Platinum(II) Phenanthroimidazoles for Targeting Telomeric G‐Quadruplexes
Identifieur interne : 002177 ( Istex/Corpus ); précédent : 002176; suivant : 002178Platinum(II) Phenanthroimidazoles for Targeting Telomeric G‐Quadruplexes
Auteurs : Katherine J. Castor ; Johanna Mancini ; Johanna Fakhoury ; Johanna Weill ; Johanna Kieltyka ; Johanna Englebienne ; Nicole Avakyan ; Nicole Mittermaier ; Nicole Autexier ; Nicole Moitessier ; Nicole SleimanSource :
- [ 1860-7179 ]
Abstract
A rationally designed progression of phenanthroimidazole platinum(II) complexes were examined for their ability to target telomere‐derived intramolecular G‐quadruplex DNA. Through the use of circular dichroism, fluorescence displacement assays, and molecular modeling we show that these complexes template and stabilize G‐quadruplexes from sequences based on the human telomeric repeat (TTAGGG)n. The greatest stabilization was observed for the p‐chlorophenyl derivative 6 (G4DC50=0.31 μM). We also show that the G‐quadruplex binding complexes are able to inhibit telomerase activity through a modified telomerase repeat amplification protocol (TRAP‐LIG assay). Preliminary cell studies show that complex 6 is preferentially cytotoxic toward cancer over normal cell lines, indicating its potential use in cancer therapy.
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DOI: 10.1002/cmdc.201100453
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Castor</name><affiliation><mods:affiliation>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</mods:affiliation></affiliation></author><author><name sortKey="Mancini, Johanna" sort="Mancini, Johanna" uniqKey="Mancini J" first="Johanna" last="Mancini">Johanna Mancini</name><affiliation><mods:affiliation>Departments of Anatomy and Cell Biology and Experimental Medicine, McGill University, Lady Davis Institute of Medical Research, 3755 Côte Ste‐Catherine Road, Montreal, QC, H3T 1E2 (Canada)</mods:affiliation></affiliation></author><author><name sortKey="Fakhoury, Johanna" sort="Fakhoury, Johanna" uniqKey="Fakhoury J" first="Johanna" last="Fakhoury">Johanna Fakhoury</name><affiliation><mods:affiliation>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</mods:affiliation></affiliation></author><author><name sortKey="Weill, Johanna" sort="Weill, Johanna" uniqKey="Weill J" first="Johanna" last="Weill">Johanna Weill</name><affiliation><mods:affiliation>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</mods:affiliation></affiliation></author><author><name sortKey="Kieltyka, Johanna" sort="Kieltyka, Johanna" uniqKey="Kieltyka J" first="Johanna" last="Kieltyka">Johanna Kieltyka</name><affiliation><mods:affiliation>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</mods:affiliation></affiliation></author><author><name sortKey="Englebienne, Johanna" sort="Englebienne, Johanna" uniqKey="Englebienne J" first="Johanna" last="Englebienne">Johanna Englebienne</name><affiliation><mods:affiliation>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</mods:affiliation></affiliation></author><author><name sortKey="Avakyan, Nicole" sort="Avakyan, Nicole" uniqKey="Avakyan N" first="Nicole" last="Avakyan">Nicole Avakyan</name><affiliation><mods:affiliation>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</mods:affiliation></affiliation></author><author><name sortKey="Mittermaier, Nicole" sort="Mittermaier, Nicole" uniqKey="Mittermaier N" first="Nicole" last="Mittermaier">Nicole Mittermaier</name><affiliation><mods:affiliation>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</mods:affiliation></affiliation></author><author><name sortKey="Autexier, Nicole" sort="Autexier, Nicole" uniqKey="Autexier N" first="Nicole" last="Autexier">Nicole Autexier</name><affiliation><mods:affiliation>Departments of Anatomy and Cell Biology and Experimental Medicine, McGill University, Lady Davis Institute of Medical Research, 3755 Côte Ste‐Catherine Road, Montreal, QC, H3T 1E2 (Canada)</mods:affiliation></affiliation><affiliation><mods:affiliation>Chantal Autexier, Departments of Anatomy and Cell Biology and Experimental Medicine, McGill University, Lady Davis Institute of Medical Research, 3755 Côte Ste‐Catherine Road, Montreal, QC, H3T 1E2 (Canada)Nicolas Moitessier, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797Hanadi F. 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Sleiman, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</mods:affiliation></affiliation></author><author><name sortKey="Moitessier, Nicole" sort="Moitessier, Nicole" uniqKey="Moitessier N" first="Nicole" last="Moitessier">Nicole Moitessier</name><affiliation><mods:affiliation>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</mods:affiliation></affiliation><affiliation><mods:affiliation>Chantal Autexier, Departments of Anatomy and Cell Biology and Experimental Medicine, McGill University, Lady Davis Institute of Medical Research, 3755 Côte Ste‐Catherine Road, Montreal, QC, H3T 1E2 (Canada)Nicolas Moitessier, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797Hanadi F. Sleiman, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</mods:affiliation></affiliation></author><author><name sortKey="Sleiman, Nicole" sort="Sleiman, Nicole" uniqKey="Sleiman