Are Pt(IV) Prodrugs That Release Combretastatin A4 True Multi-action Prodrugs?

Claudia Schmidt, Tomer Babu, Hana Kostrhunova, Annika Timm, Uttara Basu, Ingo Ott*, Valentina Gandin*, Viktor Brabec*, Dan Gibson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

"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.

Original languageEnglish
Pages (from-to)11364-11378
Number of pages15
JournalJournal of Medicinal Chemistry
Volume64
Issue number15
DOIs
StatePublished - 12 Aug 2021

Bibliographical note

Publisher Copyright:
© 2021 American Chemical Society.

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