Tridentate 3-Substituted Naphthoquinone Ruthenium Arene Complexes: Synthesis, Characterization, Aqueous Behavior, and Theoretical and Biological Studies.

Heiko Geisler,Sophia Harringer,Dominik Wenisch,Sarah Plutzar,Philipp Marquetand,Valentin Fuchs,Klaudia Cseh,Michael A Jakupec,Wolfgang Kandioller,Natalie Gajic,Julia Westermayr,Michaela Hejl

doi:10.1021/acs.inorgchem.1c01083

Heiko Geisler, Sophia Harringer + Show 10 more

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https://doi.org/10.1021/acs.inorgchem.1c01083

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Journal: Inorganic chemistry	Publication Date: Jun 11, 2021
Citations: 10	License type: CC BY 4.0

Affiliation: University of Vienna, University of Warwick

Abstract

A series of nine RuII arene complexes bearing tridentate naphthoquinone-based N,O,O-ligands was synthesized and characterized. Aqueous stability and their hydrolysis mechanism were investigated via UV/vis photometry, HPLC-MS, and density functional theory calculations. Substituents with a positive inductive effect improved their stability at physiological pH (7.4) intensely, whereas substituents such as halogens accelerated hydrolysis and formation of dimeric pyrazolate and hydroxido bridged dimers. The observed cytotoxic profile is unusual, as complexes exhibited much higher cytotoxicity in SW480 colon cancer cells than in the broadly chemo- (incl. platinum-) sensitive CH1/PA-1 teratocarcinoma cells. This activity pattern as well as reduced or slightly enhanced ROS generation and the lack of DNA interactions indicate a mode of action different from established or previously investigated classes of metallodrugs.

Highlights

Metallodrugs have played an important role in medicine for centuries and are essential for several therapeutic and diagnostic applications.[1]
We reported on organoruthenium and -osmium complexes bearing an in situ generated tridentate naphthoquinone scaffold, which were characterized by enhanced stability in aqueous media compared to their bidentate naphthoquinone analogues featuring a halido leaving group.[29]
The results showed similar Reactive oxygen species (ROS) formation in both cancer cell lines, indicating that reactive oxygen species cannot account for the differences in cytotoxic activity

Summary

Introduction

Metallodrugs have played an important role in medicine for centuries and are essential for several therapeutic and diagnostic applications.[1]. Despite the discovery that these drugs cause severe side effects (such as nephrotoxicity, myelosuppression, and neurotoxicity), they are still used as first-line agents in various cancer treatment regimens.[4] researchers are focused on identifying novel metallodrugs to overcome these drawbacks. Due to a wide range of stable oxidation states under biologically relevant conditions, acceptable ligand exchange rates, and a rich coordination chemistry, other metals of the platinum group were identified as possible alternatives.[5,6] The most auspicious representatives are ruthenium coordination compounds, which have shown promising results in (pre)clinical trials.[7] In this context, BOLD-100 (formerly, KP1339/NKP1339/IT-139) and NAMI-A are well studied representatives of octahedral RuIII complexes (Figure 1). NAMI-A showed activity against metastases in preclinical settings, where it reduced the growth and formation of lung metastases in malignant tumors.[8,9]

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