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

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.

• Authors: Claudia Schmidt, Tomer Babu, Hana Kostrhunova, Annika Timm, Uttara Basu, Ingo Ott, Valentina Gandin, Viktor Brabec, Dan Gibson
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 15 Pg. 11364-11378 (08 12 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34342437 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Ligands
• Organoplatinum Compounds
• PHB protein, human
• Prodrugs
• Prohibitins
• Carbonic Anhydrase IV
• CA4 protein, human

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Carbonic Anhydrase IV (chemistry, metabolism)
• Cell Line
• Cell Proliferation (drug effects)
• Cricetulus
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Ligands
• Molecular Structure
• Organoplatinum Compounds (chemical synthesis, chemistry, pharmacology)
• Prodrugs (chemical synthesis, chemistry, pharmacology)
• Prohibitins
• Structure-Activity Relationship