Synthesis and Evaluation of Cryptolepine Analogues for Their Potential as New Antimalarial Agents
Identifieur interne : 002261 ( Main/Exploration ); précédent : 002260; suivant : 002262Synthesis and Evaluation of Cryptolepine Analogues for Their Potential as New Antimalarial Agents
Auteurs : Colin W. Wright [Royaume-Uni] ; Jonathan Addae-Kyereme [Royaume-Uni, Ghana] ; Anthony G. Breen [Royaume-Uni] ; John E. Brown [Royaume-Uni] ; Marlene F. Cox [Royaume-Uni, Guyana] ; Simon L. Croft [Royaume-Uni] ; Yaman Gökçek [Royaume-Uni] ; Howard Kendrick [Royaume-Uni] ; Roger M. Phillips [Royaume-Uni] ; Pamela L. Pollet [Royaume-Uni]Source :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 2001.
Abstract
The indoloquinoline alkaloid cryptolepine 1 has potent in vitro antiplasmodial activity, but it is also a DNA intercalator with cytotoxic properties. We have shown that the antiplasmodial mechanism of 1 is likely to be due, at least in part, to a chloroquine-like action that does not depend on intercalation into DNA. A number of substituted analogues of 1 have been prepared that have potent activities against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and also have in common with chloroquine the inhibition of β-hematin formation in a cell-free system. Several compounds also displayed activity against Plasmodium berghei in mice, the most potent being 2,7-dibromocryptolepine 8, which suppressed parasitemia by 89% as compared to untreated infected controls at a dose of 12.5 mg kg-1 day-1 ip. No correlation was observed between in vitro cytotoxicity and the effect of compounds on the melting point of DNA (ΔTm value) or toxicity in the mouse−malaria model.
Url:
DOI: 10.1021/jm010929+
Affiliations:
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Breen</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>The School of Pharmacy and Cancer Research Unit, University of Bradford, West Yorkshire, BD7 1DP, U.K., and theDepartment of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street,London WC1E 7HT</wicri:regionArea><wicri:noRegion>London WC1E 7HT</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Brown, John E" sort="Brown, John E" uniqKey="Brown J" first="John E." last="Brown">John E. Brown</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>The School of Pharmacy and Cancer Research Unit, University of Bradford, West Yorkshire, BD7 1DP, U.K., and theDepartment of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street,London WC1E 7HT</wicri:regionArea><wicri:noRegion>London WC1E 7HT</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Cox, Marlene F" sort="Cox, Marlene F" uniqKey="Cox M" first="Marlene F." last="Cox">Marlene F. Cox</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>The School of Pharmacy and Cancer Research Unit, University of Bradford, West Yorkshire, BD7 1DP, U.K., and theDepartment of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street,London WC1E 7HT</wicri:regionArea><wicri:noRegion>London WC1E 7HT</wicri:noRegion></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Guyana</country><wicri:regionArea> Present address: Department of Chemistry, University of Guyana,P.O. Box 101110, Georgetown</wicri:regionArea><wicri:noRegion>Georgetown</wicri:noRegion></affiliation></author><author><name sortKey="Croft, Simon L" sort="Croft, Simon L" uniqKey="Croft S" first="Simon L." last="Croft">Simon L. 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Phillips</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>The School of Pharmacy and Cancer Research Unit, University of Bradford, West Yorkshire, BD7 1DP, U.K., and theDepartment of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street,London WC1E 7HT</wicri:regionArea><wicri:noRegion>London WC1E 7HT</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Pollet, Pamela L" sort="Pollet, Pamela L" uniqKey="Pollet P" first="Pamela L." last="Pollet">Pamela L. Pollet</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>The School of Pharmacy and Cancer Research Unit, University of Bradford, West Yorkshire, BD7 1DP, U.K., and theDepartment of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street,London WC1E 7HT</wicri:regionArea><wicri:noRegion>London WC1E 7HT</wicri:noRegion></affiliation><affiliation></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="2001-08-18">2001</date><date when="2001-09-13">2001</date><biblScope unit="vol">44</biblScope><biblScope unit="issue">19</biblScope><biblScope unit="page" from="3187">3187</biblScope><biblScope unit="page" to="3194">3194</biblScope></imprint><idno type="ISSN">0022-2623</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2623</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">The indoloquinoline alkaloid cryptolepine 1 has potent in vitro antiplasmodial activity, but it is also a DNA intercalator with cytotoxic properties. We have shown that the antiplasmodial mechanism of 1 is likely to be due, at least in part, to a chloroquine-like action that does not depend on intercalation into DNA. A number of substituted analogues of 1 have been prepared that have potent activities against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and also have in common with chloroquine the inhibition of β-hematin formation in a cell-free system. Several compounds also displayed activity against Plasmodium berghei in mice, the most potent being 2,7-dibromocryptolepine 8, which suppressed parasitemia by 89% as compared to untreated infected controls at a dose of 12.5 mg kg-1 day-1 ip. No correlation was observed between in vitro cytotoxicity and the effect of compounds on the melting point of DNA (ΔTm value) or toxicity in the mouse−malaria model.</div></front></TEI><affiliations><list><country><li>Ghana</li><li>Guyana</li><li>Royaume-Uni</li></country></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Wright, Colin W" sort="Wright, Colin W" uniqKey="Wright C" first="Colin W." last="Wright">Colin W. Wright</name></noRegion><name sortKey="Addae Kyereme, Jonathan" sort="Addae Kyereme, Jonathan" uniqKey="Addae Kyereme J" first="Jonathan" last="Addae-Kyereme">Jonathan Addae-Kyereme</name><name sortKey="Breen, Anthony G" sort="Breen, Anthony G" uniqKey="Breen A" first="Anthony G." last="Breen">Anthony G. Breen</name><name sortKey="Brown, John E" sort="Brown, John E" uniqKey="Brown J" first="John E." last="Brown">John E. Brown</name><name sortKey="Cox, Marlene F" sort="Cox, Marlene F" uniqKey="Cox M" first="Marlene F." last="Cox">Marlene F. Cox</name><name sortKey="Croft, Simon L" sort="Croft, Simon L" uniqKey="Croft S" first="Simon L." last="Croft">Simon L. Croft</name><name sortKey="Gokcek, Yaman" sort="Gokcek, Yaman" uniqKey="Gokcek Y" first="Yaman" last="Gökçek">Yaman Gökçek</name><name sortKey="Kendrick, Howard" sort="Kendrick, Howard" uniqKey="Kendrick H" first="Howard" last="Kendrick">Howard Kendrick</name><name sortKey="Phillips, Roger M" sort="Phillips, Roger M" uniqKey="Phillips R" first="Roger M." last="Phillips">Roger M. Phillips</name><name sortKey="Pollet, Pamela L" sort="Pollet, Pamela L" uniqKey="Pollet P" first="Pamela L." last="Pollet">Pamela L. Pollet</name><name sortKey="Wright, Colin W" sort="Wright, Colin W" uniqKey="Wright C" first="Colin W." last="Wright">Colin W. Wright</name></country><country name="Ghana"><noRegion><name sortKey="Addae Kyereme, Jonathan" sort="Addae Kyereme, Jonathan" uniqKey="Addae Kyereme J" first="Jonathan" last="Addae-Kyereme">Jonathan Addae-Kyereme</name></noRegion></country><country name="Guyana"><noRegion><name sortKey="Cox, Marlene F" sort="Cox, Marlene F" uniqKey="Cox M" first="Marlene F." last="Cox">Marlene F. Cox</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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