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5′-Trityl-Substituted Thymidine Derivatives as a Novel Class of Antileishmanial Agents: Leishmania infantum EndoG as a Potential Target
Two series of 5′‐triphenylmethyl (trityl)‐substituted thymidine derivatives were synthesized and tested against Leishmania infantum axenic promastigotes and amastigotes. Several of these compounds show significant antileishmanial activity, with IC50 values in the low micromolar range. Among these, 3...
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| Published in: | ChemMedChem 2013-07, Vol.8 (7), p.1161-1174 |
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| Main Authors: | , , , , , , , , , |
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| cited_by | cdi_FETCH-LOGICAL-c4449-cf677dbea03d37be74e148e75f93835f0641aa73600aaf330210ad24be211c053 |
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| container_end_page | 1174 |
| container_issue | 7 |
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| container_title | ChemMedChem |
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| creator | Casanova, Elena Moreno, David Gigante, Alba Rico, Eva Genes, Carlos Mario Oliva, Cristina Camarasa, María-José Gago, Federico Jiménez-Ruiz, Antonio Pérez-Pérez, María-Jesús |
| description | Two series of 5′‐triphenylmethyl (trityl)‐substituted thymidine derivatives were synthesized and tested against Leishmania infantum axenic promastigotes and amastigotes. Several of these compounds show significant antileishmanial activity, with IC50 values in the low micromolar range. Among these, 3′‐O‐(isoleucylisoleucyl)‐5′‐O‐(3,3,3‐triphenylpropanoyl)thymidine displays particularly good activity against intracellular amastigotes. Assays performed to characterize the nature of parasite cell death in the presence of the tritylthymidines indicated significant alterations in mitochondrial transmembrane potential, an increase in superoxide concentrations, and also significant decreases in DNA degradation during the cell death process. Results point to the mitochondrial nuclease LiEndoG as a target for the action of this family of compounds.
LiEndoG as drug target? Thymidine derivatives with a triphenylmethyl substituent at the 5′‐position exhibit significant activity against Leishmania infantum parasites. Characterization of cell death points toward the mitochondrial endonuclease G (LiEndoG) as a target. |
| doi_str_mv | 10.1002/cmdc.201300129 |
| format | article |
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LiEndoG as drug target? Thymidine derivatives with a triphenylmethyl substituent at the 5′‐position exhibit significant activity against Leishmania infantum parasites. Characterization of cell death points toward the mitochondrial endonuclease G (LiEndoG) as a target.</description><identifier>ISSN: 1860-7179</identifier><identifier>EISSN: 1860-7187</identifier><identifier>DOI: 10.1002/cmdc.201300129</identifier><identifier>PMID: 23625887</identifier><language>eng ; ger</language><publisher>Weinheim: WILEY-VCH Verlag</publisher><subject>amino acids ; Antiparasitic Agents - chemical synthesis ; Antiparasitic Agents - chemistry ; Antiparasitic Agents - pharmacology ; Apoptosis ; Cell Death - drug effects ; Cells ; Dose-Response Relationship, Drug ; Endodeoxyribonucleases - antagonists & inhibitors ; Endodeoxyribonucleases - metabolism ; endonucleases ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Humans ; Jurkat Cells ; leishmania ; Leishmania infantum ; Leishmania infantum - drug effects ; Leishmania infantum - enzymology ; Mitochondria - enzymology ; Molecular Structure ; Structure-Activity Relationship ; thymidine ; Thymidine - chemical synthesis ; Thymidine - chemistry ; Thymidine - pharmacology ; trityl groups</subject><ispartof>ChemMedChem, 2013-07, Vol.8 (7), p.1161-1174</ispartof><rights>Copyright © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><rights>Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><rights>Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4449-cf677dbea03d37be74e148e75f93835f0641aa73600aaf330210ad24be211c053</citedby><cites>FETCH-LOGICAL-c4449-cf677dbea03d37be74e148e75f93835f0641aa73600aaf330210ad24be211c053</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcmdc.201300129$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcmdc.201300129$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,786,790,27957,27958,50923,51032</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23625887$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Casanova, Elena</creatorcontrib><creatorcontrib>Moreno, David</creatorcontrib><creatorcontrib>Gigante, Alba</creatorcontrib><creatorcontrib>Rico, Eva</creatorcontrib><creatorcontrib>Genes, Carlos Mario</creatorcontrib><creatorcontrib>Oliva, Cristina</creatorcontrib><creatorcontrib>Camarasa, María-José</creatorcontrib><creatorcontrib>Gago, Federico</creatorcontrib><creatorcontrib>Jiménez-Ruiz, Antonio</creatorcontrib><creatorcontrib>Pérez-Pérez, María-Jesús</creatorcontrib><title>5′-Trityl-Substituted Thymidine Derivatives as a Novel Class of Antileishmanial Agents: Leishmania infantum EndoG as a Potential Target</title><title>ChemMedChem</title><addtitle>ChemMedChem</addtitle><description>Two series of 5′‐triphenylmethyl (trityl)‐substituted thymidine derivatives were synthesized and tested against Leishmania infantum axenic promastigotes and amastigotes. Several of these compounds show significant antileishmanial activity, with IC50 values in the low micromolar range. Among these, 3′‐O‐(isoleucylisoleucyl)‐5′‐O‐(3,3,3‐triphenylpropanoyl)thymidine displays particularly good activity against intracellular amastigotes. Assays performed to characterize the nature of parasite cell death in the presence of the tritylthymidines indicated significant alterations in mitochondrial transmembrane potential, an increase in superoxide concentrations, and also significant decreases in DNA degradation during the cell death process. Results point to the mitochondrial nuclease LiEndoG as a target for the action of this family of compounds.
