title: Photoactivatable Caged Prodrugs of VEGFR-2 Kinase Inhibitors.
abstract: In this study, we report on the design, synthesis, photokinetic properties and in vitro evaluation of photoactivatable caged prodrugs for the receptor tyrosine kinase VEGFR-2. Highly potent VEGFR-2 inhibitors 1 and 3 were caged by introduction of a photoremovable protecting group (PPG) to yield the caged prodrugs 4 and 5. As expected, enzymatic and cellular proliferation assays showed dramatically diminished efficacy of caged prodrugs in vitro. Upon ultraviolet (UV) irradiation of the prodrugs original inhibitory activity was completely restored and even distinctly reinforced, as was the case for the prodrug 4. The presented results are a further evidence for caging technique being an interesting approach in the protein kinase field. It could enable spatial and temporal control for the inhibition of VEGFR-2. The described photoactivatable prodrugs might be highly useful as biological probes for studying the VEGFR-2 signal transduction.
authors.affiliation: Institute of Pharmacy, University of Kiel, Gutenbergstr. 76, D-24118 Kiel, Germany. bpinchuk@pharmazie.uni-kiel.de.
authors.forename: Boris
authors.initials: B
authors.lastname: Pinchuk
authors.affiliation: Institute of Pharmacy, University of Kiel, Gutenbergstr. 76, D-24118 Kiel, Germany. rhorbert@pharmazie.uni-kiel.de.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Horbert
authors.affiliation: Institute of Pharmacy, University of Kiel, Gutenbergstr. 76, D-24118 Kiel, Germany. adoebber@pharmazie.uni-kiel.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Döbber
authors.affiliation: Institute of Pharmacy, University of Kiel, Gutenbergstr. 76, D-24118 Kiel, Germany. lkuhl@pharmazie.uni-kiel.de.
authors.forename: Lydia
authors.initials: L
authors.lastname: Kuhl
authors.affiliation: Institute of Pharmacy, University of Kiel, Gutenbergstr. 76, D-24118 Kiel, Germany. cpeifer@pharmazie.uni-kiel.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Peifer
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D015394:Molecular Structure; D055668:Photochemical Processes; D011355:Prodrugs / Q000528:radiation effects; D014466:Ultraviolet Rays; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000008:administration & dosage / Q000037:antagonists & inhibitors*
chemical_list: D011355:Prodrugs; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: 3,4-diarylmaleimides; VEGFR-2; caging; kinase inhibitors; photoactivatable prodrugs; photoremovable protecting group (PPG); receptor tyrosine kinase