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Metal piano-stool complexes based on pyridinecarbothioamide (PCA) have shown promising antiproliferative and in vivo anticancer activity, in particular [Ru(cym)(p -F-PCA)Cl]PF6 (cym is η 6- p -cymene; plecstatin-1). The impact of modifications of the PCA and π-bound ligands on biological properties has been extensively investigated. Herein, we explored the influence of exchanging the chlorido ligand with the N -heterocycles 1-methylimidazole, 1-methylbenzimidazole and pyridine. In solution, an equilibrium between the protonated and deprotonated forms of the thioamide bond was observed, which was found dictated by the solvent system with both species detected in polar solvents. [Ru(cym)(PCA)Cl]+ complexes exhibit unique behaviour in an aqueous environment where they rapidly form dimeric species after substitution of the chlorido ligand for the sulfur donor of the PCA ligand of a second complex molecule. This was also observed for the synthesised complexes with the N -heterocyclic ligands being cleaved from the Ru centre allowing for dimerisation, which may be reversed by acidification of the solution resulting in the formation of equivalent mononuclear compounds. This behaviour explains the similar biological properties of the complexes with respect to that of plecstatin-1. Replacing the chlorido ligand in [Ru(η 6- p -cymene)(p -fluoropyridinecarbothioamide)Cl]PF6 with the N -heterocycles 1-methylimidazole, 1-methylbenzimidazole and pyridine gave complexes with similar antiproliferative activities in human cancer cells at low micromolar concentrations. This can be explained by dimerisation in aqueous solution and formation of the same di-Ru complexes after cleaving of the chlorido or N -heterocycle ligands. (Image credit: Saawan Kumar.) This article belongs to the 10th Anniversary Collection of RACI and AAS Award papers. [ABSTRACT FROM AUTHOR]

The cellular accumulation and the underlying mechanisms for the two ruthenium-based anticancer complexes [RuII(cym)(HQ)Cl] 1 (cym = η6-p-cymene, HQ = 8-hydroxyquinoline) and [RuII(cym)(PCA)Cl]Cl 2 (PCA = N-fluorophenyl-2-pyridinecarbothioamide) were investigated in HCT116 human colorectal carcinoma cells. The results showed that the cellular accumulation of both complexes increased over time and with higher concentrations, and that 2 accumulates in greater quantities in cells than 1. Inhibition studies of selected cellular accumulation mechanisms indicated that both 1 and 2 may be transported into the cells by both passive diffusion and active transporters, similar to cisplatin. Efflux experiments indicated that 1 and 2 are subjected to efflux through a mechanism that does not involve p-glycoprotein, as addition of verapamil did not make any difference. Exploring the influence of the Cu transporter by addition of CuCl2 resulted in a higher accumulation of 1 and 2 whilst the amount of Pt detected was slightly reduced when cells were treated with cisplatin. Complexes 1 and 2 were further explored in zebrafish where accumulation and distribution were determined with ICP-MS and LA-ICP-MS. The results correlated with the in vitro observations and zebrafish treated with 2 showed higher Ru contents than those treated with 1. The distribution studies suggested that both complexes mainly accumulated in the intestines of the zebrafish. [ABSTRACT FROM AUTHOR]

Pt(terpyridine) complexes are well-known DNA intercalators. The introduction of an NHC co-ligand rendered such a complex highly antiproliferative in cancer cells compared to its chlorido derivative. Despite the high potency, zebrafish embryos tolerated the compound well, especially compared to cisplatin. DNA interaction studies support a mode of action related to intercalation. [ABSTRACT FROM AUTHOR]

