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Protein kinases are essential mediators in the growth and progression of cancerous tumors, rendering involved kinases an increasingly important target for therapy. However, kinase inhibitors are almost insoluble in water because of their hydrophobic aromatic nature, often lowering their availability and pharmacological efficacy. Direct drug functionalization with polar groups represents a simple strategy to improve the drug solubility, availability, and performance. Here, we present a strategy to functionalize secondary amines with oligoethylene glycol (OEG) phosphate using a one\u2010pot synthesis in three exemplary kinase inhibiting drugs Ceritinib, Crizotinib, and Palbociclib. These OEG\u2010prodrug conjugates demonstrate superior solubility in water compared to the native drugs, with the solubility increasing up to 190\u2010fold. The kinase inhibition potential is only slightly decreased for the conjugates compared to the native drugs. We further show pH dependent hydrolysis of the OEG\u2010prodrugs which releases the native drug. We observe a slow release at pH\u20053, while the conjugates remain stable over 96\u2005h under physiological conditions (pH\u20057.4). Using confocal microscopy, we verify improved cell uptake of the drug\u2010OEG conjugates into the cytoplasm of HeLa cells, further supporting our universal solubility approach.<\/jats:p>","DOI":"10.1002\/chem.202401781","type":"journal-article","created":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T22:09:45Z","timestamp":1719266985000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Phosphoramidate Prodrug Platform: One\u2010Pot Amine Functionalization of Kinase Inhibitors with Oligoethylene Glycol for Improved Water\u2010Solubility"],"prefix":"10.1002","volume":"30","author":[{"given":"Sarah","family":"Spiewok","sequence":"first","affiliation":[{"name":"Institute of Macromolecular and Organic Chemistry Ulm University  Albert-Einstein-Allee 11 89081 Ulm Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Lamla","sequence":"additional","affiliation":[{"name":"Institute of Macromolecular and Organic Chemistry Ulm University  Albert-Einstein-Allee 11 89081 Ulm Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maximilian","family":"Schaefer","sequence":"additional","affiliation":[{"name":"Institute of Macromolecular and Organic Chemistry Ulm University  Albert-Einstein-Allee 11 89081 Ulm Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0142-8001","authenticated-orcid":false,"given":"Alexander J. 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