Disordering of human telomeric G-quadruplex with novel antiproliferative anthrathiophenedione
Linear heteroareneanthracenediones have been shown to interfere with DNA functions, thereby causing death of human tumor cells and their drug resistant counterparts. Here we report the interaction of our novel antiproliferative agent 4,11-bis[(2-{[acetimido]amino}ethyl)amino]anthra[2,3-b]thiophene-5...
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| creator | Kaluzhny, Dmitry Ilyinsky, Nikolay Shchekotikhin, Andrei Sinkevich, Yuri Tsvetkov, Philipp O Tsvetkov, Vladimir Veselovsky, Alexander Livshits, Mikhail Borisova, Olga Shtil, Alexander Shchyolkina, Anna |
| description | Linear heteroareneanthracenediones have been shown to interfere with DNA functions, thereby causing death of human tumor cells and their drug resistant counterparts. Here we report the interaction of our novel antiproliferative agent 4,11-bis[(2-{[acetimido]amino}ethyl)amino]anthra[2,3-b]thiophene-5,10-dione with telomeric DNA structures studied by isothermal titration calorimetry, circular dichroism and UV absorption spectroscopy. New compound demonstrated a high affinity (K(ass)∼10⁶ M⁻¹) for human telomeric antiparallel quadruplex d(TTAGGG)₄ and duplex d(TTAGGG)₄∶d(CCCTAA)₄. Importantly, a ∼100-fold higher affinity was determined for the ligand binding to an unordered oligonucleotide d(TTAGGG TTAGAG TTAGGG TTAGGG unable to form quadruplex structures. Moreover, in the presence of Na+ the compound caused dramatic conformational perturbation of the telomeric G-quadruplex, namely, almost complete disordering of G-quartets. Disorganization of a portion of G-quartets in the presence of K+ was also detected. Molecular dynamics simulations were performed to illustrate how the binding of one molecule of the ligand might disrupt the G-quartet adjacent to the diagonal loop of telomeric G-quadruplex. Our results provide evidence for a non-trivial mode of alteration of G-quadruplex structure by tentative antiproliferative drugs. |
| doi_str_mv | 10.1371/journal.pone.0027151 |
| format | Article |
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Here we report the interaction of our novel antiproliferative agent 4,11-bis[(2-{[acetimido]amino}ethyl)amino]anthra[2,3-b]thiophene-5,10-dione with telomeric DNA structures studied by isothermal titration calorimetry, circular dichroism and UV absorption spectroscopy. New compound demonstrated a high affinity (K(ass)∼10⁶ M⁻¹) for human telomeric antiparallel quadruplex d(TTAGGG)₄ and duplex d(TTAGGG)₄∶d(CCCTAA)₄. Importantly, a ∼100-fold higher affinity was determined for the ligand binding to an unordered oligonucleotide d(TTAGGG TTAGAG TTAGGG TTAGGG unable to form quadruplex structures. Moreover, in the presence of Na+ the compound caused dramatic conformational perturbation of the telomeric G-quadruplex, namely, almost complete disordering of G-quartets. Disorganization of a portion of G-quartets in the presence of K+ was also detected. Molecular dynamics simulations were performed to illustrate how the binding of one molecule of the ligand might disrupt the G-quartet adjacent to the diagonal loop of telomeric G-quadruplex. Our results provide evidence for a non-trivial mode of alteration of G-quadruplex structure by tentative antiproliferative drugs.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0027151</identifier><identifier>PMID: 22102877</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Absorption spectroscopy ; Affinity ; Anthraquinones - chemical synthesis ; Anthraquinones - pharmacology ; Antibiotics ; Antiproliferatives ; Binding ; Biology ; Calorimetry ; Cancer ; Cell Proliferation - drug effects ; Circular Dichroism ; Colonic Neoplasms - drug therapy ; Cytotoxicity ; Deoxyribonucleic acid ; Dichroism ; DNA ; Drug resistance ; Drugs ; G-Quadruplexes - drug effects ; Glycoproteins ; Humans ; Leukemia - drug therapy ; Medicine ; Models, Molecular ; Molecular biology ; Molecular dynamics ; Molecular Dynamics Simulation ; Nucleic Acid Conformation - drug effects ; Oligonucleotides ; Oligonucleotides - genetics ; Oligonucleotides - metabolism ; Potassium - metabolism ; Sodium - metabolism ; Spectroscopy ; Telomerase ; Telomere - genetics ; Telomere - metabolism ; Thiophene ; Thiophenes - chemical synthesis ; Thiophenes - pharmacology ; Titration ; Titration calorimetry ; Tumor cells ; Tumor Cells, Cultured ; Ultraviolet absorption</subject><ispartof>PloS one, 2011-11, Vol.6 (11), p.e27151</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Kaluzhny et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Kaluzhny et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-1c6fdf1519a246d80b70b132c74549bd8214f9b370ce93bf5a0bcf6ae699d4673</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216923/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216923/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22102877$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Blagosklonny, Mikhail V.