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

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 i...

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Published inInorganic chemistry Vol. 60; no. 13; pp. 9805 - 9819
Main Authors Geisler, Heiko, Westermayr, Julia, Cseh, Klaudia, Wenisch, Dominik, Fuchs, Valentin, Harringer, Sophia, Plutzar, Sarah, Gajic, Natalie, Hejl, Michaela, Jakupec, Michael A, Marquetand, Philipp, Kandioller, Wolfgang
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 05.07.2021
Subjects
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Cell Proliferation - drug effects
Cell Survival - drug effects
Coordination Complexes - chemical synthesis
Coordination Complexes - chemistry
Coordination Complexes - pharmacology
Crystallography, X-Ray
Density Functional Theory
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Models, Molecular
Molecular Structure
Naphthoquinones - chemistry
Naphthoquinones - pharmacology
Ruthenium - chemistry
Ruthenium - pharmacology
Water - chemistry
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Summary: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.
ISSN:0020-1669
1520-510X
DOI:10.1021/acs.inorgchem.1c01083