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

0554721 - BFÚ 2022 RIV US eng J - Článek v odborném periodiku
Schmidt, C. - Babu, T. - Kostrhunová, Hana - Timm, A. - Basu, U. - Ott, I. - Gandin, V. - Brabec, Viktor - Gibson, D.
Are Pt(IV) Prodrugs That Release Combretastatin A4 True Multi-action Prodrugs?
Journal of Medicinal Chemistry. Roč. 64, č. 15 (2021), s. 11364-11378. ISSN 0022-2623. E-ISSN 1520-4804
Grant CEP: GA ČR(CZ) GA21-27514S
Institucionální podpora: RVO:68081707
Klíčová slova: molecular-mechanisms * tubulin inhibitor * anticancer agents * cisplatin * derivatives
Obor OECD: Pharmacology and pharmacy
Impakt faktor: 8.039, rok: 2021
Způsob publikování: Omezený přístup
https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00706

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)Cl-2] 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.
Trvalý link: http://hdl.handle.net/11104/0329383