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[subscript 2]] (en, ethylenediamine), is tethe...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2015
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| Online Access: | http://hdl.handle.net/1721.1/99185 https://orcid.org/0000-0002-2196-5691 |
| _version_ | 1826208181717565440 |
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| author | Kim, Eunsuk Rye, Peter T. Essigmann, John M. Croy, Robert G. |
| author2 | Massachusetts Institute of Technology. Center for Environmental Health Sciences |
| author_facet | Massachusetts Institute of Technology. Center for Environmental Health Sciences Kim, Eunsuk Rye, Peter T. Essigmann, John M. Croy, Robert G. |
| author_sort | Kim, Eunsuk |
| collection | MIT |
| 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[subscript 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[subscript 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[subscript 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[subscript 2] compound showed higher toxicity against the ER positive ovarian cancer cell line CAOV3 than did the control compound. (Est-en)PtCl[subscript 2] was also more toxic to the ER positive breast cancer line, MCF-7, than to an ER negative line, MDA-MB231. |
| first_indexed | 2024-09-23T14:01:48Z |
| format | Article |
| id | mit-1721.1/99185 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:01:48Z |
| publishDate | 2015 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/991852022-10-01T18:40:07Z A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor Kim, Eunsuk Rye, Peter T. Essigmann, John M. Croy, Robert G. Massachusetts Institute of Technology. Center for Environmental Health Sciences Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemistry Kim, Eunsuk Rye, Peter T. Essigmann, John M. Croy, Robert G. 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[subscript 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[subscript 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[subscript 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[subscript 2] compound showed higher toxicity against the ER positive ovarian cancer cell line CAOV3 than did the control compound. (Est-en)PtCl[subscript 2] was also more toxic to the ER positive breast cancer line, MCF-7, than to an ER negative line, MDA-MB231. National Institutes of Health (U.S.) (Grant CA08661) Life Sciences Research Foundation 2015-10-07T16:02:34Z 2015-10-07T16:02:34Z 2008-10 2008-10 Article http://purl.org/eprint/type/JournalArticle 01620134 http://hdl.handle.net/1721.1/99185 Kim, Eunsuk, Peter T. Rye, John M. Essigmann, and Robert G. Croy. “A Bifunctional platinum(II) Antitumor Agent That Forms DNA Adducts with Affinity for the Estrogen Receptor.” Journal of Inorganic Biochemistry 103, no. 2 (February 2009): 256–261. https://orcid.org/0000-0002-2196-5691 en_US http://dx.doi.org/10.1016/j.jinorgbio.2008.10.013 Journal of Inorganic Biochemistry Creative Commons Attribution-Noncommercial-NoDerivatives http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Kim, Eunsuk Rye, Peter T. Essigmann, John M. Croy, Robert G. A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor |
| title | A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor |
| title_full | A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor |
| title_fullStr | A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor |
| title_full_unstemmed | A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor |
| title_short | A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor |
| title_sort | bifunctional platinum ii antitumor agent that forms dna adducts with affinity for the estrogen receptor |
| url | http://hdl.handle.net/1721.1/99185 https://orcid.org/0000-0002-2196-5691 |
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