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