Naphthoquinone-derived tridentate Ru(II) and Os(II) organometallics with exceptional cytotoxicity: synthesis,...

In this work, a panel of twelve ruthenium(II) and osmium(II) derived N,O,O-tridentate complexes (1a-2f) with a variation of longer, branched and unbranched alkyl substituents was synthesized and characterized via NMR, HRMS, elemental analysis and X-ray diffraction analysis. Resilience to dissociation in biologically relevant solution was determined over 72 hours, revealing most stable complexes to derive from naphthoquinones bearing tert-butyl- and neopentyl-substituents. Osmium derived complexes were found to be generally more inert than their ruthenium counterparts. Cytotoxicity was examined, revealing IC₅₀ values in the nanomolar to lower micromolar range for derivatives 1a-2f in three human cancer lines and a typical pattern of selectivity for SW480 cells. Cellular accumulation correlated with in vitro cytotoxicity; however, longer and branched substituents did not improve the cellular accumulation. Cell cycle experiments showed consistent cell cycle inhibition in both SW480 and CH1/PA-1 cells for ruthenium-based compounds only. Indolamin-2,3-dioxygenase 1 (IDO1) inhibition assays in SKOV3 cells revealed significant inhibitory potential of Ru-Ethyl, in clear distinction to other ruthenium and osmium complexes.