Synergistic 'gold effects' of anti-vascular 4,5-diarylimidazol-2-ylidene gold(l) carbene complexes

摘要

The natural cis-stilbene combretastatin A-4 (CA-4) is a vascular disrupting agent (VDA) that leads to a vascular shutdown in solid tumors. Its activity originates from an inhibition of the polymerization of tubulin and of the functionality of the VE-cadherin/ beta-catenin complex which is crucial for cell-cell adhesion [1]. However, the insufficient cytotoxicity of CA-4 and its chemical instability in solution limits its clinical usability. A more water-soluble phosphate prodrug of CA-4 is currently undergoing clinical trials [2]. Derivatives of CA-4 with improved chemical stability and retained anti-vascular effect were obtained by incorporation of the Z-alkene in heterocycles such as imidazoles [3]. Since structurally simple imidazolium salts had already been employed as ligand precursors for anticancer N-heterocyclic carbene (NHC) complexes [4], we prepared gold carbene complexes that combine the intrinsic anti-vascular activity of CA-4 analogous imidazoles 1 (Figure 1A) with the known anti-cancer properties of gold fragments [5]. Previously, we reported on the cytotoxicity and the cellular uptake of such new gold(I)-NHC complexes [5]. Now we present first insights into the mechanism of action of two such complexes, 2a and 3 a (Figure 1A).