Synthesis of water soluble bis-triazenoquinazolines: an unusual predicted mode of binding to the epidermal growth factor receptor tyrosine kinase.
A novel type of 3,3-disubstituted bis-triazenes containing an ethylaminoethyl linker flanked by two identical anilinoquinazoline ring was synthesized. These model molecules contained an N-ethylaminomorpholine moiety designed to enhance water solubility. Despite their significant bulkiness, they blocked epidermal growth factor receptor (EGFR) tyrosine kinase in a dose-dependent manner with IC(50) values in low micromolar range. Molecular modeling to predict the interactions of the molecule with the ATP binding site of EGFR suggests that the N-ethylaminomorpholine side chain plays a binding role.
Larroque
Anne-Laure
AL
Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University/Royal Victoria Hospital, 687 Pine Avenue West, Montreal, QC H3A 1A1, Canada.
Peori
Brad
B
Williams
Christopher
C
Fang
You Qiang
YQ
Qiu
Qiyu
Q
Rachid
Zakaria
Z
Jean-Claude
Bertrand J
BJ
D066246:ErbB Receptors / Q000737:chemistry* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry; D012995:Solubility; D014226:Triazenes / Q000138:chemical synthesis* / Q000737:chemistry; D014867:Water
D011799:Quinazolines; D014226:Triazenes; D014867:Water; D066246:ErbB Receptors