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Platinum(IV) Derivatives of [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] with Diclofenac Ligands in the Axial Positions: A New Class of Potent Multi-action Agents Exhibiting Selectivity to Cancer Cells
[Image: see text] The platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)](2+) (Pt(II)56MeSS, 1) exhibits high potency across numerous cancer cell lines acting by a multimodal mechanism. However, 1 also displays side toxicity and in vivo activity; all details of its...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10291556/ https://www.ncbi.nlm.nih.gov/pubmed/37285472 http://dx.doi.org/10.1021/acs.jmedchem.3c00269 |
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author | Kostrhunova, Hana McGhie, Brondwyn S. Markova, Lenka Novakova, Olga Kasparkova, Jana Aldrich-Wright, Janice R. Brabec, Viktor |
author_facet | Kostrhunova, Hana McGhie, Brondwyn S. Markova, Lenka Novakova, Olga Kasparkova, Jana Aldrich-Wright, Janice R. Brabec, Viktor |
author_sort | Kostrhunova, Hana |
collection | PubMed |
description | [Image: see text] The platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)](2+) (Pt(II)56MeSS, 1) exhibits high potency across numerous cancer cell lines acting by a multimodal mechanism. However, 1 also displays side toxicity and in vivo activity; all details of its mechanism of action are not entirely clear. Here, we describe the synthesis and biological properties of new platinum(IV) prodrugs that combine 1 with one or two axially coordinated molecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selective drug. The results suggest that these Pt(IV) complexes exhibit mechanisms of action typical for Pt(II) complex 1 and DCF, simultaneously. The presence of DCF ligand(s) in the Pt(IV) complexes promotes the antiproliferative activity and selectivity of 1 by inhibiting lactate transporters, resulting in blockage of the glycolytic process and impairment of mitochondrial potential. Additionally, the investigated Pt(IV) complexes selectively induce cell death in cancer cells, and the Pt(IV) complexes containing DCF ligands induce hallmarks of immunogenic cell death in cancer cells. |
format | Online Article Text |
id | pubmed-10291556 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-102915562023-06-27 Platinum(IV) Derivatives of [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] with Diclofenac Ligands in the Axial Positions: A New Class of Potent Multi-action Agents Exhibiting Selectivity to Cancer Cells Kostrhunova, Hana McGhie, Brondwyn S. Markova, Lenka Novakova, Olga Kasparkova, Jana Aldrich-Wright, Janice R. Brabec, Viktor J Med Chem [Image: see text] The platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)](2+) (Pt(II)56MeSS, 1) exhibits high potency across numerous cancer cell lines acting by a multimodal mechanism. However, 1 also displays side toxicity and in vivo activity; all details of its mechanism of action are not entirely clear. Here, we describe the synthesis and biological properties of new platinum(IV) prodrugs that combine 1 with one or two axially coordinated molecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selective drug. The results suggest that these Pt(IV) complexes exhibit mechanisms of action typical for Pt(II) complex 1 and DCF, simultaneously. The presence of DCF ligand(s) in the Pt(IV) complexes promotes the antiproliferative activity and selectivity of 1 by inhibiting lactate transporters, resulting in blockage of the glycolytic process and impairment of mitochondrial potential. Additionally, the investigated Pt(IV) complexes selectively induce cell death in cancer cells, and the Pt(IV) complexes containing DCF ligands induce hallmarks of immunogenic cell death in cancer cells. American Chemical Society 2023-06-07 /pmc/articles/PMC10291556/ /pubmed/37285472 http://dx.doi.org/10.1021/acs.jmedchem.3c00269 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Kostrhunova, Hana McGhie, Brondwyn S. Markova, Lenka Novakova, Olga Kasparkova, Jana Aldrich-Wright, Janice R. Brabec, Viktor Platinum(IV) Derivatives of [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] with Diclofenac Ligands in the Axial Positions: A New Class of Potent Multi-action Agents Exhibiting Selectivity to Cancer Cells |
title | Platinum(IV)
Derivatives of [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]
with Diclofenac Ligands in the Axial Positions: A New Class of Potent
Multi-action Agents Exhibiting Selectivity to Cancer Cells |
title_full | Platinum(IV)
Derivatives of [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]
with Diclofenac Ligands in the Axial Positions: A New Class of Potent
Multi-action Agents Exhibiting Selectivity to Cancer Cells |
title_fullStr | Platinum(IV)
Derivatives of [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]
with Diclofenac Ligands in the Axial Positions: A New Class of Potent
Multi-action Agents Exhibiting Selectivity to Cancer Cells |
title_full_unstemmed | Platinum(IV)
Derivatives of [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]
with Diclofenac Ligands in the Axial Positions: A New Class of Potent
Multi-action Agents Exhibiting Selectivity to Cancer Cells |
title_short | Platinum(IV)
Derivatives of [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]
with Diclofenac Ligands in the Axial Positions: A New Class of Potent
Multi-action Agents Exhibiting Selectivity to Cancer Cells |
title_sort | platinum(iv)
derivatives of [pt(1s,2s-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]
with diclofenac ligands in the axial positions: a new class of potent
multi-action agents exhibiting selectivity to cancer cells |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10291556/ https://www.ncbi.nlm.nih.gov/pubmed/37285472 http://dx.doi.org/10.1021/acs.jmedchem.3c00269 |
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