Cytotoxicity, Cellular Uptake, and DNA Interactions of New Monodentate Ruthenium(II) Complexes Containing Terphenyl Arenes
We have compared the cancer cell cytotoxicity, cell uptake, and DNA binding properties of the isomeric terphenyl complexes [(η6-arene)Ru(en)Cl]+, where the arene is ortho- (2), meta- (3), or para-terphenyl (1) (o-, m-, or p-terp). Complex 1, the X-ray crystal structure of which confirms that it has...
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| Veröffentlicht in: | Journal of medicinal chemistry 2008-09, Vol.51 (17), p.5310-5319 |
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| creator | Bugarcic, Tijana Nováková, Olga Zerzánková, Lenka Vrána, Oldřich Kašpárková, Jana Habtemariam, Abraha Parsons, Simon Sadler, Peter J Brabec, Viktor |
| description | We have compared the cancer cell cytotoxicity, cell uptake, and DNA binding properties of the isomeric terphenyl complexes [(η6-arene)Ru(en)Cl]+, where the arene is ortho- (2), meta- (3), or para-terphenyl (1) (o-, m-, or p-terp). Complex 1, the X-ray crystal structure of which confirms that it has the classical “piano-stool” geometry, has a similar potency to cisplatin but is not cross-resistant and has a much higher activity than 2 or 3. The extent of Ru uptake into A2780 or A2780cis cells does not correlate with potency. Complex 1 binds to DNA rapidly and quantitatively, preferentially to guanine residues, and causes significant DNA unwinding. Circular and linear dichroism, competitive binding experiments with ethidium bromide, DNA melting, and surface-enhanced Raman spectroscopic data are consistent with combined intercalative and monofunctional (coordination) binding mode of complex 1. This unusual DNA binding mode may therefore make a major contribution to the high potency of complex 1. |
| doi_str_mv | 10.1021/jm8003043 |
| format | Article |
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Complex 1, the X-ray crystal structure of which confirms that it has the classical “piano-stool” geometry, has a similar potency to cisplatin but is not cross-resistant and has a much higher activity than 2 or 3. The extent of Ru uptake into A2780 or A2780cis cells does not correlate with potency. Complex 1 binds to DNA rapidly and quantitatively, preferentially to guanine residues, and causes significant DNA unwinding. Circular and linear dichroism, competitive binding experiments with ethidium bromide, DNA melting, and surface-enhanced Raman spectroscopic data are consistent with combined intercalative and monofunctional (coordination) binding mode of complex 1. This unusual DNA binding mode may therefore make a major contribution to the high potency of complex 1.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm8003043</identifier><identifier>PMID: 18702458</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Antineoplastic agents ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Binding Sites ; Biological and medical sciences ; Cell Line, Tumor ; Crystallography, X-Ray ; DNA - chemistry ; DNA - drug effects ; DNA - metabolism ; DNA, Superhelical ; General aspects ; Guanine - metabolism ; Humans ; Medical sciences ; Neoplasms - drug therapy ; Neoplasms - pathology ; Nucleic Acid Denaturation ; Organometallic Compounds - metabolism ; Organometallic Compounds - pharmacokinetics ; Organometallic Compounds - pharmacology ; Pharmacology. Drug treatments ; Ruthenium ; Spectrum Analysis ; Structure-Activity Relationship ; Terphenyl Compounds - chemistry ; Terphenyl Compounds - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2008-09, Vol.51 (17), p.5310-5319</ispartof><rights>Copyright © 2008 American Chemical