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In this study, we report the synthesis, anticancer and biological properties of three doubly cyclometalated phenylbenzimidazole derived ruthenium(ii) organometallics () and their corresponding three organic ligands. The structures of were fully characterized by various analytical techniques, and the meso stereoisomer of the doubly cyclometalated ruthenacycle was unambiguously confirmed by single crystal X-ray diffraction. The anticancer effects of the newly synthesized compounds were tested against selected human cancer cell lines AGS (gastric carcinoma), SK-hep-1 (hepatocellular carcinoma), and HCT-15 (colorectal carcinoma). The growth inhibitory effects of ruthenacycles on cancer cells were found to be considerably more effective against the abovementioned cancer cells than the reference drug oxaliplatin. Compound exhibited a more specific effect on the AGS cells. Gene-fishing and ELISA array were performed to analyze the target genes and cytokine secretion by . As a result, a significant reduction was observed in RPS21 by . Moreover, increased the secretion of cytokines such as IFNγ in macrophages and reduced the release of cytokines such as rantes and IGF-1. These results show that could be a very good anticancer drug through the regulation of the RPS21 gene and cytokines.

Three new large hexanuclear metalla-prisms 9-11 incorporating 1,3, 5-tris(pyridin-4-ylethynyl)benzene (tpeb) 4 and one of the dinuclear arene ruthenium clips [Ru2(p-iPrC6H4Me)2(OO∩OO)][CF3SO3]2 (OO∩OO =2,5-dioxydo-1,4-benzoquinonato [dobq] 1, 5,8-dihydroxy-1,4-naphthaquinonato (donq) 2, and 6,11-dihydroxy-5,12-naphthacenedionato [dotq] 3), which encapsulate the guest molecule ellagic acid (2,3,7,8-tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione, 5) were prepared. All complexes were isolated as triflate salts in good yields and were fully characterized by (1)H NMR spectroscopy and electrospray ionization mass spectrometry. The photophysical properties of these metalla-prisms were also investigated. Compounds 9 and 10 showed potent antioxidant activity, but 10 had the superior ORACPE value (1.30 ± 0.020). Ellagic acid (5) and compound 11 showed weaker activity than that of Trolox. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that the metalla-prism compounds exhibit anticancer properties in vitro. Compound 10 inhibited the growth of all cancer cell lines at micromolar concentrations, with the highest cytotoxicity observed against A549 human lung cancer cells (IC50 =25.9 μM). However, these compounds had a lower anti-cancer activity than that of doxorubicin. In a tumoricidal assay, ellagic acid (5) and compound 10 induced cytotoxicity in tumor cells, while doxorubicin did not. While free ellagic acid had no effect on the granulocyte-colony stimulating factor and regulated on activation normal T cell expressed and secreted protein, the encapsulated metalla-prism 10 stimulated granulocyte-colony stimulating factor and reduced regulated on activation normal T cell expressed and secreted protein expression in the RAW264.7 macrophage line. Our results show that ellagic acid encapsulated in metalla-prisms inhibited cancer cells via the modulation of mRNA induction and protein expression levels of the granulocyte-colony stimulating factor and regulated on activation normal T cell expressed and secreted protein in macrophages.

