Azolate gold(I) phosphane complexes as innovative therapies for the treatment of HER2-driven breast cancer

Gold(I) compounds have been known as cytotoxic agents since 30 years ago1. Lastly, the inhibition activity studies on compounds (such as LAuL’, where L is a phosphane and L’ a co-ligand) led to the individuation of a likely molecular target2, renewing the interest on the field of these metallodrugs. In the design of active gold compounds, the proper hydro / lipophilic balancing provides the lowering of the overall toxicity, maintaining both a good cellular uptake and anticancer properties. Imidazoles and pyrazoles as co-ligands afford to gold(I) phosphane compounds having cytotoxic activity, but enough polarity to be soluble in physiological media. Different azolate gold(I)phosphane complexes have been synthesized. They contain substituents on imidazole or pyrazole ligands such as R = NO2, CF3, CN, Cl, CH2OH) or substituents such as COOH or COONHEt3 in the phosphane moiety. Some of them have been already tested as antitumoral in some panels of cancer cells, resulting active3. In this work we present the study of the cytotoxic effects of several gold(I) compounds and a natural compound on an in vitro model of HER2-overexpressing breast cancer. We tested the effectiveness of these compounds as potential anticancer agents on SKBR-3 cell line, a human breast cancer cell line that overexpresses the HER2 (Neu/ErbB-2) gene product4. These cells display an epithelial morphology in tissue culture and are a useful preclinical model to screen for new therapeutic agents which could overcome the drawback of resistance to HER2-targeted therapies5. In order to screen the cytotoxic activity of these new compounds on SKBR-3 cells we performed different cell viability assays. As conclusion we observed a detrimental effect on the cytotoxicity for those compounds having an ionic structure or highly hydrophilic polar substituents on the azolate or phosphane ligands and a remarkable activity for those compounds having the Ph3PAu+ moiety and substituted imidazolate as co-ligands. 1) Benoît Bertrand, and Angela Casini. Dalton Trans., 2014, 43, 4209. DOI: 10.1039/c3dt52524d 2) a) Peter J. Barnard, Susan J. Berners-Price. Coord. Chem. Rev. 2007, 251, 1889–1902. DOI:10.1016/j.ccr.2007.04.006. b) A. Bindoli, M. P. Rigobello, G. Scutari, C. Gabbiani, A. Casini, L. Messori, Coord. Chem. Rev., 2009, 253, 1692–1707. DOI: 10.1016/j.ccr.2009.02.026. 3) a) R. Galassi, A. Burini, S. Ricci, M. Pellei, M. P. Rigobello, A. Citta, A. Dolmella, V. Gandin, C Marzano. Dalton Trans., 2012, 41, 5307. DOI: 10.1039/c2dt11781a b) 4) Fogh J, Fogh JM, Orfeo T, 1977, One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice. J Natl Cancer Inst. , 59(1):221-6. DOI: 10.1016/j.bmcl.2013.11.058. 5) Saturnino C, Sirignano E, Botta A, Sinicropi MS, Caruso A, Pisano A, Lappano R, Maggiolini M, Longo P, 2014, New titanocene derivatives with high antiproliferative activity against breast cancer cells. Bioorg Med Chem Lett., 1;24(1):136-40. DOI: 10.1016/j.bmcl.2013.11.058.