Synthesis, Reactivity, and Biological Activity of Gold(I) Complexes Modified with Thiourea-Functionalized Tyrosine Kinase Inhibitors

Thiourea-modified
3-chloro-4-fluoroanilino-quinazoline derivatives
have been studied as potential receptor-targeted carrier ligands in
linear gold­(I) complexes. The molecules mimic the epidermal growth
factor receptor (EGFR) tyrosine kinase-targeted inhibitor gefitinib.
Thiourea groups were either directly attached to quinazoline-C6 (compounds 4, 5, and 7) or linked to this position
via a flexible ethylamino chain (compound 9). Compound 7 acts as a thiourea-S/quinazoline-N1 mixed-donor ligand, giving the unexpected dinuclear complex
[{Au­(μ-7-S,N)}2]­X2 (X = Cl–, SCN–) (12a,b) (X-ray crystallography, electrospray mass
spectrometry). Derivative 9 forms a stable linear complex,
[Au­(PEt3)­(9-S)]­(NO3) (13). The biological activity of the carrier
ligands and corresponding gold­(I) complexes was studied in NCI-H460
and NCI-H1975 lung cancer cells. Compound 9 partially
overcomes resistance to gefitinib in NCI-H1975, a lung cancer cell
line characterized by a L858R/T790M mutation in EGFR (IC50 values of 1.7 and 30 μM, respectively). The corresponding
gold complex (13) maintains activity in the low-micromolar
concentration range similar to the metal-free carrier. Compound 9 and the corresponding [Au­(PEt3)] complex, 13, inhibit EGFR kinase-mediated phosphorylation with sub-micromolar
IC50 values similar to those observed for gefitinib under
the same assay conditions. Potential mechanisms of action and reactions
in biological media of this new type of hybrid agent, as well as shortcomings
of the current design are discussed.