Double-Strand DNA Breaks Induced by Paracyclophane Gold(I) Complexes

Gold(I) complexes of ClickPhos [2.2]paracyclophane ligands were synthesized in excellent yields and fully characterized by spectroscopic methods as well as X-ray crystallography. The complexes exhibit a rigid ligand backbone and a triazolyl moiety and were systematically studied with respect to their cytotoxic properties. In combination with the ionic complex [(GemPhos)Au(tht)][ClO4] (tht=tetrahydrothiophene), in which the gold(I) atom exhibits a distorted trigonal coordination sphere of two phosphines and a labile tht ligand, their efficiency in cytotoxicity was investigated in HeLa, MCF7, and HCT116 cells as well as in a zebrafish model. Their cytotoxicity and their mechanisms of action are different and involve apoptosis, necrosis, and DNA damage. The compounds presented herein are potent metal-based cytostatics displaying LD50 values from 3.5-38m in different tumor cell lines and induce double-strand DNA breaks (DSB) as shown by H2AX phosphorylation (H2AX) at foci of DSBs.