Nano-sized multinuclear ruthenium complexes have rapidly emerged as promising therapeutic candidates with unique anticancer activities. Here, we describe the coordination-driven self-assembly and anticancer activities of a set of three organometallic tetranuclear Ru(II) molecular bowls. [2+2] Coordination-driven self-assembly of 3, 6-bis(pyridin-3- ylethynyl) phenanthrene (bpep) (1) and one of the three dinuclear arene ruthenium clips, [(η6-p-iPrC6H4Me)2Ru2-(OO\OO)][OTf]2 (OO\OO =2, 5-dioxido-1, 4-benzoquinonato, OTf = triflate) (2), 5, 8-dioxido-1, 4-naphthoquinonato (3), or 6, 11-dioxido-5, 12-naphthacenediona (4), resulted in three molecular bowls 5-7 of general formula [{(η6-p-iPrC6H4Me)2Ru2-(OO\OO)}2(bpep)2][OTf]4. All molecular bowls were obtained as triflate salts in very good yields (>90%) and were fully characterized using multinuclear nuclear magnetic resonance (NMR), electrospray ionization-mass spectrometry (ESI-MS), and elemental analysis. The structure of the representative molecular bowl 5 was confirmed by single-crystal X-ray diffraction analysis. The anticancer activities of molecular bowls 5-7 were determined by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide, autophagy, and Western blot analysis. Bowl 6 showed the strongest cytotoxicity in AGS human gastric carcinoma cells and was more cytotoxic than doxorubicin. In addition, autophagic activity and the ratio of apoptotic cell death increased in AGS cells by treatment with bowl 6. Bowl 6 also induced autophagosome formation via upregulation of p62 and promotion of the conversion of LC3-I to LC3-II. Moreover, bowl 6 promoted apoptotic cell death through downregulation of Akt/mTOR activation, followed by increased caspase-3 activity. These results suggest that bowl 6 induces gastric cancer cell death via modulation of autophagy and apoptosis. Bowl 6 is a potent anticancer agent and a potential treatment for human gastric cancer that merits further study.

New tetranuclear cationic metalla-bowls 5–7 with the general formula [Ru4(p-cymene)4(N∩N)2(OO∩OO)2]4+ (N∩N=2,6-bis(N-(4-pyridyl carbamoyl)pyridine, OO∩OO=2,5-dihydroxy-1,4-benzoquinonato (5), OO∩OO=5,8-dioxydo-1,4-naphthaquinonato (6), OO∩OO=hoxonato (7)) were prepared by the reaction of the respective dinuclear ruthenium complexes 2–4 with a bispyridine amide donor ligand 1 in methanol in the presence of AgO3SCF3.These new molecular metalla-bowls were fully characterized by analytical techniques including elemental analysis as well as 1H and 13C NMR and HR-ESI-MS spectroscopy. The structure of metalla-bowl 6 was determined from X-ray crystal diffraction data. A UV/visible study was also carried out for the entire suite of new complexes. As with recent studies of similar arene–Ru complexes, the inhibition of cell growth by metalla-bowls was established against SK-hep-1 (liver cancer), AGS (gastric cancer), and HCT-15 (colorectal cancer) human cancer cell lines. Inhibition of cell growth by 6 was found to be considerably stronger against all cancer cell lines than the anticancer drugs, doxorubicin and cisplatin. In particular, in colorectal cancer cells, expression of the cancer suppressor genes APC and p53 was increased following exposure to 6.

Thetwo new large molecular metalla-rectangles 6and 8were obtained by the reaction of the two different arene–rutheniumacceptors [Ru2(p-cymene)2(μ-η4-C2O4)Cl2] (2) and [Ru2(p-cymene)2(donq)(Cl)2] (donq = 5,8-dioxido-1,4-naphthoquinonato) (4) with a symmetrical N,N′-bis(4-(pyridin-4-ylethynyl)phenyl)terephthalamide(1) donor ligand. Both metalla-rectangles were isolatedin good yields as triflate salts and were characterized by multinuclearNMR, ESI–MS, and UV–vis spectroscopy. X-ray crystallographyof 6confirmed a molecular metalla-rectangle. The cytotoxicitiesof metalla-rectangles 6–9were establishedin SK-hep-1 (liver cancer), AGS (gastric cancer), and HCT-15 (colorectalcancer) human cancer cell lines. The cytotoxicity of metalla-rectangle 8was found to be considerably stronger against all cancercell lines, even much more effective than the well-known anticancerdrugs doxorubicin and cisplatin. In addition, expressions of APC andp53, colorectal cancer suppressor genes, were significantly increasedfollowing exposure to the metalla-rectangle 8. [ABSTRACT FROM AUTHOR]