Gold(iii) complexes containing (non)protonated oligopyridines—unexpected results in cancer drug research

Abstract

Two novel gold(III) complexes with doubly protonated forms of phenanthrolines, (neocH₂)[AuCl₄]·Cl (1) and (1,7-phenH₂)[AuCl₄]·NO₃ (2), were synthesized using the oligopyridines 2,9-dimethyl-1,10-phenanthroline (neocuproine, neoc) and 1,7-phenanthroline (1,7-phen). The structures of the compounds were established using single-crystal X-ray diffraction analysis. In crystals 1 and 2, the tetrachloroaurate anions form a whole network of various non-covalent interactions with protonated forms of oligopyridines (neocH₂²⁺, neocH⁺, 1,7-phenH₂²⁺) and Cl⁻/NO₃⁻ anions (N/C–H⋯Cl, N–H⋯O, Au⋯π, Au–C⋯π, π⋯π). A comparative study of the stability of complexes 1 and 2, as well as complexes with coordinated oligopyridines, i.e., [Au(neoc)Cl₃] (1a), [Au(1,7-phen)Cl₃] (2a), [Au(1,10-phen)Cl₂]PF₆ (3, 1,10-phen is 1,10-phenanthroline) and [Au(bpy)Cl₂]PF₆ (4, bpy is 2,2′-bipyridine), was carried out in DMSO and aqueous solutions. When complexes 1a, 2a, 3, and 4 were tested with glutathione (GSH) under near-physiological conditions, they formed gold(I) complexes of the type [Au(GSH)₂]³⁻. The in vitro biological activities of the complexes were determined against mycobacterial strains (Mycolicibacterium smegmatis and Mycobacterium tuberculosis H37Rv) and a number of test cancer lines. A high level of selective activity was detected for 1 in relation to a non-cancerous human fibroblast culture – the selectivity index (SI) was 371 compared to the cancer cell line HCT116. Molecular docking studies showed that compound 1 forms protein–gold supramolecular complexes with high affinity and stability.