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, and Dan Gibson. 2021. “Are Pt(IV) Prodrugs That Release Combretastatin A4 True Multi-action Prodrugs?” Journal of Medicinal Chemistry, 64, 15, Pp. 11364–11378.


"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.