title: Synthesis, reactivity, and biological activity of gold(I) complexes modified with thiourea-functionalized tyrosine kinase inhibitors.
abstract: 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.
authors: †Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, United States.
authors: Mu
authors: M
authors: Yang
authors: †Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, United States.
authors: Amanda J
authors: AJ
authors: Pickard
authors: ‡School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, PR China.
authors: Xin
authors: X
authors: Qiao
authors: †Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, United States.
authors: Matthew J
authors: MJ
authors: Gueble
authors: †Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, United States.
authors: Cynthia S
authors: CS
authors: Day
authors: §Department of Internal Medicine, Hematology-Oncology Section, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, United States.
authors: Gregory L
authors: GL
authors: Kucera
authors: †Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, United States.
authors: Ulrich
authors: U
authors: Bierbach
mesh_terms: D000077716:Afatinib; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000077156:Gefitinib; D006046:Gold / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology; D013890:Thiourea / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D056831:Coordination Complexes; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D006046:Gold; D013890:Thiourea; D000077156:Gefitinib