Novel Maleimide Linkers Based on a Piperazine Motif for Strongly Increased Aqueous Solubility
- Author(s)
- Martijn Dijkstra, Hemma Schueffl, Anja Federa, Caroline Kast, Alexander Unterlercher, Bernhard K. Keppler, Petra Heffeter, Christian R. Kowol
- Abstract
Maleimides remain very popular conjugation moieties in the fields of bio(in)organic chemistry and biotechnology. They are particularly interesting for endogenous albumin binding in the bloodstream to exploit the enhanced permeability and retention (EPR) effect and to increase tumor accumulation of anticancer drugs. However, during drug development, insufficient aqueous solubility is frequently a limiting factor. In the present study, four new maleimide linkers were synthesized containing a water-soluble piperazine scaffold. Respective maleimide-platinum(IV)-acetato complexes demonstrated similar hydrolytic stability, albumin-binding kinetics, in vivo serum pharmacokinetics and tissue distribution compared to a reference platinum(IV)-PEG4-maleimide complex. To test the aqueous solubility, platinum(IV)-maleimide complexes containing the highly lipophilic drug ibuprofen were synthesized. Indeed, the compounds containing the new piperazine linkers displayed increased solubility (up to 370 mM) in different aqueous media, whereas the PEG4-maleimide reference was only marginally soluble. Finally, the synthetic toolbox of the new piperazine maleimides was also expanded to pure organic derivatives by conjugation to valine-citrulline-para-aminobenzyl-OH derivatives via peptide and thiourea bonds.
- Organisation(s)
- Department of Inorganic Chemistry, Faculty of Chemistry
- External organisation(s)
- Vienna Doctoral School in Chemistry (DoSChem), Medizinische Universität Wien, Research Cluster Translational Cancer Therapy Research
- Journal
- ACS Omega
- ISSN
- 2470-1343
- DOI
- https://doi.org/10.1021/acsomega.4c10825
- Publication date
- 2025
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 204004 Organic chemical technology, 301904 Cancer research
- ASJC Scopus subject areas
- General Chemistry, General Chemical Engineering
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/6579deae-0b64-4fc3-92f6-c9c1b4813025