Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile
Monofunctional platinum(II) complexes of general formula cis-[Pt(NH3)2(N-heterocycle)Cl]Cl bind DNA at a single site, inducing little distortion in the double helix. Despite this behavior, these compounds display significant antitumor properties, with a different spectrum of activity than that of cl...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2013
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| Online Access: | http://hdl.handle.net/1721.1/76786 https://orcid.org/0000-0002-2693-4982 |
| _version_ | 1811076776347041792 |
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| author | Park, Ga Young Wilson, Justin Jeff Song, Ying Lippard, Stephen J. |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Park, Ga Young Wilson, Justin Jeff Song, Ying Lippard, Stephen J. |
| author_sort | Park, Ga Young |
| collection | MIT |
| description | Monofunctional platinum(II) complexes of general formula cis-[Pt(NH3)2(N-heterocycle)Cl]Cl bind DNA at a single site, inducing little distortion in the double helix. Despite this behavior, these compounds display significant antitumor properties, with a different spectrum of activity than that of classic bifunctional cross-linking agents like cisplatin. To discover the most potent monofunctional platinum(II) compounds, the N-heterocycle was systematically varied to generate a small library of new compounds, with guidance from the X-ray structure of RNA polymerase II (Pol II) stalled at a monofunctional pyriplatin-DNA adduct. In pyriplatin, the N-heterocycle is pyridine. The most effective complex evaluated was phenanthriplatin, cis-[Pt(NH3)2(phenanthridine)Cl]NO3, which exhibits significantly greater activity than the Food and Drug Administration-approved drugs cisplatin and oxaliplatin. Studies of phenanthriplatin in the National Cancer Institute 60-cell tumor panel screen revealed a spectrum of activity distinct from that of these clinically validated anticancer agents. The cellular uptake of phenanthriplatin is substantially greater than that of cisplatin and pyriplatin because of the hydrophobicity of the phenanthridine ligand. Phenanthriplatin binds more effectively to 5′-deoxyguanosine monophosphate than to N-acetyl methionine, whereas pyriplatin reacts equally well with both reagents. This chemistry supports DNA as a viable cellular target for phenanthriplatin and suggests that it may avoid cytoplasmic platinum scavengers with sulfur-donor ligands that convey drug resistance. With the use of globally platinated Gaussia luciferase vectors, we determined that phenanthriplatin inhibits transcription in live mammalian cells as effectively as cisplatin, despite its inability to form DNA cross-links. |
| first_indexed | 2024-09-23T10:27:17Z |
| format | Article |
| id | mit-1721.1/76786 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:27:17Z |
| publishDate | 2013 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/767862022-09-27T09:36:46Z Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile Park, Ga Young Wilson, Justin Jeff Song, Ying Lippard, Stephen J. Massachusetts Institute of Technology. Department of Chemistry Park, Ga Young Wilson, Justin Jeff Song, Ying Lippard, Stephen J. Monofunctional platinum(II) complexes of general formula cis-[Pt(NH3)2(N-heterocycle)Cl]Cl bind DNA at a single site, inducing little distortion in the double helix. Despite this behavior, these compounds display significant antitumor properties, with a different spectrum of activity than that of classic bifunctional cross-linking agents like cisplatin. To discover the most potent monofunctional platinum(II) compounds, the N-heterocycle was systematically varied to generate a small library of new compounds, with guidance from the X-ray structure of RNA polymerase II (Pol II) stalled at a monofunctional pyriplatin-DNA adduct. In pyriplatin, the N-heterocycle is pyridine. The most effective complex evaluated was phenanthriplatin, cis-[Pt(NH3)2(phenanthridine)Cl]NO3, which exhibits significantly greater activity than the Food and Drug Administration-approved drugs cisplatin and oxaliplatin. Studies of phenanthriplatin in the National Cancer Institute 60-cell tumor panel screen revealed a spectrum of activity distinct from that of these clinically validated anticancer agents. The cellular uptake of phenanthriplatin is substantially greater than that of cisplatin and pyriplatin because of the hydrophobicity of the phenanthridine ligand. Phenanthriplatin binds more effectively to 5′-deoxyguanosine monophosphate than to N-acetyl methionine, whereas pyriplatin reacts equally well with both reagents. This chemistry supports DNA as a viable cellular target for phenanthriplatin and suggests that it may avoid cytoplasmic platinum scavengers with sulfur-donor ligands that convey drug resistance. With the use of globally platinated Gaussia luciferase vectors, we determined that phenanthriplatin inhibits transcription in live mammalian cells as effectively as cisplatin, despite its inability to form DNA cross-links. National Cancer Institute (U.S.) (Grant CA034992) S. Leslie Misrock Foundation (Postdoctoral Fellowship) 2013-02-12T21:36:54Z 2013-02-12T21:36:54Z 2012-07 2012-05 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/76786 Park, G. Y. et al. “Phenanthriplatin, a Monofunctional DNA-binding Platinum Anticancer Drug Candidate with Unusual Potency and Cellular Activity Profile.” Proceedings of the National Academy of Sciences 109.30 (2012): 11987–11992. Web. https://orcid.org/0000-0002-2693-4982 en_US http://dx.doi.org/10.1073/pnas.1207670109 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Park, Ga Young Wilson, Justin Jeff Song, Ying Lippard, Stephen J. Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile |
| title | Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile |
| title_full | Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile |
| title_fullStr | Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile |
| title_full_unstemmed | Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile |
| title_short | Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile |
| title_sort | phenanthriplatin a monofunctional dna binding platinum anticancer drug candidate with unusual potency and cellular activity profile |
| url | http://hdl.handle.net/1721.1/76786 https://orcid.org/0000-0002-2693-4982 |
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