FUNCTIONALIZED TYROSINE KINASE INHIBITORS MODIFIED WITH PRECIOUS METAL ELECTROPHILES AND METHODS ASSOCIATED THEREWITH

摘要

Newly synthesized thiourea-modified 3-chloro-4-fluoroanilino-quinazoline derivatives have been studied as terminal carrier ligands in linear gold(I) complexes. The molecules mimic the tyrosine kinase inhibitor gefitinib (by computational docking experiments). Thiourea groups were either directly attached to quinazoline-C6 or linked to this position via a flexible ethylamino chain. One compound tested acts as a thiourea-S/quinazoline-N1 mixed-donor ligand, giving an unusual dinuclear complex as determined by X-ray crystallography and/or electrospray mass spectrometry. One compound formed the desired stable linear complex. The biological activity of the carrier ligands and corresponding gold(I) complexes was studied in NCI-H460 and NCI-H1975 lung cancer cells. One compound that was tested partially overcomes resistance to gefitinib in NCI-H1975 (with IC50 values of 1.7 and 30 μM, respectively), and the corresponding gold complex (13) maintains activity in the low-micromolar concentration range.