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    Are Pt(IV) Prodrugs That Release Combretastatin A4 True Multi-action Prodrugs?
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    • Claudia Schmidt
      Claudia Schmidt
      Institute for Drug Research, School of Pharmacy, The Hebrew University, 91120 Jerusalem, Israel
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    • Tomer Babu
      Tomer Babu
      Institute for Drug Research, School of Pharmacy, The Hebrew University, 91120 Jerusalem, Israel
      More by Tomer Babu
    • Hana Kostrhunova
      Hana Kostrhunova
      Institute of Biophysics, Czech Academy of Sciences, Academy of Sciences, Kralovopolska 135, 61265 Brno, Czech Republic
      More by Hana Kostrhunova
    • Annika Timm
      Annika Timm
      Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany
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    • Uttara Basu
      Uttara Basu
      Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany
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    • Ingo Ott*
      Ingo Ott
      Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany
      *Email: [email protected]
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    • Valentina Gandin*
      Valentina Gandin
      Dipartimento di Scienze del Farmaco, Universita di Padova, Via Marzolo 5, 35131 Padova, Italy
      *Email: [email protected]
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    • Viktor Brabec*
      Viktor Brabec
      Institute of Biophysics, Czech Academy of Sciences, Academy of Sciences, Kralovopolska 135, 61265 Brno, Czech Republic
      Department of Biophysics, Faculty of Science, Palacky University in Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0002-8233-1393
    • Dan Gibson*
      Dan Gibson
      Institute for Drug Research, School of Pharmacy, The Hebrew University, 91120 Jerusalem, Israel
      *Email: [email protected]
      More by Dan Gibson
      Orcidhttps://orcid.org/0000-0002-1631-4018
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2021, 64, 15, 11364–11378
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    https://doi.org/10.1021/acs.jmedchem.1c00706
    Published August 3, 2021
    Copyright © 2021 American Chemical Society
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    Abstract

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    “Multi-action” Pt(IV) derivatives of cisplatin with combretastatin A4 (CA4) bioactive ligands that are conjugated to Pt(IV) by carbonate are unique because the ligand (IC50 < 10 nM) is dramatically 1000-folds more cytotoxic than cisplatin in vitro. The Pt(IV)-CA4 prodrugs were as cytotoxic as CA4 itself, indicating that the platinum moiety probably plays an insignificant role in triggering cytotoxicity, suggesting that the Pt(IV)-CA4 complexes act as prodrugs for CA4 rather than as true multi-action prodrugs. In vivo tests (Lewis lung carcinoma) show that ctc-[Pt(NH3)2(PhB)(CA4)Cl2] inhibited tumor growth by 93% compared to CA4 (67%), cisplatin (84%), and 1:1:1 cisplatin/CA4/PhB (85%) while displaying <5% body weight loss compared to cisplatin (20%) or CA4 (10%). In this case, and perhaps with other extremely potent bioactive ligands, platinum(IV) acts merely as a self-immolative carrier triggered by reduction in the cancer cell with only a minor contribution to cytotoxicity.

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    Supporting Information

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2021, 64, 15, 11364–11378
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.1c00706
    Published August 3, 2021
    Copyright © 2021 American Chemical Society
    Request reuse permissions

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