Are Pt(IV) prodrugs that release combretastatin A4 true multi-action prodrugs?

Journal: Journal of Medicinal Chemistry
Authors: Schmidt, C., Babu, T., Kostrhunova, H., Timm, A., Basu, U., Ott, I., Gandin, V., Brabec, V., Gibson, D.
Year: 2021

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

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.1c00706