# Naphthoquinone-derived tridentate Ru(ii) and Os(ii) organometallics with exceptional cytotoxicity: synthesis, characterization, stability in aqueous solution and biological in vitro evaluation

## TL;DR

This study presents new organometallic complexes with promising cancer-fighting properties, showing high stability and selectivity in cell tests.

## Contribution

The paper introduces novel N,O,O-tridentate Ru(ii) and Os(ii) complexes with exceptional cytotoxicity and stability in aqueous solutions.

## Key findings

- Osmium complexes were more inert than ruthenium ones in biologically relevant solutions.
- Ru-Ethyl showed significant IDO1 inhibition in SKOV3 cells compared to other complexes.
- Cell cycle inhibition was observed only for ruthenium-based compounds in specific cell lines.

## Abstract

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.

A panel of organometallic N,O,O-tridentate complexes bearing different alkyl substituents is presented. The impact on stability in aqueous systems, cytotoxicity, cellular accumulation, cell cycle and IDO inhibition is discussed.