</contributor><creatorcontrib>Kaluzhny, Dmitry</creatorcontrib><creatorcontrib>Ilyinsky, Nikolay</creatorcontrib><creatorcontrib>Shchekotikhin, Andrei</creatorcontrib><creatorcontrib>Sinkevich, Yuri</creatorcontrib><creatorcontrib>Tsvetkov, Philipp O</creatorcontrib><creatorcontrib>Tsvetkov, Vladimir</creatorcontrib><creatorcontrib>Veselovsky, Alexander</creatorcontrib><creatorcontrib>Livshits, Mikhail</creatorcontrib><creatorcontrib>Borisova, Olga</creatorcontrib><creatorcontrib>Shtil, Alexander</creatorcontrib><creatorcontrib>Shchyolkina, Anna</creatorcontrib><title>Disordering of human telomeric G-quadruplex with novel antiproliferative anthrathiophenedione</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Linear heteroareneanthracenediones have been shown to interfere with DNA functions, thereby causing death of human tumor cells and their drug resistant counterparts. Here we report the interaction of our novel antiproliferative agent 4,11-bis[(2-{[acetimido]amino}ethyl)amino]anthra[2,3-b]thiophene-5,10-dione with telomeric DNA structures studied by isothermal titration calorimetry, circular dichroism and UV absorption spectroscopy. New compound demonstrated a high affinity (K(ass)∼10⁶ M⁻¹) for human telomeric antiparallel quadruplex d(TTAGGG)₄ and duplex d(TTAGGG)₄∶d(CCCTAA)₄. Importantly, a ∼100-fold higher affinity was determined for the ligand binding to an unordered oligonucleotide d(TTAGGG TTAGAG TTAGGG TTAGGG unable to form quadruplex structures. Moreover, in the presence of Na+ the compound caused dramatic conformational perturbation of the telomeric G-quadruplex, namely, almost complete disordering of G-quartets. Disorganization of a portion of G-quartets in the presence of K+ was also detected. Molecular dynamics simulations were performed to illustrate how the binding of one molecule of the ligand might disrupt the G-quartet adjacent to the diagonal loop of telomeric G-quadruplex. Our results provide evidence for a non-trivial mode of alteration of G-quadruplex structure by tentative antiproliferative drugs.</description><subject>Absorption spectroscopy</subject><subject>Affinity</subject><subject>Anthraquinones - chemical synthesis</subject><subject>Anthraquinones - pharmacology</subject><subject>Antibiotics</subject><subject>Antiproliferatives</subject><subject>Binding</subject><subject>Biology</subject><subject>Calorimetry</subject><subject>Cancer</subject><subject>Cell Proliferation - drug effects</subject><subject>Circular Dichroism</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Cytotoxicity</subject><subject>Deoxyribonucleic acid</subject><subject>Dichroism</subject><subject>DNA</subject><subject>Drug resistance</subject><subject>Drugs</subject><subject>G-Quadruplexes - drug effects</subject><subject>Glycoproteins</subject><subject>Humans</subject><subject>Leukemia - drug therapy</subject><subject>Medicine</subject><subject>Models, Molecular</subject><subject>Molecular biology</subject><subject>Molecular dynamics</subject><subject>Molecular Dynamics Simulation</subject><subject>Nucleic Acid Conformation - drug effects</subject><subject>Oligonucleotides</subject><subject>Oligonucleotides - genetics</subject><subject>Oligonucleotides - metabolism</subject><subject>Potassium - metabolism</subject><subject>Sodium - metabolism</subject><subject>Spectroscopy</subject><subject>Telomerase</subject><subject>Telomere - genetics</subject><subject>Telomere - metabolism</subject><subject>Thiophene</subject><subject>Thiophenes - chemical synthesis</subject><subject>Thiophenes - pharmacology</subject><subject>Titration</subject><subject>Titration calorimetry</subject><subject>Tumor cells</subject><subject>Tumor Cells, Cultured</subject><subject>Ultraviolet