Preclinical Anticancer Activity of an Electron‐Deficient Organoruthenium(II) Complex

Abstract

Ruthenium compounds have been shown to be promising alternatives to platinum(II) drugs. However, their clinical success depends on achieving mechanisms of action that overcome Pt‐resistance mechanisms. Electron‐deficient organoruthenium complexes are an understudied class of compounds that exhibit unusual reactivity in solution and might offer novel anticancer mechanisms of action. Here, we evaluate the in vitro and in vivo anticancer properties of the electron‐deficient organoruthenium complex [(p‐cymene)Ru(maleonitriledithiolate)]. This compound is found to be highly cytotoxic: 5 to 60 times more potent than cisplatin towards ovarian (A2780 and A2780cisR), colon (HCT116 p53+/+ and HCT116 p53−/−), and non‐small cell lung H460 cancer cell lines. It shows no cross‐resistance and is equally cytotoxic to both A2780 and A2780cisR cell lines. Furthermore, unlike cisplatin, the remarkable in vitro antiproliferative activity of this compound appears to be p53‐independent. In vivo evaluation in the hollow‐fibre assay across a panel of cancer cell types and subcutaneous H460 non‐small cell lung cancer xenograft model hints at the activity of the complex. Although the impressive in vitro data are not fully corroborated by the in vivo follow‐up, this work is the first preclinical study of electron‐deficient half‐sandwich complexes and highlights their promise as anticancer drug candidates.

Synthesis, Characterisation and In Vitro Anticancer Activity of Catalytically Active Indole-Based Half-Sandwich Complexes

“…The possibility of using compounds 1-4 as a transfer hydrogenation catalyst to reduce NAD + was investigated (Materials and Methods section). Compounds 1-4 reduced NAD + with turnover frequencies (TOF) between 6 and 15 h −1 (Table 1), which is within the range of previously reported compounds [51,53,[74][75][76]. Remarkably, under the conditions here reported (MeOD/D 2 O 1:1 v/v, 310 K, pH* 7.4 ± 0.2), the iridium complex 2 reduced nine molar equivalents of NAD + within the initial 10 min.…”

“…In order to determine whether ROS formation is a plausible explanation for the activity of these compounds, A2780 cells were treated at IC 50 concentrations of 1 – 4 in combination with increasing concentrations of N -acetylcysteine (NAC; 0, 2, 5 and 10 mM; Figure 4 ). NAC is a known compound that can act as an ROS scavenger in cells and can be used to counteract the effects of complexes that affect ROS levels [ 76 , 77 ]. Interestingly, the addition of complexes 1 and 2 to NAC-supplemented cells leads to a significant decrease of the cell viability.…”

“…complexes that affect ROS levels [76,77]. Interestingly, the addition of complexes 1 and 2 to NACsupplemented cells leads to a significant decrease of the cell viability.…”

<p>Ruthenium Complexes as Anticancer Agents: A Brief History and Perspectives</p>

“…Some have shown a promising characterization as an immune-modulating anticancer agent, 145 excellent redox potential, 97 strong topoisomerase inhibitor, 98 while others have shown encouraging results such as antimetastatic activity, tubulin formation inhibition, and high selectivity against cancer cells over normal cells. [146][147][148] Recent investigations cover structurally novel scaffolds including electron-deficient ruthenium complexes 149 and macromolecular ligands such as dendrimers. 150 In this review, we present a brief description of Ru-based anticancer complexes.…”

Oxidative Stress in Cancer Therapy: Friend or Enemy?

“…Barry and co‐workers demonstrated that electron‐deficient metal complexes can also induce the production of high levels of ROS in cancer cells with the complex [( p ‐cymene)Ru(maleonitriledithiolate)] increasing ROS levels in ovarian A2780 cancer cells and the ROS‐scavenger NAC inhibiting the cytotoxicity of this metal complex (Figure 9). [143] …”