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

Abstract

Four mononuclear [(L-L) Ru(tatpp)] and two dinuclear [(L-L) Ru(tatpp)Ru(L-L) ] 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 (Me phen) or 4,7-diphenyl-1,10-phenanthroline (Ph phen). 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 (IC ) 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 IC 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 (IC values <15 μm), Ru-tatpp complexes as a class are surprisingly well tolerated in animals relative to other RPCs.

Monomeric and dimeric coordinatively saturated and substitutionally inert Ru(ii) polypyridyl complexes as anticancer drug candidates

“…All the Ru(II) complexes carrying non-redox active ligands were found to be slightly active against the cell lines tested. 164 Complexes 112 and 113 (shown in Figure 26) are the most lipophilic complexes containing the tatpp ligand examined in this work and showed consistent cytotoxicity against malignant cell lines (IC 50 ≈ 10 µM). 164 At the same time, they were also well-tolerated by non- malignant MFC10 cells.…”

“…164 Complexes 112 and 113 (shown in Figure 26) are the most lipophilic complexes containing the tatpp ligand examined in this work and showed consistent cytotoxicity against malignant cell lines (IC 50 ≈ 10 µM). 164 At the same time, they were also well-tolerated by non- malignant MFC10 cells. This data is in complete agreement with the trend found during the in vitro AChE inhibition studies.…”

“…This data is in complete agreement with the trend found during the in vitro AChE inhibition studies. 164 It is clear, that the lipophilicity is inversely proportional to the AChE inhibition ability. Moreover, in vivo toxicity studies suggested that the tatpp ligand might be responsible for lowering the observed toxicity.…”

“…164 In this work, they carried out a structure-activity relationship study examining the cytotoxicity of Ru(II) polypyridyl complexes against three malignant (MCF7, CCL228, and H358) and one non-malignant (MCF10) human cultured cell lines. All the Ru(II) complexes carrying non-redox active ligands were found to be slightly active against the cell lines tested.…”

“…Moreover, in vivo toxicity studies suggested that the tatpp ligand might be responsible for lowering the observed toxicity. 164 In 2017, MacDonnell and co-workers proposed a mechanistic model to explain the dependency of the DNA cleavage on oxygen concentration. 165 In more detail, they performed cell-free experiments, whose data supported the mechanistic pathway shown in Figure 27.…”