Two-Step Synthesis of Achiral Dispiro-1,2,4,5-tetraoxanes with Outstanding Antimalarial Activity, Low Toxicity, and High-Stability Profiles
Identifieur interne : 001933 ( Main/Exploration ); précédent : 001932; suivant : 001934Two-Step Synthesis of Achiral Dispiro-1,2,4,5-tetraoxanes with Outstanding Antimalarial Activity, Low Toxicity, and High-Stability Profiles
Auteurs : Gemma L. Ellis [Espagne] ; Richard Amewu [Espagne] ; Sunil Sabbani [Espagne] ; Paul A. Stocks [Espagne] ; Alison Shone [Espagne] ; Deborah Stanford [Espagne] ; Peter Gibbons [Espagne] ; Jill Davies [Espagne] ; Livia Vivas [Espagne] ; Sarah Charnaud [Espagne] ; Emily Bongard [Espagne] ; Charlotte Hall [Espagne] ; Karen Rimmer [Espagne] ; Sonia Lozanom [Espagne] ; María Jesús [Espagne] ; Domingo Gargallo [Espagne] ; Stephen A. Ward [Espagne] ; Paul M. O Eill [Espagne, Royaume-Uni]Source :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 2008.
Abstract
A rapid, two-step synthesis of a range of dispiro-1,2,4,5-tetraoxanes with potent antimalarial activity both in vitro and in vivo has been achieved. These 1,2,4,5-tetraoxanes have been proven to be superior to 1,2,4-trioxolanes in terms of stability and to be superior to trioxane analogues in terms of both stability and activity. Selected analogues have in vitro nanomolar antimalarial activity and good oral activity and are nontoxic in screens for both cytotoxicity and genotoxicity. The synthesis of a fluorescent 7-nitrobenza-2-oxa-1,3-diazole (NBD) tagged tetraoxane probe and use of laser scanning confocal microscopy techniques have shown that tagged molecules accumulate selectively only in parasite infected erythrocytes and that intraparasitic formation of adducts could be inhibited by co-incubation with the iron chelator desferrioxamine (DFO).
Url:
DOI: 10.1021/jm701435h
Affiliations:
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Ellis</name><affiliation wicri:level="3"><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K., Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, U.K., and GlaxoSmithKline, S.A. Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Amewu, Richard" sort="Amewu, Richard" uniqKey="Amewu R" first="Richard" last="Amewu">Richard Amewu</name><affiliation wicri:level="3"><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K., Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, U.K., and GlaxoSmithKline, S.A. Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Sabbani, Sunil" sort="Sabbani, Sunil" uniqKey="Sabbani S" first="Sunil" last="Sabbani">Sunil Sabbani</name><affiliation wicri:level="3"><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K., Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, U.K., and GlaxoSmithKline, S.A. 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Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Gibbons, Peter" sort="Gibbons, Peter" uniqKey="Gibbons P" first="Peter" last="Gibbons">Peter Gibbons</name><affiliation wicri:level="3"><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K., Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, U.K., and GlaxoSmithKline, S.A. Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Davies, Jill" sort="Davies, Jill" uniqKey="Davies J" first="Jill" last="Davies">Jill Davies</name><affiliation wicri:level="3"><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K., Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, U.K., and GlaxoSmithKline, S.A. Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Vivas, Livia" sort="Vivas, Livia" uniqKey="Vivas L" first="Livia" last="Vivas">Livia Vivas</name><affiliation wicri:level="3"><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K., Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, U.K., and GlaxoSmithKline, S.A. Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Charnaud, Sarah" sort="Charnaud, Sarah" uniqKey="Charnaud S" first="Sarah" last="Charnaud">Sarah Charnaud</name><affiliation wicri:level="3"><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K., Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, U.K., and GlaxoSmithKline, S.A. Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Bongard, Emily" sort="Bongard, Emily" uniqKey="Bongard E" first="Emily" last="Bongard">Emily Bongard</name><affiliation wicri:level="3"><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K., Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, U.K., and GlaxoSmithKline, S.A. Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Hall, Charlotte" sort="Hall, Charlotte" uniqKey="Hall C" first="Charlotte" last="Hall">Charlotte Hall</name><affiliation wicri:level="3"><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K., Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, U.K., and GlaxoSmithKline, S.A. Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Rimmer, Karen" sort="Rimmer, Karen" uniqKey="Rimmer K" first="Karen" last="Rimmer">Karen Rimmer</name><affiliation wicri:level="3"><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K., Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, U.K., and GlaxoSmithKline, S.A. Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Lozanom, Sonia" sort="Lozanom, Sonia" uniqKey="Lozanom S" first="Sonia" last="Lozanom">Sonia Lozanom</name><affiliation wicri:level="3"><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K., Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, U.K., and GlaxoSmithKline, S.A. Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Jesus, Maria" sort="Jesus, Maria" uniqKey="Jesus M" first="María" last="Jesús">María Jesús</name><affiliation wicri:level="3"><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K., Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, U.K., and GlaxoSmithKline, S.A. Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Gargallo, Domingo" sort="Gargallo, Domingo" uniqKey="Gargallo D" first="Domingo" last="Gargallo">Domingo Gargallo</name><affiliation wicri:level="3"><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K., Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, U.K., and GlaxoSmithKline, S.A. Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Ward, Stephen A" sort="Ward, Stephen A" uniqKey="Ward S" first="Stephen A." last="Ward">Stephen A. Ward</name><affiliation wicri:level="3"><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K., Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, U.K., and GlaxoSmithKline, S.A. Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="O Eill, Paul M" sort="O Eill, Paul M" uniqKey="O Eill P" first="Paul M." last="O Eill">Paul M. O Eill</name><affiliation wicri:level="3"><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, U.K., Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, U.K., and GlaxoSmithKline, S.A. Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Royaume-Uni</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="2008-03-15">2008</date><date when="2008-04-10">2008</date><biblScope unit="vol">51</biblScope><biblScope unit="issue">7</biblScope><biblScope unit="page" from="2170">2170</biblScope><biblScope unit="page" to="2177">2177</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">A rapid, two-step synthesis of a range of dispiro-1,2,4,5-tetraoxanes with potent antimalarial activity both in vitro and in vivo has been achieved. These 1,2,4,5-tetraoxanes have been proven to be superior to 1,2,4-trioxolanes in terms of stability and to be superior to trioxane analogues in terms of both stability and activity. Selected analogues have in vitro nanomolar antimalarial activity and good oral activity and are nontoxic in screens for both cytotoxicity and genotoxicity. The synthesis of a fluorescent 7-nitrobenza-2-oxa-1,3-diazole (NBD) tagged tetraoxane probe and use of laser scanning confocal microscopy techniques have shown that tagged molecules accumulate selectively only in parasite infected erythrocytes and that intraparasitic formation of adducts could be inhibited by co-incubation with the iron chelator desferrioxamine (DFO).</div></front></TEI><affiliations><list><country><li>Espagne</li><li>Royaume-Uni</li></country><region><li>Communauté de Madrid</li></region><settlement><li>Madrid</li></settlement></list><tree><country name="Espagne"><region name="Communauté de Madrid"><name sortKey="Ellis, Gemma L" sort="Ellis, Gemma L" uniqKey="Ellis G" first="Gemma L." last="Ellis">Gemma L. Ellis</name></region><name sortKey="Amewu, Richard" sort="Amewu, Richard" uniqKey="Amewu R" first="Richard" last="Amewu">Richard Amewu</name><name sortKey="Bongard, Emily" sort="Bongard, Emily" uniqKey="Bongard E" first="Emily" last="Bongard">Emily Bongard</name><name sortKey="Charnaud, Sarah" sort="Charnaud, Sarah" uniqKey="Charnaud S" first="Sarah" last="Charnaud">Sarah Charnaud</name><name sortKey="Davies, Jill" sort="Davies, Jill" uniqKey="Davies J" first="Jill" last="Davies">Jill Davies</name><name sortKey="Gargallo, Domingo" sort="Gargallo, Domingo" uniqKey="Gargallo D" first="Domingo" last="Gargallo">Domingo Gargallo</name><name sortKey="Gibbons, Peter" sort="Gibbons, Peter" uniqKey="Gibbons P" first="Peter" last="Gibbons">Peter Gibbons</name><name sortKey="Hall, Charlotte" sort="Hall, Charlotte" uniqKey="Hall C" first="Charlotte" last="Hall">Charlotte Hall</name><name sortKey="Jesus, Maria" sort="Jesus, Maria" uniqKey="Jesus M" first="María" last="Jesús">María Jesús</name><name sortKey="Lozanom, Sonia" sort="Lozanom, Sonia" uniqKey="Lozanom S" first="Sonia" last="Lozanom">Sonia Lozanom</name><name sortKey="O Eill, Paul M" sort="O Eill, Paul M" uniqKey="O Eill P" first="Paul M." last="O Eill">Paul M. O Eill</name><name sortKey="Rimmer, Karen" sort="Rimmer, Karen" uniqKey="Rimmer K" first="Karen" last="Rimmer">Karen Rimmer</name><name sortKey="Sabbani, Sunil" sort="Sabbani, Sunil" uniqKey="Sabbani S" first="Sunil" last="Sabbani">Sunil Sabbani</name><name sortKey="Shone, Alison" sort="Shone, Alison" uniqKey="Shone A" first="Alison" last="Shone">Alison Shone</name><name sortKey="Stanford, Deborah" sort="Stanford, Deborah" uniqKey="Stanford D" first="Deborah" last="Stanford">Deborah Stanford</name><name sortKey="Stocks, Paul A" sort="Stocks, Paul A" uniqKey="Stocks P" first="Paul A." last="Stocks">Paul A. Stocks</name><name sortKey="Vivas, Livia" sort="Vivas, Livia" uniqKey="Vivas L" first="Livia" last="Vivas">Livia Vivas</name><name sortKey="Ward, Stephen A" sort="Ward, Stephen A" uniqKey="Ward S" first="Stephen A." last="Ward">Stephen A. Ward</name></country><country name="Royaume-Uni"><noRegion><name sortKey="O Eill, Paul M" sort="O Eill, Paul M" uniqKey="O Eill P" first="Paul M." last="O Eill">Paul M. O Eill</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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