Triazolyl-Functionalized N-Heterocyclic Carbene Half-Sandwich Compounds: Coordination Mode, Reactivity and in†vitro Anticancer Activity.

We report investigations on the anticancer activity of organometallic [MII/III (η6 -p-cymene/η5 -pentamethylcyclopentadienyl)] (M=Ru, Os, Rh, and Ir) complexes of N-heterocyclic carbenes (NHCs) substituted with a triazolyl moiety. Depending on the precursors, the NHC ligands displayed either mono- or bidentate coordination via the NHC carbon atom or as N,C-donors. The metal complexes were investigated for their stability in aqueous solution, with the interpretation supported by density functional theory calculations, and reactivity to biomolecules. In vitro cytotoxicity studies suggested that the nature of both the metal center and the lipophilicity of the ligand determine the biological properties of this class of compounds. The IrIII complex 5 d bearing a benzimidazole-derived ligand was the most cytotoxic with an IC50 value of 10 µM against NCI-H460 non-small cell lung carcinoma cells. Cell uptake and distribution studies using X-ray fluorescence microscopy revealed localization of 5 d in the cytoplasm of cancer cells.

Application of X-ray absorption and X-ray fluorescence techniques to the study of metallodrug action.

X-ray absorption spectroscopy and X-ray fluorescence microscopy are two synchrotron-based techniques frequently deployed either individually or in tandem to investigate the fates of metallodrugs and their biotransformation products in physiologically relevant sample material. These X-ray methods confer advantages over other analytical techniques in that they are nondestructive and require minimal chemical or physical manipulation of the sample before analysis, conserving both chemical and spatial information of the element(s) under investigation. In this review, we present selected examples of the use of X-ray absorption spectroscopy and X-ray fluorescence microscopy in studies of metallodrug speciation and localisation in vivo, in cell spheroids and in intact tissues and organs, and offer recent highlights in the advances of these techniques as they pertain to research on metallodrug action.

Thiourea-Derived Chelating Ligands and Their Organometallic Compounds: Investigations into Their Anticancer Activity.

Thiones have been investigated as ligands in metal complexes with catalytic and biological activity. We report the synthesis, characterization, and biological evaluation of a series of MII/III complexes of the general formulae [MII(cym)(L)Cl]X (cym = η6-p-cymene) or [MIII(Cp*)(L)Cl]X (Cp* = η5-pentamethylcyclopentadienyl), where X = Cl- or PF6-, and L represents heterocyclic derivatives of thiourea. The thiones feature a benzyl-triazolyl pendant and they act as bidentate ligands via N,S-coordination to the metal centers. Several derivatives have been investigated by single-crystal X-ray diffraction analysis. NMR investigations showed a counterion-dependent shift of several protons due to the interaction with the counterions. These NMR investigations were complemented with X-ray diffraction analysis data and the effects of different counterions on the secondary coordination sphere were also investigated by DFT calculations. In biological studies, the Ir benzimidazole derivative was found to accumulate in the cytoplasm and it was the most cytotoxic derivative investigated.

Potent Inhibition of Thioredoxin Reductase by the Rh Derivatives of Anticancer M(arene/Cp*)(NHC)Cl2 Complexes.

Metal complexes provide a versatile platform to develop novel anticancer pharmacophores, and they form stable compounds with N-heterocyclic carbene (NHC) ligands, some of which have been shown to inhibit the cancer-related selenoenzyme thioredoxin reductase (TrxR). To expand a library of isostructural NHC complexes, we report here the preparation of RhIII- and IrIII(Cp*)(NHC)Cl2 (Cp* = η5-pentamethylcyclopentadienyl) compounds and comparison of their properties to the RuII- and OsII(cym) analogues (cym = η6-p-cymene). Like the RuII- and OsII(cym) complexes, the RhIII- and IrIII(Cp*) derivatives exhibit cytotoxic activity with half maximal inhibitory concentration (IC50) values in the low micromolar range against a set of four human cancer cell lines. In studies on the uptake and localization of the compounds in cancer cells by X-ray fluorescence microscopy, the Ru and Os derivatives were shown to accumulate in the cytoplasmic region of treated cells. In an attempt to tie the localization of the compounds to the inhibition of the tentative target TrxR, it was surprisingly found that only the Rh complexes showed significant inhibitory activity at IC50 values of ∼1 µM, independent of the substituents on the NHC ligand. This indicates that, although TrxR may be a potential target for anticancer metal complexes, it is unlikely the main target or the sole target for the Ru, Os, and Ir compounds described here, and other targets should be considered. In contrast, Rh(Cp*)(NHC)Cl2 complexes may be a scaffold for the development of TrxR inhibitors.

Confocal Volumetric µXRF and Fluorescence Computed µ-Tomography Reveals Arsenic Three-Dimensional Distribution within Intact Pteris vittata Fronds.

The fern Pteris vittata has been the subject of numerous studies because of its extreme arsenic hyperaccumulation characteristics. However, information on the arsenic chemical speciation and distribution across cell types within intact frozen-hydrated Pteris vittata fronds is necessary to better understand the arsenic biotransformation pathways in this unusual fern. While 2D X-ray absorption spectroscopy imaging studies show that different chemical forms of arsenic, As(III) and As(V), occur across the plant organs, depth-resolved information on arsenic distribution and chemical speciation in different cell types within tissues of Pteris vittata have not been reported. By using a combination of planar and confocal µ-X-ray fluorescence imaging and fluorescence computed µ-tomography, we reveal, in this study, the localization of arsenic in the endodermis and pericycle surrounding the vascular bundles in the rachis and the pinnules of the fern. Arsenic is also accumulated in the vascular bundles connecting into each sporangium, and in some mature sori. The use of 2D X-ray absorption near edge structure imaging allows for deciphering arsenic speciation across the tissues, revealing arsenate in the vascular bundles and arsenite in the endodermis and pericycle. This study demonstrates how different advanced synchrotron X-ray microscopy techniques can be complementary in revealing, at tissue and cellular levels, elemental distribution and chemical speciation in hyperaccumulator plants.