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.

Using a modular library format in conjunction with cell viability (MTS) and flow cytometry assays, 90 cationic complexes [AuPL] n+ (P = phosphine ligand; L = thiourea derivative or chloride) were studied for their antiproliferative activity in CD8 + T lymphocyte cells.

Although T cells play a critical role in protection from viruses, bacteria and tumors, they also cause autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). Unwanted T cell responses during organ transplant, graft versus host disease (GVHD), and allergies are also major clinical problems. While drugs are available to suppress unwanted immune responses they have limited efficacy with serious side effects. Thus new therapeutics limiting T cell activation, proliferation and function can make an immediate clinical impact. To identify new suppressors of lymphocyte activation, proliferation and function, we examined the immunosuppressive activity of gold(I) analogues of platinum-acridine antitumor agents. We found that the gold complex, Au-ACRAMTU-PEt3 is a potent suppressor of murine and human T cell activation. Preincubation with Au-ACRAMTU-PEt3 suppresses the proliferation of CD4+ and CD8+ T cells at a similar concentration as pharmaceutical grade cyclosporine A. Au-ACRAMTU-PEt3 pretreatment decreases the production of IFNγ, TNFα, IL-2, and IL-17 by human and murine CD4+ and CD8+ T cells. When mice were treated with Au-ACRAMTU-PEt3 during viral infection the expansion of virus-specific CD8+ T cells was decreased 10-fold and viral load was elevated. Taken together these results demonstrate that Au-ACRAMTU-PEt3 has potent immunosuppressive activity that could be used to suppress immune responses during transplantation and autoimmunity.

Hybrid molecules have been developed which are comprised of a tyrosine kinase-targeted, quinazoline-based scaffold and a flexibly linked dia(m)minechloridoPt(ii) moiety. The target compounds maintain high affinity and selectivity for ErbB family kinase proteins and one of the derivatives induces platinum adducts with a pharmacologically important cysteine residue.