Three new dicyanidoaurate(I)-based complexes exhibiting significant antiproliferative property: synthesis and characterization

Abstract

The Au(CN)(2)(-) ion and its metal-ligand compounds have recently gained considerable interest in industrial applications such as optical diagnostics systems as well as pharmacology with antirheumatic and antitumor activity. Here, [Ni-2(N-bishydeten)(2)][Au(mu-CN)(2)](3)[Au(CN)(2)]center dot H2O (C1), [Cu-2(N-bishydeten)(2)][Au(mu-CN)(2)](3)[Au(CN)(2)]center dot H2O (C2), and [Zn-2(mu-N-bishydetenH)(N-bishydeten)(NC)(2)Au][Au(CN)(2)] (C3) were synthesized by reaction of the metal salts with N,N-bis(2-hydroxyethyl)ethylenediamine (N-bisyhdeten) and K[Au(CN)(2)]. The Au(I) compounds were characterized using elemental analysis and FT-IR. ESI-MS and thermal measurement techniques and their pharmacological properties were also tested. The DNA/bovine serum albumin (BSA) interactions of these compounds were demonstrated by spectrophotometric titration, fluorometric ethidium bromide kinetics, and DNA electrophoresis studies, and the stability of these compounds in physiological solution was also determined. The findings indicate that these compounds displayed a DNA/BSA-binding activity similar to that of cisplatin and exhibited a strong aqueous stability. The Au(I) compounds were potent antiproliferative agents with low necrotic activity and exhibited dose-dependent growth inhibition of cancer cells with IC50 value of 0.12-0.73 mu M. Accumulation of p53 and decrease in Bcl-2 in cells exposed to Au(I) compounds may be the main causes for apoptotic effects, such as DNA fragmentation and nuclear collapse. Investigations regarding the mode of action of Au(I) compounds on cells revealed that they reduce the cell migration rate and the level of cytoskeletal proteins, namely CK7 and CK20. On the basis of this evidence, we suggest that strong antiproliferative activity, low necrotic effect, and micromolar dose range observed for Au(I) compounds make them suitable candidates for further pharmacological evaluation as chemotherapeutic agents in colon and cervix cancer.