Interaction of gold N-heterocyclic carbenes with nucleic acids

Metal complexes with N-heterocyclic carbenic ligands (NHCs) have found applications not only in catalysis but also as anticancer agents [1]. In particular, Gold-NHCs turned out to be particular promising. First of all, they are stable complexes whose synthesis is relatively simple. Moreover, their biological and targeting properties can be tuned by modifying substituents on the carbenic ligand. Preclinical studies showed antiproliferative properties both in vitro and in vivo andencouraging results on selectivity [2]. These compounds target mitochondria and proteins, among which of paramount importance is the selenoenzyme Thioredoxin reductase. However, more recent studies also consider their interaction with dsDNA or G-quadruplexes [3]. Indeed, on the one hand is now clear that most often one single target cannot exhaustively justify the biological action of a metallodrug; on the other hand, cancer is such a complex series of genetic diseases that a single target therapy may not be effective enough. Therefore, some of the latest approaches on anticancer metallodrug design include the synthesis of multitargeting platforms [4]. Within this frame, we synthesized and chemically characterized a Gold monocarbene with a planar aromatic moiety able to interact with dsDNA. Binding with natural DNA has been characterized by means of different spectroscopic methods. Moreover, inhibition of purified Thioredoxin reductase has been measured. Preliminary in vitro cytotoxicity experiments show moderate antiproliferative activity. In addition, single crystals of bis-(1-buthyl-3-methyl)imidazol-2-ylidene-gold hexafluorophosphate with the human telomere Tel-23 have been obtained. The adduct has been also characterized in solution by means of ESI-MS, circular dichroism and melting experiments. [1] L. Oehninger, R. Rubbiani, I. Ott, Dalton Trans 2013, 42, 3269- 3284. [2] Zou T., LumC.T., Lok C-N., Zhanga J-J., Che C-M., Chem. Soc. Rev., 2015, 44, 8786-8801. [3] F. Papi, C. Bazzicalupi, M. Ferraroni, L. Massai, B. Bertrand, P. Gratteri, D. Colangelo, L. Messori, Chem. Eur. J., 2017, 23, 13784- 13791. [4] T. Zou, C.N. Lok, P.K. Wan, Z.F. Zhang, S.K. Fung, C.M. Che, Curr. Op. Chem. Biol., 2018, 43, 30-36.