A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor
A strategy is described for the re-design of DNA damaging platinum(II) complexes to afford elevated toxicity towards cancer cells expressing the estrogen receptor (ER). Two platinum-based toxicants are described in which a DNA damaging warhead, [Pt(en)Cl 2] (en, ethylenediamine), is tethered to eith...
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| Veröffentlicht in: | Journal of inorganic biochemistry 2009-02, Vol.103 (2), p.256-261 |
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| creator | Kim, Eunsuk Rye, Peter T. Essigmann, John M. Croy, Robert G. |
| description | A strategy is described for the re-design of DNA damaging platinum(II) complexes to afford elevated toxicity towards cancer cells expressing the estrogen receptor (ER). Two platinum-based toxicants are described in which a DNA damaging warhead, [Pt(en)Cl
2] (en, ethylenediamine), is tethered to either of two functional groups. The first agent, [6-(2-amino-ethylamino)-hexyl]-carbamic acid 2-[6-(7α-estra-1,3,5,(10)-triene)-hexylamino]-ethyl ester platinum(II) dichloride ((Est-en)PtCl
2), terminates in a ligand for the ER. The second agent is a control compound lacking the steroid; this compound,
N-[6-(2-amino-ethylamino)-hexyl]-benzamide platinum(II) dichloride ((Bz-en)PtCl
2)), terminates in a benzamide moiety, which lacks affinity for the ER. Using a competitive binding assay, Est-en had 28% relative binding affinity (RBA) for the ER as compared to 17β-estradiol. After covalent binding to a synthetic DNA duplex 16-mer, the compound retained its affinity for the ER; specificity of the binding event was demonstrated by the ability of free 17β-estradiol as a competitor to disrupt the DNA adduct-ER complex. The (Est-en)PtCl
2 compound showed higher toxicity against the ER positive ovarian cancer cell line CAOV3 than did the control compound. (Est-en)PtCl
2 was also more toxic to the ER positive breast cancer line, MCF-7, than to an ER negative line, MDA-MB231. |
| doi_str_mv | 10.1016/j.jinorgbio.2008.10.013 |
| format | Article |
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2] (en, ethylenediamine), is tethered to either of two functional groups. The first agent, [6-(2-amino-ethylamino)-hexyl]-carbamic acid 2-[6-(7α-estra-1,3,5,(10)-triene)-hexylamino]-ethyl ester platinum(II) dichloride ((Est-en)PtCl
2), terminates in a ligand for the ER. The second agent is a control compound lacking the steroid; this compound,
N-[6-(2-amino-ethylamino)-hexyl]-benzamide platinum(II) dichloride ((Bz-en)PtCl
2)), terminates in a benzamide moiety, which lacks affinity for the ER. Using a competitive binding assay, Est-en had 28% relative binding affinity (RBA) for the ER as compared to 17β-estradiol. After covalent binding to a synthetic DNA duplex 16-mer, the compound retained its affinity for the ER; specificity of the binding event was demonstrated by the ability of free 17β-estradiol as a competitor to disrupt the DNA adduct-ER complex. The (Est-en)PtCl
2 compound showed higher toxicity against the ER positive ovarian cancer cell line CAOV3 than did the control compound. (Est-en)PtCl
2 was also more toxic to the ER positive breast cancer line, MCF-7, than to an ER negative line, MDA-MB231.</description><identifier>ISSN: 0162-0134</identifier><identifier>EISSN: 1873-3344</identifier><identifier>DOI: 10.1016/j.jinorgbio.2008.10.013</identifier><identifier>PMID: 19054566</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - metabolism ; Breast and ovarian cancers ; Breast Neoplasms - metabolism ; Cell Line, Tumor ; Cytotoxic agent ; DNA Adducts - metabolism ; DNA Damage ; Drug Design ; Estradiol - metabolism ; Estrenes - chemical synthesis ; Estrenes - chemistry ; Estrenes - metabolism ; Estrogen receptor ; Female ; Humans ; Organoplatinum Compounds - chemical synthesis ; Organoplatinum Compounds - chemistry ; Organoplatinum Compounds - metabolism ; Ovarian Neoplasms - metabolism ; Pt(II)-estrogen anticancer drug ; Receptors, Estrogen - metabolism</subject><ispartof>Journal of inorganic biochemistry, 2009-02, Vol.103 (2), p.256-261</ispartof><rights>2008 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c473t-9825ac56c8199c7889e21cfaca5dfc078188f395ea07d8df4e3e94b95a5bf1a23</citedby><cites>FETCH-LOGICAL-c473t-9825ac56c8199c7889e21cfaca5dfc078188f395ea07d8df4e3e94b95a5bf1a23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jinorgbio.2008.10.013$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,315,782,786,887,3554,27933,27934,46004</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19054566$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Eunsuk</creatorcontrib><creatorcontrib>Rye, Peter T.</creatorcontrib><creatorcontrib>Essigmann, John M.</creatorcontrib><creatorcontrib>Croy, Robert G.</creatorcontrib><title>A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor</title><title>Journal of inorganic biochemistry</title><addtitle>J Inorg Biochem</addtitle><description>A strategy is described for the re-design of DNA damaging platinum(II) complexes to afford elevated toxicity towards cancer cells expressing the estrogen receptor (ER). Two platinum-based toxicants are described in which a DNA damaging warhead, [Pt(en)Cl
2] (en, ethylenediamine), is tethered to either of two functional groups. The first agent, [6-(2-amino-ethylamino)-hexyl]-carbamic acid 2-[6-(7α-estra-1,3,5,(10)-triene)-hexylamino]-ethyl ester platinum(II) dichloride ((Est-en)PtCl
2), terminates in a ligand for the ER. The second agent is a control compound lacking the steroid; this compound,
N-[6-(2-amino-ethylamino)-hexyl]-benzamide platinum(II) dichloride ((Bz-en)PtCl
2)), terminates in a benzamide moiety, which lacks affinity for the ER. Using a competitive binding assay, Est-en had 28% relative binding affinity (RBA) for the ER as compared to 17β-estradiol. After covalent binding to a synthetic DNA duplex 16-mer, the compound retained its affinity for the ER; specificity of the binding event was demonstrated by the ability of free 17β-estradiol as a competitor to disrupt the DNA adduct-ER complex. The (Est-en)PtCl
2 compound showed higher toxicity against the ER positive ovarian cancer cell line CAOV3 than did the control compound. (Est-en)PtCl
2 was also more toxic to the ER positive breast cancer line, MCF-7, than to an ER negative line, MDA-MB231.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - metabolism</subject><subject>Breast and ovarian cancers</subject><subject>Breast Neoplasms - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cytotoxic agent</subject><subject>DNA Adducts - metabolism</subject><subject>DNA Damage</subject><subject>Drug Design</subject><subject>Estradiol - metabolism</subject><subject>Estrenes - chemical synthesis</subject><subject>Estrenes - chemistry</subject><subject>Estrenes - metabolism</subject><subject>Estrogen receptor</subject><subject>Female</subject><subject>Humans</subject><subject>Organoplatinum Compounds - chemical synthesis</subject><subject>Organoplatinum Compounds - chemistry</subject><subject>Organoplatinum Compounds - metabolism</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Pt(II)-estrogen anticancer drug</subject><subject>Receptors, Estrogen - metabolism</subject><issn>0162-0134</issn><issn>1873-3344</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1PwyAYx4nR6Jx-BeWoh05oy0ovJouvSxa96Jk8pbDRrLAA1fjtZZnx5eSJ5Pm_kR9C55RMKKHTq27SGev8sjFukhPC03VCaLGHRpRXRVYUZbmPRsmZZ-lcHqHjEDpCCGNldYiOaE1YyabTEepmuDF6sDIaZ2GNN2uIxg79xXx-icFGE4feeQxLZSOOK4hYO98HfPs0w9C2g4wBv5u4wqC1sSZ-bPVkVFiF6F2KYa-k2kTnT9CBhnVQp1_vGL3e373cPGaL54f5zWyRybIqYlbznIFkU8lpXcuK81rlVGqQwFotScUp57qomQJStbzVpSpUXTY1A9ZoCnkxRte73s3Q9KqV6ece1mLjTQ_-Qzgw4q9izUos3ZvI0yLLeSqodgXSuxC80t9ZSsQWv-jEN36xxb8VEueUPPs9_ZP74p0Ms51BJQBvRnkRpFFWqtYkTFG0zvw78gmRdp5s</recordid><startdate>20090201</startdate><enddate>20090201</enddate><creator>Kim, Eunsuk</creator><creator>Rye, Peter T.</creator><creator>Essigmann, John M.</creator><creator>Croy, Robert G.