Society</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-88db5ddc41536d7d625f3a1a3f783faaa5b29467b479855ff7e9700ae24b958e3</citedby><cites>FETCH-LOGICAL-a381t-88db5ddc41536d7d625f3a1a3f783faaa5b29467b479855ff7e9700ae24b958e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm8003043$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm8003043$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,27055,27903,27904,56717,56767</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20627896$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18702458$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bugarcic, Tijana</creatorcontrib><creatorcontrib>Nováková, Olga</creatorcontrib><creatorcontrib>Zerzánková, Lenka</creatorcontrib><creatorcontrib>Vrána, Oldřich</creatorcontrib><creatorcontrib>Kašpárková, Jana</creatorcontrib><creatorcontrib>Habtemariam, Abraha</creatorcontrib><creatorcontrib>Parsons, Simon</creatorcontrib><creatorcontrib>Sadler, Peter J</creatorcontrib><creatorcontrib>Brabec, Viktor</creatorcontrib><title>Cytotoxicity, Cellular Uptake, and DNA Interactions of New Monodentate Ruthenium(II) Complexes Containing Terphenyl Arenes</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>We have compared the cancer cell cytotoxicity, cell uptake, and DNA binding properties of the isomeric terphenyl complexes [(η6-arene)Ru(en)Cl]+, where the arene is ortho- (2), meta- (3), or para-terphenyl (1) (o-, m-, or p-terp). Complex 1, the X-ray crystal structure of which confirms that it has the classical “piano-stool” geometry, has a similar potency to cisplatin but is not cross-resistant and has a much higher activity than 2 or 3. The extent of Ru uptake into A2780 or A2780cis cells does not correlate with potency. Complex 1 binds to DNA rapidly and quantitatively, preferentially to guanine residues, and causes significant DNA unwinding. Circular and linear dichroism, competitive binding experiments with ethidium bromide, DNA melting, and surface-enhanced Raman spectroscopic data are consistent with combined intercalative and monofunctional (coordination) binding mode of complex 1. This unusual DNA binding mode may therefore make a major contribution to the high potency of complex 1.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Cell Line, Tumor</subject><subject>Crystallography, X-Ray</subject><subject>DNA - chemistry</subject><subject>DNA - drug effects</subject><subject>DNA - metabolism</subject><subject>DNA, Superhelical</subject><subject>General aspects</subject><subject>Guanine - metabolism</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - pathology</subject><subject>Nucleic Acid Denaturation</subject><subject>Organometallic Compounds - metabolism</subject><subject>Organometallic Compounds - pharmacokinetics</subject><subject>Organometallic Compounds - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Ruthenium</subject><subject>Spectrum Analysis</subject><subject>Structure-Activity Relationship</subject><subject>Terphenyl Compounds - chemistry</subject><subject>Terphenyl Compounds - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0EFv0zAUB3ALgVgZHPgCyBcQkxZw7Dh2jlU2oNIYaOvK0XKTF3CX2MF2tJZPj1Gr7sLpWXo__eX3R-h1Tj7khOYfN4MkhJGCPUGznFOSFZIUT9GMEEozWlJ2gl6EsCEJ5ZQ9Rye5FIQWXM7Qn3oXXXRb05i4O8c19P3Ua4_vxqjv4Rxr2-KL6zle2AheN9E4G7Dr8DU84K_OuhZs1BHwzRR_gTXT8H6xOMO1G8YethDSK-2NNfYnXoIfk9n1eO7BQniJnnW6D_DqME_R3afLZf0lu_r2eVHPrzLNZB4zKds1b9umyDkrW9GWlHdM55p1QrJOa83XtCpKsS5EJTnvOgGVIEQDLdYVl8BO0bt97ujd7wlCVIMJTTpUW3BTUGWVKhNSJHi2h413IXjo1OjNoP1O5UT9K1odi072zSF0Wg_QPspDswm8PQAdGt13XtvGhKOjpKRCVmVy2d6ZEGF73Gt_r0rBBFfL77fqVqx-3NQXK7V6zNVNUBs3eZu6-88H_wKMhqDW</recordid><startdate>20080911</startdate><enddate>20080911</enddate><creator>Bugarcic, Tijana</creator><creator>Nováková, Olga</creator><creator>Zerzánková, Lenka</creator><creator>Vrána, Oldřich</creator><creator>Kašpárková, Jana</creator><creator>Habtemariam, Abraha</creator><creator>Parsons, Simon</creator><creator>Sadler, Peter J</creator><creator>Brabec, Viktor</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</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>7X8</scope></search><sort><creationdate>20080911</creationdate><title>Cytotoxicity, Cellular Uptake, and DNA Interactions of New Monodentate Ruthenium(II) Complexes Containing Terphenyl Arenes</title><author>Bugarcic, Tijana ; Nováková, Olga ; Zerzánková, Lenka ; Vrána, Oldřich ; Kašpárková, Jana ; Habtemariam, Abraha ; Parsons, Simon ; Sadler, Peter J ; Brabec, Viktor</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a381t-88db5ddc41536d7d625f3a1a3f783faaa5b29467b479855ff7e9700ae24b958e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Cell Line, Tumor</topic><topic>Crystallography, X-Ray</topic><topic>DNA - chemistry</topic><topic>DNA - drug effects</topic><topic>DNA - metabolism</topic><topic>DNA, Superhelical</topic><topic>General aspects</topic><topic>Guanine - metabolism</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - pathology</topic><topic>Nucleic Acid Denaturation</topic><topic>Organometallic Compounds - metabolism</topic><topic>Organometallic Compounds - pharmacokinetics</topic><topic>Organometallic Compounds - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Ruthenium</topic><topic>Spectrum Analysis</topic><topic>Structure-Activity Relationship</topic><topic>Terphenyl Compounds - chemistry</topic><topic>Terphenyl Compounds - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bugarcic, Tijana</creatorcontrib><creatorcontrib>Nováková, Olga</creatorcontrib><creatorcontrib>Zerzánková, Lenka</creatorcontrib><creatorcontrib>Vrána, Oldřich</creatorcontrib><creatorcontrib>Kašpárková, Jana</creatorcontrib><creatorcontrib>Habtemariam, Abraha</creatorcontrib><creatorcontrib>Parsons, Simon</creatorcontrib><creatorcontrib>Sadler, Peter J</creatorcontrib><creatorcontrib>Brabec, Viktor</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bugarcic, Tijana</au><au>Nováková, Olga</au><au>Zerzánková, Lenka</au><au>Vrána, Oldřich</au><au>Kašpárková, Jana</au><au>Habtemariam, Abraha</au><au>Parsons, Simon</au><au>Sadler, Peter J</au><au>Brabec, Viktor</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cytotoxicity, Cellular Uptake, and DNA Interactions of New Monodentate Ruthenium(II) Complexes Containing Terphenyl Arenes</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2008-09-11</date><risdate>2008</risdate><volume>51</volume><issue>17</issue><spage>5310</spage><epage>5319</epage><pages>5310-5319</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>We have compared the cancer cell cytotoxicity, cell uptake, and DNA binding properties of the isomeric terphenyl complexes [(η6-arene)Ru(en)Cl]+, where the arene is ortho- (2), meta- (3), or para-terphenyl (1) (o-, m-, or p-terp). Complex 1, the X-ray crystal structure of which confirms that it has the classical “piano-stool” geometry, has a similar potency to cisplatin but is not cross-resistant and has a much higher activity than 2 or 3. The extent of Ru uptake into A2780 or A2780cis cells does not correlate with potency. Complex 1 binds to DNA rapidly and quantitatively, preferentially to guanine residues, and causes significant DNA unwinding. Circular and linear dichroism, competitive binding experiments with ethidium bromide, DNA melting, and surface-enhanced Raman spectroscopic data are consistent with combined intercalative and monofunctional (coordination) binding mode of complex 1. This unusual DNA binding mode may therefore make a major contribution to the high potency of complex 1.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>18702458</pmid><doi>10.1021/jm8003043</doi><tpages>10</tpages></addata></record> |
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| subjects | Animals Antineoplastic agents Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Binding Sites Biological and medical sciences Cell Line, Tumor Crystallography, X-Ray DNA - chemistry DNA - drug effects DNA - metabolism DNA, Superhelical General aspects Guanine - metabolism Humans Medical sciences Neoplasms - drug therapy Neoplasms - pathology Nucleic Acid Denaturation Organometallic Compounds - metabolism Organometallic Compounds - pharmacokinetics Organometallic Compounds - pharmacology Pharmacology. Drug treatments Ruthenium Spectrum Analysis Structure-Activity Relationship Terphenyl Compounds - chemistry Terphenyl Compounds - pharmacology |
| title | Cytotoxicity, Cellular Uptake, and DNA Interactions of New Monodentate Ruthenium(II) Complexes Containing Terphenyl Arenes |
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