N" first="Nicole" last="Sleiman">Nicole Sleiman</name><affiliation><mods:affiliation>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</mods:affiliation></affiliation><affiliation><mods:affiliation>Chantal Autexier, Departments of Anatomy and Cell Biology and Experimental Medicine, McGill University, Lady Davis Institute of Medical Research, 3755 Côte Ste‐Catherine Road, Montreal, QC, H3T 1E2 (Canada)Nicolas Moitessier, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797Hanadi F. Sleiman, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</mods:affiliation></affiliation></author></analytic><series><idno type="ISSN">1860-7179</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1860-7179</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">A rationally designed progression of phenanthroimidazole platinum(II) complexes were examined for their ability to target telomere‐derived intramolecular G‐quadruplex DNA. Through the use of circular dichroism, fluorescence displacement assays, and molecular modeling we show that these complexes template and stabilize G‐quadruplexes from sequences based on the human telomeric repeat (TTAGGG)n. The greatest stabilization was observed for the p‐chlorophenyl derivative 6 (G4DC50=0.31 μM). We also show that the G‐quadruplex binding complexes are able to inhibit telomerase activity through a modified telomerase repeat amplification protocol (TRAP‐LIG assay). Preliminary cell studies show that complex 6 is preferentially cytotoxic toward cancer over normal cell lines, indicating its potential use in cancer therapy.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Katherine J. Castor</name><affiliations><json:string>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</json:string></affiliations></json:item><json:item><name>Johanna Mancini</name><affiliations><json:string>Departments of Anatomy and Cell Biology and Experimental Medicine, McGill University, Lady Davis Institute of Medical Research, 3755 Côte Ste‐Catherine Road, Montreal, QC, H3T 1E2 (Canada)</json:string></affiliations></json:item><json:item><name>Dr. Fakhoury</name><affiliations><json:string>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</json:string></affiliations></json:item><json:item><name>Dr. Weill</name><affiliations><json:string>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</json:string></affiliations></json:item><json:item><name>Dr. Kieltyka</name><affiliations><json:string>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</json:string></affiliations></json:item><json:item><name>Dr. Englebienne</name><affiliations><json:string>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</json:string></affiliations></json:item><json:item><name>Nicole Avakyan</name><affiliations><json:string>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</json:string></affiliations></json:item><json:item><name>Prof. Mittermaier</name><affiliations><json:string>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</json:string></affiliations></json:item><json:item><name>Prof. Autexier</name><affiliations><json:string>Departments of Anatomy and Cell Biology and Experimental Medicine, McGill University, Lady Davis Institute of Medical Research, 3755 Côte Ste‐Catherine Road, Montreal, QC, H3T 1E2 (Canada)</json:string><json:string>Chantal Autexier, Departments of Anatomy and Cell Biology and Experimental Medicine, McGill University, Lady Davis Institute of Medical Research, 3755 Côte Ste‐Catherine Road, Montreal, QC, H3T 1E2 (Canada)Nicolas Moitessier, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797Hanadi F. Sleiman, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</json:string></affiliations></json:item><json:item><name>Prof. Moitessier</name><affiliations><json:string>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</json:string><json:string>Chantal Autexier, Departments of Anatomy and Cell Biology and Experimental Medicine, McGill University, Lady Davis Institute of Medical Research, 3755 Côte Ste‐Catherine Road, Montreal, QC, H3T 1E2 (Canada)Nicolas Moitessier, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797Hanadi F. Sleiman, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</json:string></affiliations></json:item><json:item><name>Prof. Sleiman</name><affiliations><json:string>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</json:string><json:string>Chantal Autexier, Departments of Anatomy and Cell Biology and Experimental Medicine, McGill University, Lady Davis Institute of Medical Research, 3755 Côte Ste‐Catherine Road, Montreal, QC, H3T 1E2 (Canada)Nicolas Moitessier, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797Hanadi F. 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G‐Quadruplexes</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Platinum(II) Phenanthroimidazoles for Targeting Telomeric G‐Quadruplexes</title></titleInfo><name type="personal"><namePart type="given">Katherine J.</namePart><namePart type="family">Castor</namePart><affiliation>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Johanna</namePart><namePart type="family">Mancini</namePart><affiliation>Departments of Anatomy and Cell Biology and Experimental Medicine, McGill University, Lady Davis Institute of Medical Research, 3755 Côte Ste‐Catherine Road, Montreal, QC, H3T 1E2 (Canada)</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="termsOfAddress">Dr.