</creator><general>Elsevier Inc</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>5PM</scope></search><sort><creationdate>20090201</creationdate><title>A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor</title><author>Kim, Eunsuk ; Rye, Peter T. ; Essigmann, John M. ; Croy, Robert G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c473t-9825ac56c8199c7889e21cfaca5dfc078188f395ea07d8df4e3e94b95a5bf1a23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - metabolism</topic><topic>Breast and ovarian cancers</topic><topic>Breast Neoplasms - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cytotoxic agent</topic><topic>DNA Adducts - metabolism</topic><topic>DNA Damage</topic><topic>Drug Design</topic><topic>Estradiol - metabolism</topic><topic>Estrenes - chemical synthesis</topic><topic>Estrenes - chemistry</topic><topic>Estrenes - metabolism</topic><topic>Estrogen receptor</topic><topic>Female</topic><topic>Humans</topic><topic>Organoplatinum Compounds - chemical synthesis</topic><topic>Organoplatinum Compounds - chemistry</topic><topic>Organoplatinum Compounds - metabolism</topic><topic>Ovarian Neoplasms - metabolism</topic><topic>Pt(II)-estrogen anticancer drug</topic><topic>Receptors, Estrogen - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Eunsuk</creatorcontrib><creatorcontrib>Rye, Peter T.</creatorcontrib><creatorcontrib>Essigmann, John M.</creatorcontrib><creatorcontrib>Croy, Robert G.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of inorganic biochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Eunsuk</au><au>Rye, Peter T.</au><au>Essigmann, John M.</au><au>Croy, Robert G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor</atitle><jtitle>Journal of inorganic biochemistry</jtitle><addtitle>J Inorg Biochem</addtitle><date>2009-02-01</date><risdate>2009</risdate><volume>103</volume><issue>2</issue><spage>256</spage><epage>261</epage><pages>256-261</pages><issn>0162-0134</issn><eissn>1873-3344</eissn><abstract>A strategy is described for the re-design of DNA damaging platinum(II) complexes to afford elevated toxicity towards cancer cells expressing the estrogen receptor (ER). Two platinum-based toxicants are described in which a DNA damaging warhead, [Pt(en)Cl
2] (en, ethylenediamine), is tethered to either of two functional groups. The first agent, [6-(2-amino-ethylamino)-hexyl]-carbamic acid 2-[6-(7α-estra-1,3,5,(10)-triene)-hexylamino]-ethyl ester platinum(II) dichloride ((Est-en)PtCl
2), terminates in a ligand for the ER. The second agent is a control compound lacking the steroid; this compound,
N-[6-(2-amino-ethylamino)-hexyl]-benzamide platinum(II) dichloride ((Bz-en)PtCl
2)), terminates in a benzamide moiety, which lacks affinity for the ER. Using a competitive binding assay, Est-en had 28% relative binding affinity (RBA) for the ER as compared to 17β-estradiol. After covalent binding to a synthetic DNA duplex 16-mer, the compound retained its affinity for the ER; specificity of the binding event was demonstrated by the ability of free 17β-estradiol as a competitor to disrupt the DNA adduct-ER complex. The (Est-en)PtCl
2 compound showed higher toxicity against the ER positive ovarian cancer cell line CAOV3 than did the control compound. (Est-en)PtCl
2 was also more toxic to the ER positive breast cancer line, MCF-7, than to an ER negative line, MDA-MB231.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>19054566</pmid><doi>10.1016/j.jinorgbio.2008.10.013</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - metabolism Breast and ovarian cancers Breast Neoplasms - metabolism Cell Line, Tumor Cytotoxic agent DNA Adducts - metabolism DNA Damage Drug Design Estradiol - metabolism Estrenes - chemical synthesis Estrenes - chemistry Estrenes - metabolism Estrogen receptor Female Humans Organoplatinum Compounds - chemical synthesis Organoplatinum Compounds - chemistry Organoplatinum Compounds - metabolism Ovarian Neoplasms - metabolism Pt(II)-estrogen anticancer drug Receptors, Estrogen - metabolism |
| title | A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor |
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