absorption</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl2L1DAUhoso7rr6D0QLguBFx3y0SXMjLKuuAwsLft1JSPMxzdA23SQd139vxukuU1CQXCS8ec6bw8mbZc8hWEFM4dutm_wgutXoBr0CAFFYwQfZKWQYFQQB_PDofJI9CWELQIVrQh5nJwhBgGpKT7Mf721wXmlvh03uTN5OvRjyqDvXJ03ml8XNJJSfxk7f5j9tbPPB7XSXiyHa0bvOGu1FtDu9V9p0bK0bWz1oZVNfT7NHRnRBP5v3s-zbxw9fLz4VV9eX64vzq0ISBmMBJTHKpP6ZQCVRNWgoaCBGkpZVyRpVI1ga1mAKpGa4MZUAjTREaMKYKgnFZ9nLg-_YucDnyQQOMUSwYpCUiVgfCOXElo_e9sL_4k5Y_kdwfsOFj1Z2mkNJpWlozYSqS0WV0BACiksoMapqBpLXu_m1qem1knqIXnQL0-XNYFu-cTuOESQM4WTwajbw7mbSIf6j5ZnaiNSVHYxLZrK3QfLzkpKaIFbtqdVfqLSU7q1Mf2Bs0hcFbxYFiYn6Nm7EFAJff_n8_-z19yX7-ohttehiG1w3xRSEsATLAyi9C8Frcz85CPg-2nfT4Pto8znaqezF8dTvi-6yjH8DPU31ZA</recordid><startdate>20111115</startdate><enddate>20111115</enddate><creator>Kaluzhny, Dmitry</creator><creator>Ilyinsky, Nikolay</creator><creator>Shchekotikhin, Andrei</creator><creator>Sinkevich, Yuri</creator><creator>Tsvetkov, Philipp O</creator><creator>Tsvetkov, Vladimir</creator><creator>Veselovsky, Alexander</creator><creator>Livshits, Mikhail</creator><creator>Borisova, Olga</creator><creator>Shtil, Alexander</creator><creator>Shchyolkina, Anna</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20111115</creationdate><title>Disordering of human telomeric G-quadruplex with novel antiproliferative anthrathiophenedione</title><author>Kaluzhny, Dmitry ; Ilyinsky, Nikolay ; Shchekotikhin, Andrei ; Sinkevich, Yuri ; Tsvetkov, Philipp O ; Tsvetkov, Vladimir ; Veselovsky, Alexander ; Livshits, Mikhail ; Borisova, Olga ; Shtil, Alexander ; Shchyolkina, Anna</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c691t-1c6fdf1519a246d80b70b132c74549bd8214f9b370ce93bf5a0bcf6ae699d4673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Absorption spectroscopy</topic><topic>Affinity</topic><topic>Anthraquinones - 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Here we report the interaction of our novel antiproliferative agent 4,11-bis[(2-{[acetimido]amino}ethyl)amino]anthra[2,3-b]thiophene-5,10-dione with telomeric DNA structures studied by isothermal titration calorimetry, circular dichroism and UV absorption spectroscopy. New compound demonstrated a high affinity (K(ass)∼10⁶ M⁻¹) for human telomeric antiparallel quadruplex d(TTAGGG)₄ and duplex d(TTAGGG)₄∶d(CCCTAA)₄. Importantly, a ∼100-fold higher affinity was determined for the ligand binding to an unordered oligonucleotide d(TTAGGG TTAGAG TTAGGG TTAGGG unable to form quadruplex structures. Moreover, in the presence of Na+ the compound caused dramatic conformational perturbation of the telomeric G-quadruplex, namely, almost complete disordering of G-quartets. Disorganization of a portion of G-quartets in the presence of K+ was also detected. Molecular dynamics simulations were performed to illustrate how the binding of one molecule of the ligand might disrupt the G-quartet adjacent to the diagonal loop of telomeric G-quadruplex. Our results provide evidence for a non-trivial mode of alteration of G-quadruplex structure by tentative antiproliferative drugs.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22102877</pmid><doi>10.1371/journal.pone.0027151</doi><tpages>e27151</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-11, Vol.6 (11), p.e27151 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1312159164 |
| source | PubMed Central Free; MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Absorption spectroscopy Affinity Anthraquinones - chemical synthesis Anthraquinones - pharmacology Antibiotics Antiproliferatives Binding Biology Calorimetry Cancer Cell Proliferation - drug effects Circular Dichroism Colonic Neoplasms - drug therapy Cytotoxicity Deoxyribonucleic acid Dichroism DNA Drug resistance Drugs G-Quadruplexes - drug effects Glycoproteins Humans Leukemia - drug therapy Medicine Models, Molecular Molecular biology Molecular dynamics Molecular Dynamics Simulation Nucleic Acid Conformation - drug effects Oligonucleotides Oligonucleotides - genetics Oligonucleotides - metabolism Potassium - metabolism Sodium - metabolism Spectroscopy Telomerase Telomere - genetics Telomere - metabolism Thiophene Thiophenes - chemical synthesis Thiophenes - pharmacology Titration Titration calorimetry Tumor cells Tumor Cells, Cultured Ultraviolet absorption |
| title | Disordering of human telomeric G-quadruplex with novel antiproliferative anthrathiophenedione |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-03T13%3A27%3A28IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Disordering%20of%20human%20telomeric%20G-quadruplex%20with%20novel%20antiproliferative%20anthrathiophenedione&rft.jtitle=PloS%20one&rft.au=Kaluzhny,%20Dmitry&rft.date=2011-11-15&rft.volume=6&rft.issue=11&rft.spage=e27151&rft.pages=e27151-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0027151&rft_dat=%3Cgale_plos_%3EA476862954%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1312159164&rft_id=info:pmid/22102877&rft_galeid=A476862954&rft_doaj_id=oai_doaj_org_article_1c7cfb789ad84d7dae1107341c325890&rfr_iscdi=true |