A new [PdPtL4]4+ heterobimetallic cage containing hydrazone linkages has been synthesised using the sub-component self-assembly approach. 1H and DOSY nuclear magnetic resonance (NMR) spectroscopy and electrospray ionisation mass spectrometry (ESIMS) data were consistent with the formation of the [PdPtL4]4+ architecture. The cage was stimulus-responsive and could be partially disassembled and reassembled by the addition of dimethylaminopyridine (DMAP) and p-tolenesulfonic acid (TsOH), respectively. Additionally, the stability of the hydrazone cage against hydrolysis in the presence of water and nucleophilic decomposition in the presence of guest molecules was compared to a previously synthesised imine-containing [PdPtL4]4+ cage. It was established that the hydrazone linkage was more resistant to hydrolysis. Furthermore, the host–guest (HG) chemistry with a series of drug and drug-like molecules was examined. The hydrazone cage was shown to interact with cisplatin while the smaller imine cage was shown to interact with 5-fluorouracil and oxaliplatin in CD3CN. No HG interactions were observed in the more polar d6-DMSO. In vitro antiproliferative activity studies demonstrated both cages were active against the cancer cell lines tested and displayed half-maximal inhibitory (IC50) values in the range of 25–35 μM. Most [PdPtL4]4+-drug mixtures tested had higher IC50 values than the hosts. However, the [PdPtL4]4+ cages, and [PdPtL4]4+:drug mixtures were less cytotoxic than the well established anticancer drugs cisplatin, oxaliplatin and 5-fluorouracil. [ABSTRACT FROM AUTHOR]

Two new di(2,2'-bipyridine) ligands, 2,6-bis([2,2'-bipyridin]-5-ylethynyl)pyridine ( L1 ) and bis(4-([2,2'-bipyridin]-5-ylethynyl)phenyl)methane ( L2 ) were synthesized and used to generate two metallosupramolecular [Fe 2 ( L ) 3 ](BF 4 ) 4 cylinders. The ligands and cylinders were characterized using elemental analysis, electrospray ionization mass spectrometry, UV-vis, 1 H-, 13 C and DOSY nuclear magnetic resonance (NMR) spectroscopies. The molecular structures of the [Fe 2 ( L ) 3 ](BF 4 ) 4 cylinders were confirmed using X-ray crystallography. Both the [Fe 2 ( L1 ) 3 ](BF 4 ) 4 and [Fe 2 ( L2 ) 3 ](BF 4 ) 4 complexes crystallized as racemic ( rac ) mixtures of the ΔΔ (P) and ΛΛ (M) helicates. However, 1 H NMR spectra showed that in solution the larger [Fe 2 ( L2 ) 3 ](BF 4 ) 4 was a mixture of the rac -ΔΔ/ΛΛ and meso -ΔΛ isomers. The host-guest chemistry of the helicates, which both feature a central cavity, was examined with several small drug molecules. However, none of the potential guests were found to bind within the helicates. In vitro cytotoxicity assays demonstrated that both helicates were active against four cancer cell lines. The smaller [Fe 2 ( L1 ) 3 ](BF 4 ) 4 system displayed low μM activity against the HCT116 (IC 50 = 7.1 ± 0.5 μM) and NCI-H460 (IC 50 = 4.9 ± 0.4 μM) cancer cells. While the antiproliferative effects against all the cell lines examined were less than the well-known anticancer drug cisplatin, their modes of action would be expected to be very different., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lisboa, Riisom, Vasdev, Jamieson, Wright, Hartinger and Crowley.)

Ruthenium-based complexes have attracted attention as promising anticancer candidates due to their lower general toxicity than the widely used platinum drugs. The complex [Ru II (η 6 -p-cymene)(8-oxyquinolinato)Cl] 1 has shown significant cytotoxic activity in cancer cells, independent of the cellular uptake. In an attempt to rationalize this finding, we investigated the fate of 1 in cells as well as developed an analysis method for 1 and its derivatives based on molecular mass spectrometry. The methods were applied for the analysis of cell medium and HCT116 human colorectal cancer cell lysate samples. The amount of Ru detected in cell lysate after treatment with 1 by ICP-MS was virtually time-independent, while the Ru content in the cell pellet increased significantly over the course of 24 h. The compound was still detectable by LC-ESI-TOF-MS after 24 h in cell lysate as its [1- Cl] + ion that may be formed directly from 1 or after a chlorido-aqua ligand exchange reaction facilitated in the cytosol.