</namePart><namePart 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type="family">Autexier</namePart><affiliation>Departments of Anatomy and Cell Biology and Experimental Medicine, McGill University, Lady Davis Institute of Medical Research, 3755 Côte Ste‐Catherine Road, Montreal, QC, H3T 1E2 (Canada)</affiliation><affiliation>Chantal Autexier, Departments of Anatomy and Cell Biology and Experimental Medicine, McGill University, Lady Davis Institute of Medical Research, 3755 Côte Ste‐Catherine Road, Montreal, QC, H3T 1E2 (Canada)Nicolas Moitessier, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797Hanadi F. Sleiman, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="termsOfAddress">Prof.</namePart><namePart type="family">Moitessier</namePart><affiliation>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</affiliation><affiliation>Chantal Autexier, Departments of Anatomy and Cell Biology and Experimental Medicine, McGill University, Lady Davis Institute of Medical Research, 3755 Côte Ste‐Catherine Road, Montreal, QC, H3T 1E2 (Canada)Nicolas Moitessier, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797Hanadi F. Sleiman, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="termsOfAddress">Prof.</namePart><namePart type="family">Sleiman</namePart><affiliation>Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</affiliation><affiliation>Chantal Autexier, Departments of Anatomy and Cell Biology and Experimental Medicine, McGill University, Lady Davis Institute of Medical Research, 3755 Côte Ste‐Catherine Road, Montreal, QC, H3T 1E2 (Canada)Nicolas Moitessier, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797Hanadi F. Sleiman, Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC, H3A 2K6 (Canada), Fax: (+1) 514‐398‐3797</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>WILEY‐VCH Verlag</publisher><place><placeTerm type="text">Weinheim</placeTerm></place><dateIssued encoding="w3cdtf">2012-01-02</dateIssued><dateCaptured encoding="w3cdtf">2011-09-29</dateCaptured><copyrightDate encoding="w3cdtf">2012</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">8</extent><extent unit="tables">1</extent><extent unit="references">45</extent></physicalDescription><abstract>A rationally designed progression of phenanthroimidazole platinum(II) complexes were examined for their ability to target telomere‐derived intramolecular G‐quadruplex DNA. Through the use of circular dichroism, fluorescence displacement assays, and molecular modeling we show that these complexes template and stabilize G‐quadruplexes from sequences based on the human telomeric repeat (TTAGGG)n. The greatest stabilization was observed for the p‐chlorophenyl derivative 6 (G4DC50=0.31 μM). We also show that the G‐quadruplex binding complexes are able to inhibit telomerase activity through a modified telomerase repeat amplification protocol (TRAP‐LIG assay). Preliminary cell studies show that complex 6 is preferentially cytotoxic toward cancer over normal cell lines, indicating its potential use in cancer therapy.</abstract><abstract>A rational progression of π‐extended phenanthroimidazole PtII complexes were synthesized. Their interactions with and relative binding affinities for human telomere‐derived quadruplex DNA were studied by CD, FID assays, molecular modeling, and a TRAP assay. Significant binding affinity and selectivity for quadruplex DNA over duplex DNA was observed; this led to promising preliminary cytotoxicity studies for [(CLIP)Pt(en)] in cancer cells.</abstract><note type="funding">Canadian Institute for Health Research (CIHR) - No. MOP‐89978; </note><subject lang="en"><genre>keywords</genre><topic>antitumor agents</topic><topic>G‐quadruplexes</topic><topic>human telomeres</topic><topic>phenanthroimidazole</topic><topic>platinum</topic></subject><relatedItem type="host"><titleInfo><title>ChemMedChem</title></titleInfo><titleInfo type="abbreviated"><title>ChemMedChem</title></titleInfo><genre type="journal">journal</genre><note type="content"> Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer‐reviewed, but not copy‐edited or typeset. They are made available as submitted by the authors.Supporting Info Item: miscellaneous_information - </note><subject><genre>article-category</genre><topic>Full Paper</topic></subject><identifier type="ISSN">1860-7179</identifier><identifier type="eISSN">1860-7187</identifier><identifier type="DOI">10.1002/(ISSN)1860-7187</identifier><identifier type="PublisherID">CMDC</identifier><part><date>2012</date><detail type="volume"><caption>vol.</caption><number>7</number></detail><detail type="issue"><caption>no.</caption><number>1</number></detail><extent unit="pages"><start>85</start><end>94</end><total>10</total></extent></part></relatedItem><identifier type="istex">0EF6AF011A4A4F5E982B830E10D42935F4A36FEB</identifier><identifier type="DOI">10.1002/cmdc.201100453</identifier><identifier type="ArticleID">CMDC201100453</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2012 WILEY‐VCH Verlag GmbH & Co. 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