Emission tuning of fluorescent kinase inhibitors: conjugation length and substituent effects.
Fluorescent N-phenyl-4-aminoquinazoline probes targeting the ATP-binding pocket of the ERBB family of receptor tyrosine kinases are reported. Extension of the aromatic quinazoline core with fluorophore "arms" through substitution at the 6- position of the quinazoline core with phenyl, styryl, and phenylbutadienyl moieties was predicted by means of TD-DFT calculations to produce probes with tunable photoexcitation energies and excited states possessing charge-transfer character. Optical spectroscopy identified several synthesized probes that are nonemissive in aqueous solutions and exhibit emission enhancements in solvents of low polarity, suggesting good performance as turn-on fluorophores. Ligand-induced ERBB2 phosphorylation assays demonstrate that despite chemical modification to the quinazoline core these probes still function as ERBB2 inhibitors in MCF7 cells. Two probes were found to exhibit ERBB2-induced fluorescence, demonstrating the utility of these probes as turn-on, fluoroescent kinase inhibitors.
Department of Chemistry, University of Miami , 1301 Memorial Drive, Coral Gables, Florida 33146, United States.
Jyothi
J
Dhuguru
Wenjun
W
Liu
Walter G
WG
Gonzalez
W Michael
WM
Babinchak
Jaroslava
J
Miksovska
Ralf
R
Landgraf
James N
JN
Wilson
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000737:chemistry*; D008024:Ligands; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D011789:Quantum Theory; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013050:Spectrometry, Fluorescence
D000255:Adenosine Triphosphate; D005456:Fluorescent Dyes; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C000594667:N-phenyl-4-aminoquinazoline