Lapachol and lawsone in the design of new ruthenium(II)-diphosphine complexes as promising anticancer metallodrugs.

Abstract

The development of metal complexes containing natural products is a remarkable strategy to develop new anticancer candidates. Thus, we report here on the preparation of two new Ru(II)/diphosphine complexes containing Lapachol (Lap) and Lawsone (Law): (1) [Ru(Lap)(dppm)2]PF6 and (2) [Ru(Law)(dppm)2]PF6, where dppm = bis(diphenylphosphino)methane. The complexes were synthetized and fully characterized by elemental analyses, molar conductivity, UV-Vis, IR, 31P{1H}, 1H and 13C NMR, and the crystal structure of the complex (1) was determined by X-ray diffraction. Complexes (1) and (2) showed high in vitro cytotoxicity against four cancer cells (MDA-MB-231, MCF-7, A549 and DU-145), with IC50 values in the micromolar range (0.03 to 2.70 M). Importantly, complexes (1) and (2) were more active than the cisplatin, the drug used as a reference in the cytotoxic assays. Moreover, complex (1) showed high selectivity to triple-negative breast cancer cells (MDA-MB-231). Studies of the mechanism of action in MDA-MB-231 cancer cells showed that complex (1) inhibit cell migration, colony formation, and induces cell cycle arrest and apoptosis by activation of the mitochondrial pathway through the loss of mitochondrial membrane potential (m). Furthermore, the complex (1) induces ROS generation in MDA-MB-231 cells, which can cause DNA damage. Finally, complexes (1) and (2) interact with DNA by minor grooves and show a moderate interaction with BSA, with the involvement of hydrophobic interactions. Essentially, Ru(II)/diphosphine-naphthoquinone complexes have remarkable cytotoxic effects with high selectivity to triple-negative breast cancer (MDA-MB-231) and could be promising anticancer candidates for cancer treatment.