Insertion of (Bioactive) Equatorial Ligands into Platinum(IV) Complexes

Author(s): Alexander Kastner, Hemma Schueffl, Patrick A. Yassemipour, Bernhard K. Keppler, Petra Heffeter, Christian R. Kowol
Abstract: Platinum(IV) prodrugs are highly interesting alternatives to platinum(II) anticancer therapeutics due to their increased tumor selectivity and reduced side effects. In contrast to the established theory, we recently observed that the equatorial ligand(s) of e.g. oxaliplatin(IV) complexes can be hydrolyzed with formation of [(DACH)Pt(OH_eq)₂(OAc_ax)₂]. In the work presented here, we investigated the reactivity and synthetic usability of this complex to be exploited as a precursor for the development of novel platinum(IV) complexes, not able to be synthesized by conventional protocols. Indeed, we could substitute the equatorial hydroxido ligand(s) e.g. by one or two monodentate biotin ligands (which would be oxidized under standard methods). The formed complexes turned out to be very stable with slow ligand release after reduction, ideal for long-circulating tumor-targeting strategies. Therefore, two platinum(IV) complexes with equatorial maleimides, capable of exploiting serum albumin as a natural nanocarrier, were synthesized as well. The complexes showed massively prolonged plasma half-life and distinctly improved anticancer activity in vivo compared to oxaliplatin. Taken together, the newly developed synthetic platform allows the simple and specific insertion of equatorial ligands into platinum(IV) complexes. This will enable the attachment of three different (bioactive) moieties generating targeted triple-action platinum(IV) prodrugs within one single platinum complex.
Organisation(s): Department of Inorganic Chemistry
External organisation(s): Medizinische Universität Wien, Research Cluster Translational Cancer Therapy Research, Vienna Doctoral School in Chemistry (DoSChem)
Journal: Angewandte Chemie - International Edition
Volume: 62
ISSN: 1433-7851
DOI: https://doi.org/10.1002/anie.202311468
Publication date: 09-2023
Peer reviewed: Yes
Austrian Fields of Science 2012: 104003 Inorganic chemistry, 301904 Cancer research
Keywords
ASJC Scopus subject areas: Catalysis, General Chemistry
Sustainable Development Goals: SDG 3 - Good Health and Well-being
Portal url: https://ucrisportal.univie.ac.at/en/publications/c7fad694-cef4-4e44-a4a5-3a88d7afae3f