Guy L F" sort="Lemiere, Guy L F" uniqKey="Lemiere G" first="Guy L. F." last="Lemière">Guy L. F. Lemière</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Department of Chemistry, University of Antwerp.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
<orgName type="university">Université d'Anvers</orgName>
</affiliation>
</author>
<author><name sortKey="Vlietinck, Arnold" sort="Vlietinck, Arnold" uniqKey="Vlietinck A" first="Arnold" last="Vlietinck">Arnold Vlietinck</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Department of Pharmaceutical Sciences, University of Antwerp.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
<orgName type="university">Université d'Anvers</orgName>
</affiliation>
</author>
<author><name sortKey="Pieters, Luc" sort="Pieters, Luc" uniqKey="Pieters L" first="Luc" last="Pieters">Luc Pieters</name>
<affiliation wicri:level="1"><mods:affiliation>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen, Belgium</mods:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, Department ofChemistry, University of Antwerp, B-2020 Antwerp, Belgium, INSERM U-524, Institut de Recherches sur le Cancer de Lille,F-59045 Lille, France, Institute of Chemistry, University of Liège, Sart-Tilman (B6), B-4000 Liège, Belgium, CRCE,Histology−Cytology, Institute of Anatomy (L3), University of Liège, B-4020 Liège, Belgium, Rega Institute for MedicalResearch, B-3000 Leuven, Belgium, and Tibotec-Virco NV, B-2800 Mechelen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="4"><mods:affiliation> Department of Pharmaceutical Sciences, University of Antwerp.</mods:affiliation>
<country>Belgique</country>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
<orgName type="university">Université d'Anvers</orgName>
</affiliation>
<affiliation wicri:level="1"><mods:affiliation> To whom correspondence should be addressed. Phone and fax: (32)3 820 27 09. E-mail pieters@uia.ua.ac.be.</mods:affiliation>
<country wicri:rule="url">Belgique</country>
</affiliation>
</author>
</analytic>
<monogr></monogr>
<series><title level="j" type="main">Journal of Medicinal Chemistry</title>
<title level="j" type="abbrev">J. Med. Chem.</title>
<idno type="ISSN">0022-2623</idno>
<idno type="eISSN">1520-4804</idno>
<imprint><publisher>American Chemical Society</publisher>
<date type="e-published" when="2002-06-29">2002</date>
<date when="2002-08-01">2002</date>
<biblScope unit="vol">45</biblScope>
<biblScope unit="issue">16</biblScope>
<biblScope unit="page" from="3497">3497</biblScope>
<biblScope unit="page" to="3508">3508</biblScope>
</imprint>
<idno type="ISSN">0022-2623</idno>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt><idno type="ISSN">0022-2623</idno>
</seriesStmt>
</fileDesc>
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<front><div type="abstract">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 β-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 β-hematin formation. 2-Bromoneocryptolepine was the most selective compound with an IC50 value against chloroquine-resistant P. falciparum of 4.0 μM in the absence of cytotoxicity (IC50 > 32 μM). Although cryptolepine, a known lead for antimalarials also originally isolated from Cryptolepis sanguinolenta, was more active (IC50 = 2.0 μM), 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.</div>
</front>
</TEI>
</record>
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