Synthesis and Characterization of Pt(IV) Fluorescein Conjugates to Investigate Pt(IV) Intracellular Transformations
Pt(IV) anticancer compounds typically operate as prodrugs that are reduced in the hypoxic environment of cancer cells, losing two axial ligands in the process to generate active Pt(II) species. Here we report the synthesis of two fluorescent Pt(IV) prodrugs of cisplatin in order to image and evaluat...
| Main Authors: | , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
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American Chemical Society (ACS)
2015
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| Online Access: | http://hdl.handle.net/1721.1/95477 https://orcid.org/0000-0002-2693-4982 |
| _version_ | 1811081849768771584 |
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| author | Song, Ying Suntharalingam, Kogularamanan Yeung, Jessica S. Royzen, Maksim Lippard, Stephen J. |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Song, Ying Suntharalingam, Kogularamanan Yeung, Jessica S. Royzen, Maksim Lippard, Stephen J. |
| author_sort | Song, Ying |
| collection | MIT |
| description | Pt(IV) anticancer compounds typically operate as prodrugs that are reduced in the hypoxic environment of cancer cells, losing two axial ligands in the process to generate active Pt(II) species. Here we report the synthesis of two fluorescent Pt(IV) prodrugs of cisplatin in order to image and evaluate the Pt(IV) reduction process in simulated and real biological environments. Treatment of the complexes dissolved in PBS buffer with reducing agents typically encountered in cells, glutathione or ascorbate, afforded a 3- to 5-fold fluorescence turn-on owing to reduction and loss of their fluorescein-based axial ligands, which are quenched when bound to platinum. Both Pt(IV) conjugates displayed moderate cytotoxicity against human cancer cell lines, with IC[subscript 50] values higher than that of cisplatin. Immunoblotting and DNA flow cytometry analyses of one of the complexes, Pt(IV)FL[subscript 2], revealed that it damages DNA, causes cell cycle arrest in S or G2/M depending on exposure time, and ultimately triggers apoptotic cell death. Fluorescence microscopic studies prove that Pt(IV)FL[subscript 2] enters cells intact and undergoes reduction intracellularly. The results are best interpreted in terms of a model in which the axial fluorescein ligands are expelled through lysosomes, with the platinum(II) moiety generated in the process binding to genomic DNA, which results in cell death. |
| first_indexed | 2024-09-23T11:53:27Z |
| format | Article |
| id | mit-1721.1/95477 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:53:27Z |
| publishDate | 2015 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/954772022-10-01T06:43:30Z Synthesis and Characterization of Pt(IV) Fluorescein Conjugates to Investigate Pt(IV) Intracellular Transformations Song, Ying Suntharalingam, Kogularamanan Yeung, Jessica S. Royzen, Maksim Lippard, Stephen J. Massachusetts Institute of Technology. Department of Chemistry Lippard, Stephen J. Song, Ying Suntharalingam, Kogularamanan Royzen, Maksim Pt(IV) anticancer compounds typically operate as prodrugs that are reduced in the hypoxic environment of cancer cells, losing two axial ligands in the process to generate active Pt(II) species. Here we report the synthesis of two fluorescent Pt(IV) prodrugs of cisplatin in order to image and evaluate the Pt(IV) reduction process in simulated and real biological environments. Treatment of the complexes dissolved in PBS buffer with reducing agents typically encountered in cells, glutathione or ascorbate, afforded a 3- to 5-fold fluorescence turn-on owing to reduction and loss of their fluorescein-based axial ligands, which are quenched when bound to platinum. Both Pt(IV) conjugates displayed moderate cytotoxicity against human cancer cell lines, with IC[subscript 50] values higher than that of cisplatin. Immunoblotting and DNA flow cytometry analyses of one of the complexes, Pt(IV)FL[subscript 2], revealed that it damages DNA, causes cell cycle arrest in S or G2/M depending on exposure time, and ultimately triggers apoptotic cell death. Fluorescence microscopic studies prove that Pt(IV)FL[subscript 2] enters cells intact and undergoes reduction intracellularly. The results are best interpreted in terms of a model in which the axial fluorescein ligands are expelled through lysosomes, with the platinum(II) moiety generated in the process binding to genomic DNA, which results in cell death. National Cancer Institute (U.S.) (Grant CA034992) National Institutes of Health (U.S.) (Grant 1S10RR13886-01) 2015-02-24T15:46:22Z 2015-02-24T15:46:22Z 2013-08 2013-08 Article http://purl.org/eprint/type/JournalArticle 1043-1802 1520-4812 http://hdl.handle.net/1721.1/95477 Song, Ying, Kogularamanan Suntharalingam, Jessica S. Yeung, Maksim Royzen, and Stephen J. Lippard. “Synthesis and Characterization of Pt(IV) Fluorescein Conjugates to Investigate Pt(IV) Intracellular Transformations.” Bioconjugate Chemistry 24, no. 10 (October 16, 2013): 1733–1740. https://orcid.org/0000-0002-2693-4982 en_US http://dx.doi.org/10.1021/bc400281a Bioconjugate Chemistry 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 American Chemical Society (ACS) PMC |
| spellingShingle | Song, Ying Suntharalingam, Kogularamanan Yeung, Jessica S. Royzen, Maksim Lippard, Stephen J. Synthesis and Characterization of Pt(IV) Fluorescein Conjugates to Investigate Pt(IV) Intracellular Transformations |
| title | Synthesis and Characterization of Pt(IV) Fluorescein Conjugates to Investigate Pt(IV) Intracellular Transformations |
| title_full | Synthesis and Characterization of Pt(IV) Fluorescein Conjugates to Investigate Pt(IV) Intracellular Transformations |
| title_fullStr | Synthesis and Characterization of Pt(IV) Fluorescein Conjugates to Investigate Pt(IV) Intracellular Transformations |
| title_full_unstemmed | Synthesis and Characterization of Pt(IV) Fluorescein Conjugates to Investigate Pt(IV) Intracellular Transformations |
| title_short | Synthesis and Characterization of Pt(IV) Fluorescein Conjugates to Investigate Pt(IV) Intracellular Transformations |
| title_sort | synthesis and characterization of pt iv fluorescein conjugates to investigate pt iv intracellular transformations |
| url | http://hdl.handle.net/1721.1/95477 https://orcid.org/0000-0002-2693-4982 |
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