Platinum(IV)-Estramustine Multiaction Prodrugs Are Effective Antiproliferative Agents against Prostate Cancer Cells
Herein, we describe the synthesis, characterization, and biological properties of Pt(IV) derivatives of cisplatin with estramustine at the first axial position, which is known to disrupt the microtubule assembly and act as an androgen antagonist, and varying the second axial position using an innoce...
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| Vydáno v: | Journal of medicinal chemistry Ročník 63; číslo 22; s. 13861 |
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| Hlavní autoři: | , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
25.11.2020
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| ISSN: | 1520-4804, 1520-4804 |
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| Abstract | Herein, we describe the synthesis, characterization, and biological properties of Pt(IV) derivatives of cisplatin with estramustine at the first axial position, which is known to disrupt the microtubule assembly and act as an androgen antagonist, and varying the second axial position using an innocent ligand (acetate or hydroxyl) to prepare dual-action and triple-action prodrugs with known inhibitors of histone deacetylase, cyclooxygenase, and pyruvate dehydrogenase kinase. We demonstrate superior antiproliferative activity at submicromolar concentrations of the prodrugs against a panel of cancer cell lines, particularly against prostate cancer cell lines. The results obtained in this study exemplify the complex mode of action of "multiaction" Pt(IV) prodrugs. Interestingly, changing the second axial ligand in the Pt-estramustine complex has a significant effect on the mode of action, suggesting that all three components of the Pt(IV) prodrugs (platinum moiety and axial ligands) contribute to the killing of cells and not just one dominant component. |
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| AbstractList | Herein, we describe the synthesis, characterization, and biological properties of Pt(IV) derivatives of cisplatin with estramustine at the first axial position, which is known to disrupt the microtubule assembly and act as an androgen antagonist, and varying the second axial position using an innocent ligand (acetate or hydroxyl) to prepare dual-action and triple-action prodrugs with known inhibitors of histone deacetylase, cyclooxygenase, and pyruvate dehydrogenase kinase. We demonstrate superior antiproliferative activity at submicromolar concentrations of the prodrugs against a panel of cancer cell lines, particularly against prostate cancer cell lines. The results obtained in this study exemplify the complex mode of action of "multiaction" Pt(IV) prodrugs. Interestingly, changing the second axial ligand in the Pt-estramustine complex has a significant effect on the mode of action, suggesting that all three components of the Pt(IV) prodrugs (platinum moiety and axial ligands) contribute to the killing of cells and not just one dominant component.Herein, we describe the synthesis, characterization, and biological properties of Pt(IV) derivatives of cisplatin with estramustine at the first axial position, which is known to disrupt the microtubule assembly and act as an androgen antagonist, and varying the second axial position using an innocent ligand (acetate or hydroxyl) to prepare dual-action and triple-action prodrugs with known inhibitors of histone deacetylase, cyclooxygenase, and pyruvate dehydrogenase kinase. We demonstrate superior antiproliferative activity at submicromolar concentrations of the prodrugs against a panel of cancer cell lines, particularly against prostate cancer cell lines. The results obtained in this study exemplify the complex mode of action of "multiaction" Pt(IV) prodrugs. Interestingly, changing the second axial ligand in the Pt-estramustine complex has a significant effect on the mode of action, suggesting that all three components of the Pt(IV) prodrugs (platinum moiety and axial ligands) contribute to the killing of cells and not just one dominant component. Herein, we describe the synthesis, characterization, and biological properties of Pt(IV) derivatives of cisplatin with estramustine at the first axial position, which is known to disrupt the microtubule assembly and act as an androgen antagonist, and varying the second axial position using an innocent ligand (acetate or hydroxyl) to prepare dual-action and triple-action prodrugs with known inhibitors of histone deacetylase, cyclooxygenase, and pyruvate dehydrogenase kinase. We demonstrate superior antiproliferative activity at submicromolar concentrations of the prodrugs against a panel of cancer cell lines, particularly against prostate cancer cell lines. The results obtained in this study exemplify the complex mode of action of "multiaction" Pt(IV) prodrugs. Interestingly, changing the second axial ligand in the Pt-estramustine complex has a significant effect on the mode of action, suggesting that all three components of the Pt(IV) prodrugs (platinum moiety and axial ligands) contribute to the killing of cells and not just one dominant component. |
| Author | Gibson, Dan Karmakar, Subhendu Brabec, Viktor Ctvrtlikova, Tereza Novohradsky, Vojtech Kostrhunova, Hana |
| Author_xml | – sequence: 1 givenname: Subhendu orcidid: 0000-0002-4840-3015 surname: Karmakar fullname: Karmakar, Subhendu organization: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel – sequence: 2 givenname: Hana surname: Kostrhunova fullname: Kostrhunova, Hana organization: Institute of Biophysics, Czech Academy of Sciences, Kralovopolska 135, Brno CZ-61265, Czech Republic – sequence: 3 givenname: Tereza surname: Ctvrtlikova fullname: Ctvrtlikova, Tereza organization: Institute of Biophysics, Czech Academy of Sciences, Kralovopolska 135, Brno CZ-61265, Czech Republic – sequence: 4 givenname: Vojtech orcidid: 0000-0003-4381-8403 surname: Novohradsky fullname: Novohradsky, Vojtech organization: Institute of Biophysics, Czech Academy of Sciences, Kralovopolska 135, Brno CZ-61265, Czech Republic – sequence: 5 givenname: Dan orcidid: 0000-0002-1631-4018 surname: Gibson fullname: Gibson, Dan organization: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel – sequence: 6 givenname: Viktor orcidid: 0000-0002-8233-1393 surname: Brabec fullname: Brabec, Viktor organization: Institute of Biophysics, Czech Academy of Sciences, Kralovopolska 135, Brno CZ-61265, Czech Republic |
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| SubjectTerms | Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cisplatin - chemistry Drug Screening Assays, Antitumor Estramustine - chemistry Humans Male Prodrugs - chemistry Prodrugs - pharmacology Prostatic Neoplasms - drug therapy Prostatic Neoplasms - pathology Tumor Cells, Cultured |
| Title | Platinum(IV)-Estramustine Multiaction Prodrugs Are Effective Antiproliferative Agents against Prostate Cancer Cells |
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