Dijkstra Martijn, Schueffl Hemma, Federa Anja, Kast Caroline, Unterlercher Alexander, Keppler Bernhard K, Heffeter Petra, Kowol Christian R
University of Vienna, Faculty of Chemistry, Institute of Inorganic Chemistry, Waehringer Str. 42, 1090 Vienna, Austria.
University of Vienna, Vienna Doctoral School in Chemistry (DoSChem), Waehringer Str. 42, 1090 Vienna, Austria.
ACS Omega. 2025 Jan 31;10(5):5047-5063. doi: 10.1021/acsomega.4c10825. eCollection 2025 Feb 11.
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, 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--aminobenzyl-OH derivatives via peptide and thiourea bonds.
马来酰亚胺在生物（有机）化学和生物技术领域仍然是非常受欢迎的共轭基团。它们对于血液中内源性白蛋白结合特别有意义，以利用增强的通透性和滞留（EPR）效应并增加抗癌药物在肿瘤中的蓄积。然而，在药物开发过程中，水溶性不足常常是一个限制因素。在本研究中，合成了四种含有水溶性哌嗪支架的新型马来酰亚胺连接体。与参考铂（IV）-聚乙二醇4-马来酰亚胺配合物相比，相应的马来酰亚胺-铂（IV）-乙酸酯配合物表现出相似的水解稳定性、白蛋白结合动力学、血清药代动力学和组织分布。为了测试水溶性，合成了含有高亲脂性药物布洛芬的铂（IV）-马来酰亚胺配合物。的确，含有新型哌嗪连接体的化合物在不同水性介质中的溶解度增加（高达370 mM），而聚乙二醇4-马来酰亚胺参考物仅微溶。最后，通过肽键和硫脲键与缬氨酸-瓜氨酸-氨基苄基-OH衍生物偶联，新型哌嗪马来酰亚胺的合成工具箱也扩展到了纯有机衍生物。
