Synthesis, DNA Cleavage Activity, Cytotoxicity, Acetylcholinesterase Inhibition, and Acute Murine Toxicity of Redox‐Active Ruthenium(II) Polypyridyl Complexes

• Published in: ChemMedChem 2017-07, Vol.12 (13), p.1055-1069
• Main Authors: Alatrash, Nagham, Narh, Eugenia S., Yadav, Abhishek, Kim, Mahn‐Jong, Janaratne, Thamara, Gabriel, James, MacDonnell, Frederick M.
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Acute toxicity; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Biotechnology; Cell Line, Tumor; Cell lines; Chelation; Chemical reduction; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Cholinesterase Inhibitors - toxicity; Cisplatin - pharmacology; Cleavage; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Coordination Complexes - toxicity; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Cleavage - drug effects; Glutathione; heterocycles; Humans; Inhibition; Ligands; Lipophilicity; Mass Spectrometry; Maximum Tolerated Dose; Mice, Inbred BALB C; Mice, Inbred C57BL; Oxidation-Reduction; Proton Magnetic Resonance Spectroscopy; Reducing agents; Ruthenium; Ruthenium - chemistry; Ruthenium compounds; synthesis; tatpp; Toxicity
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201700240

Four mononuclear [(L‐L)2Ru(tatpp)]2+ and two dinuclear [(L‐L)2Ru(tatpp)Ru(L‐L)2]4+ ruthenium(II) polypyridyl complexes (RPCs) containing the 9,11,20,22‐tetraazatetrapyrido[3,2‐a:2′,3′‐c:3′′,2′′‐l:2′′′,3′′′‐n]pentacene (tatpp) ligand were synthesized, in which L‐L is a chelating diamine ligand such as 2,2′‐bipyridine (bpy), 1,10‐phenanthroline (phen), 3,4,7,8‐tetramethyl‐1,10‐phenanthroline (Me4phen) or 4,7‐diphenyl‐1,10‐phenanthroline (Ph2phen). These Ru–tatpp analogues all undergo reduction reactions with modest reducing agents, such as glutathione (GSH), at pH 7. These, plus several structurally related but non‐redox‐active RPCs, were screened for DNA cleavage activity, cytotoxicity, acetylcholinesterase (AChE) inhibition, and acute mouse toxicity, and their activities were examined with respect to redox activity and lipophilicity. All of the redox‐active RPCs show single‐strand DNA cleavage in the presence of GSH, whereas none of the non‐redox‐active RPCs do. Low‐micromolar cytotoxicity (IC50) against malignant H358, CCL228, and MCF7 cultured cell lines was mainly restricted to the redox‐active RPCs; however, they were substantially less toxic toward nonmalignant MCF10 cells. The IC50 values for AChE inhibition in cell‐free assays and the acute toxicity of RPCs in mice revealed that whereas most RPCs show potent inhibitory action against AChE (IC50 values