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- Title
Platinum(IV) Complexes Featuring Axial Michael Acceptor Ligands - Synthesis, Characterization, and Cytotoxicity.
- Authors
Sommerfeld, Nadine S.; Strohhofer, Daniel; Cseh, Klaudia; Theiner, Sarah; Jakupec, Michael A.; Koellensperger, Gunda; Galanski, Markus; Keppler, Bernhard K.
- Abstract
A series of four new (1R,2R)-cyclohexane-1,2-diamineplatinum(IV) complexes featuring axial Michael acceptor ligands on the basis of the thiol-affine maleimide moiety is presented. The complexes vary in their equatorial ligand sphere (bearing additionally one bidentate oxalate ligand or two monodentate acetate ligands) as well as in their axial Michael acceptor unit (pyrroledione, methylenedioxopyrrolidine, methyldioxodihydropyrrole). Hydrolysis, reaction behavior towards cysteine in water and phosphate buffered saline, and towards human serum albumin was monitored using HPLC, 1H NMR spectroscopy and size exclusion chromatography coupled to ICP-MS, respectively. Reaction with cysteine at pH = 7 was in-stant and complete within three minutes. In contrast, derivatization of the maleimide moiety resulted in decreased binding kinetics of the complex, especially within the first hour of incubation with human serum. In stability studies using analytical HPLC and ¹H NMR spectroscopic measurements, we observed a concentration-dependent stability for the maleimide-containing complex 3 and the methyl derivatized compound 4. A significant increase in hydrolysis rate (up to 100%) was found at 0.01 mM in comparison to a solution of 1 mM. In contrast, the exocyclic derivatization (5, 6) led to an overall stability in water. The antiproliferative behavior revealed IC50 values mainly in the low micromolar range for all complexes.
- Subjects
PLATINUM compounds; LIGANDS (Chemistry); CHEMICAL synthesis; HYDROLYSIS; ANTINEOPLASTIC agents
- Publication
European Journal of Inorganic Chemistry, 2017, Vol 2017, Issue 34, p4049
- ISSN
1434-1948
- Publication type
Article
- DOI
10.1002/ejic.201700753