Bis(1,4-dihydro-2-methyl-1-phenyl-4-thioxo-3-pyridiolato)zinc(II) exhibits strong cytotoxicity and a high intracellular accumulation in cultured vascular endothelial cells

Abstract

Although cytotoxicity of inorganic metals has been well investigated, little is known about the cytotoxicity of organic-inorganic hybrid molecules. The cytotoxicity of zinc complexes was evaluated using a culture system of vascular endothelial cells. We found that bis(1,4-dihydro-2-methyl-1-phenyl-4-thioxo-3-pyridiolato)zinc(II), termed Zn-06, exhibited strong cytotoxicity in vascular smooth muscle cells, epithelial cells, fibroblastic cells, and vascular endothelial cells. This study showed that the tetracoordinate structure of the Zn-06 molecule, which contains two sulfur and two oxygen atoms attached to the zinc atom, facilitated its accumulation within vascular endothelial cells whereas the whole structure of the zinc complex was involved in its cytotoxicity in the cells. The present data suggest that a part of the structure, especially the binding site of the metal atom, was responsible for accumulation of zinc complexes, and the entire structure is responsible for their cytotoxicity in vascular endothelial cells. Recently, we have proposed bio-organometallics, a research strategy in biology that uses organic-inorganic hybrid molecules, as a tool to analyze biological systems (Fujie et al., 2016a). This research strategy succeeded in revealing the intracellular signal transduction of metallothionein induction (Fujie et al., 2016b) and that of syndecan-4 expression (Hara et al.,

Transcriptional Induction of Cystathionine γ-Lyase, a Reactive Sulfur-Producing Enzyme, by Copper Diethyldithiocarbamate in Cultured Vascular Endothelial Cells

“…We characterized the cytotoxicity of the hybrid molecules and applied this strategy to studies of intracellular signaling pathways that mediate regulation of vascular endothelial cell functions. Organic-inorganic hybrid molecules exhibit unique cytotoxicity in vascular endothelial cells [14][15][16][17][18]. Specifically, the cytotoxicity of organic-inorganic hybrid molecules is not simply dependent on their hydrophobicity, intracellular accumulation, molecular structures, or the intramolecular metals they contain.…”

Intracellular accumulation-independent cytotoxicity of pentavalent organoantimony compounds in cultured vascular endothelial cells

“…These results suggest that organic-inorganic hybrid molecules can accumulate within vascular endothelial cells independently of the hydrophobicity. Our research group has previously reported the cytotoxicity of organic-inorganic hybrid molecules in vascular endothelial cells (Murakami et al, 2015;Kohri et al, 2015;Hara et al, 2016Hara et al, , 2018bFujie et al, 2019b). These reports indicate that, in general, organic-inorganic hybrid molecules that easily accumulate within the cells exhibit strong cytotoxicity.…”

Zn(ii)2,9-dimethyl-1,10-phenanthroline stimulates cultured bovine aortic endothelial cell proliferation

“…On the other hand, we have previously reported that the cytotoxicity of organic-inorganic hybrid molecules is independent of the cytotoxicity of either the ligand alone or the intramolecular metal in its inorganic form. 18,22,23,[29][30][31][32] Activation of the NF-E2-related factor-2 by organic-inorganic hybrid molecules depends on the type of the coordinated metal ion. 33 Thus, it seems that the biological activities of organic-inorganic hybrid molecules depend on the interaction between the ligand structure and the intramolecular metal.…”

“…As the results obtained using this method are consistent with morphological evaluation of cells, this kit has been widely used for cytotoxicity assays. 18,[20][21][22][23] Furthermore, we assessed the cytotoxicity of Zn-12 by morphological observations and by evaluating lactate dehydrogenase leakage, in this study.…”