LiEndoG as drug target? Thymidine derivatives with a triphenylmethyl substituent at the 5′‐position exhibit significant activity against Leishmania infantum parasites. Characterization of cell death points toward the mitochondrial endonuclease G (LiEndoG) as a target.</description><subject>amino acids</subject><subject>Antiparasitic Agents - chemical synthesis</subject><subject>Antiparasitic Agents - chemistry</subject><subject>Antiparasitic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Cell Death - drug effects</subject><subject>Cells</subject><subject>Dose-Response Relationship, Drug</subject><subject>Endodeoxyribonucleases - antagonists & inhibitors</subject><subject>Endodeoxyribonucleases - metabolism</subject><subject>endonucleases</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Jurkat Cells</subject><subject>leishmania</subject><subject>Leishmania infantum</subject><subject>Leishmania infantum - drug effects</subject><subject>Leishmania infantum - enzymology</subject><subject>Mitochondria - enzymology</subject><subject>Molecular Structure</subject><subject>Structure-Activity Relationship</subject><subject>thymidine</subject><subject>Thymidine - chemical synthesis</subject><subject>Thymidine - chemistry</subject><subject>Thymidine - pharmacology</subject><subject>trityl groups</subject><issn>1860-7179</issn><issn>1860-7187</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNqFkctu1DAUhi0EoqWwZYkssWGTwbfYDrtpWgbUoSAYYGk5yUnrkkuxnYHZseV1eCSehIxSIsSm0pF8ZH3_Lx19CD2mZEEJYc_LtioXjFBOCGXZHXRItSSJolrdnXeVHaAHIVwRIoSm-j46YFyyVGt1iH6mv3_8SjbexV2TfBiKEF0cIlR4c7lrXeU6wCfg3dZGt4WA7Tj4vN9Cg_PGhoD7Gi-76Bpw4bK1nbMNXl5AF8MLvJ7_sOtq28Whxadd1a-mlnd9HLl9YGP9BcSH6F5tmwCPbt4j9PHl6SZ_lazfrl7ny3VSCiGypKylUlUBlvCKqwKUACo0qLTOuOZpTaSg1iouCbG25pwwSmzFRAGM0pKk_Ag9m3qvff91gBBN60IJTWM76IdgqOAZ45oyeTvKFSMq06ka0af_oVf94LvxkD01qpFSipFaTFTp-xA81Obau9b6naHE7H2avU8z-xwDT25qh6KFasb_ChyBbAK-jQ52t9SZ_M1J_m95MmVdiPB9zlr_xUjFVWo-n69M_j7Vx2fizHzifwC_vrvf</recordid><startdate>201307</startdate><enddate>201307</enddate><creator>Casanova, Elena</creator><creator>Moreno, David</creator><creator>Gigante, Alba</creator><creator>Rico, Eva</creator><creator>Genes, Carlos Mario</creator><creator>Oliva, Cristina</creator><creator>Camarasa, María-José</creator><creator>Gago, Federico</creator><creator>Jiménez-Ruiz, Antonio</creator><creator>Pérez-Pérez, María-Jesús</creator><general>WILEY-VCH Verlag</general><general>WILEY‐VCH Verlag</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>M7N</scope></search><sort><creationdate>201307</creationdate><title>5′-Trityl-Substituted Thymidine Derivatives as a Novel Class of Antileishmanial Agents: Leishmania infantum EndoG as a Potential Target</title><author>Casanova, Elena ; Moreno, David ; Gigante, Alba ; Rico, Eva ; Genes, Carlos Mario ; Oliva, Cristina ; Camarasa, María-José ; Gago, Federico ; Jiménez-Ruiz, Antonio ; Pérez-Pérez, María-Jesús</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4449-cf677dbea03d37be74e148e75f93835f0641aa73600aaf330210ad24be211c053</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng ; ger</language><creationdate>2013</creationdate><topic>amino acids</topic><topic>Antiparasitic Agents - chemical synthesis</topic><topic>Antiparasitic Agents - chemistry</topic><topic>Antiparasitic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Cell Death - drug effects</topic><topic>Cells</topic><topic>Dose-Response Relationship, Drug</topic><topic>Endodeoxyribonucleases - antagonists & inhibitors</topic><topic>Endodeoxyribonucleases - metabolism</topic><topic>endonucleases</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Jurkat Cells</topic><topic>leishmania</topic><topic>Leishmania infantum</topic><topic>Leishmania infantum - drug effects</topic><topic>Leishmania infantum - enzymology</topic><topic>Mitochondria - enzymology</topic><topic>Molecular Structure</topic><topic>Structure-Activity Relationship</topic><topic>thymidine</topic><topic>Thymidine - chemical synthesis</topic><topic>Thymidine - chemistry</topic><topic>Thymidine - pharmacology</topic><topic>trityl groups</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Casanova, Elena</creatorcontrib><creatorcontrib>Moreno, David</creatorcontrib><creatorcontrib>Gigante, Alba</creatorcontrib><creatorcontrib>Rico, Eva</creatorcontrib><creatorcontrib>Genes, Carlos Mario</creatorcontrib><creatorcontrib>Oliva, Cristina</creatorcontrib><creatorcontrib>Camarasa, María-José</creatorcontrib><creatorcontrib>Gago, Federico</creatorcontrib><creatorcontrib>Jiménez-Ruiz, Antonio</creatorcontrib><creatorcontrib>Pérez-Pérez, María-Jesús</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><jtitle>ChemMedChem</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Casanova, Elena</au><au>Moreno, David</au><au>Gigante, Alba</au><au>Rico, Eva</au><au>Genes, Carlos Mario</au><au>Oliva, Cristina</au><au>Camarasa, María-José</au><au>Gago, Federico</au><au>Jiménez-Ruiz, Antonio</au><au>Pérez-Pérez, María-Jesús</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>5′-Trityl-Substituted Thymidine Derivatives as a Novel Class of Antileishmanial Agents: Leishmania infantum EndoG as a Potential Target</atitle><jtitle>ChemMedChem</jtitle><addtitle>ChemMedChem</addtitle><date>2013-07</date><risdate>2013</risdate><volume>8</volume><issue>7</issue><spage>1161</spage><epage>1174</epage><pages>1161-1174</pages><issn>1860-7179</issn><eissn>1860-7187</eissn><notes>istex:D135B43F933861698AC843D9B94A82D48FDE1D74</notes><notes>ArticleID:CMDC201300129</notes><notes>ark:/67375/WNG-CR58BK4K-V</notes><notes>FSE</notes><notes>MEC</notes><notes>Junta de Comunidades de Castilla-La Mancha - No. POII10-0180-7897</notes><notes>Viceconserjería de Ciencia y Tecnología</notes><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>ObjectType-Article-2</notes><notes>ObjectType-Feature-1</notes><abstract>Two series of 5′‐triphenylmethyl (trityl)‐substituted thymidine derivatives were synthesized and tested against Leishmania infantum axenic promastigotes and amastigotes. Several of these compounds show significant antileishmanial activity, with IC50 values in the low micromolar range. Among these, 3′‐O‐(isoleucylisoleucyl)‐5′‐O‐(3,3,3‐triphenylpropanoyl)thymidine displays particularly good activity against intracellular amastigotes. Assays performed to characterize the nature of parasite cell death in the presence of the tritylthymidines indicated significant alterations in mitochondrial transmembrane potential, an increase in superoxide concentrations, and also significant decreases in DNA degradation during the cell death process. Results point to the mitochondrial nuclease LiEndoG as a target for the action of this family of compounds.
LiEndoG as drug target? Thymidine derivatives with a triphenylmethyl substituent at the 5′‐position exhibit significant activity against Leishmania infantum parasites. Characterization of cell death points toward the mitochondrial endonuclease G (LiEndoG) as a target.</abstract><cop>Weinheim</cop><pub>WILEY-VCH Verlag</pub><pmid>23625887</pmid><doi>10.1002/cmdc.201300129</doi><tpages>14</tpages></addata></record> |
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| subjects | amino acids Antiparasitic Agents - chemical synthesis Antiparasitic Agents - chemistry Antiparasitic Agents - pharmacology Apoptosis Cell Death - drug effects Cells Dose-Response Relationship, Drug Endodeoxyribonucleases - antagonists & inhibitors Endodeoxyribonucleases - metabolism endonucleases Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Jurkat Cells leishmania Leishmania infantum Leishmania infantum - drug effects Leishmania infantum - enzymology Mitochondria - enzymology Molecular Structure Structure-Activity Relationship thymidine Thymidine - chemical synthesis Thymidine - chemistry Thymidine - pharmacology trityl groups |
| title | 5′-Trityl-Substituted Thymidine Derivatives as a Novel Class of Antileishmanial Agents: Leishmania infantum EndoG as a Potential Target |
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