Gold lights the way: A bidentate cyclophane N‐heterocyclic carbene ligand has been used to synthesize a new dinuclear AuI complex of the formula [Au2L2]2+. The short Au⋅⋅⋅Au distance imposed by the rigid cyclophane ligand leads to a red‐shifted luminescence profile that enables the complex to be used as a luminescent probe for distribution studies in single living cancer cells.

Simultaneous multi-element imaging using NanoSIMS (nanoscale secondary ion mass spectrometry), exploiting the novel combination of 195Pt and 15N in platinum-am(m)ine antitumour drugs, provides information on the internalisation and subcellular localisation of both metal and ligands, and allows identification of ligand exchange.

Gold(I) phosphine complexes, such as [Au(d2pype)(2)]Cl, (1, where d2pype is 1,2-bis(di-2-pyridyl phosphinoethane)), belong to a class of promising chemotherapeutic candidates that have been shown to be selectively toxic to tumourigenic cells, and may act via uptake into tumour cell mitochondria. For a more holistic understanding of their mechanism of action, a deeper knowledge of their subcellular distribution is required, but to date this has been limited by a lack of suitable imaging techniques. In this study the subcellular distribution of gold was visualised in situ in human breast cancer cells treated with 1, using nano-scale secondary ion mass spectrometry. NanoSIMS ion maps of (12)C(14)N(-), (31)P(-), (34)S(-) and (197)Au(-) allowed, for the first time, visualisation of cellular morphology simultaneously with subcellular distribution of gold. Energy filtered transmission electron microscopy (EFTEM) element maps for gold were also obtained, allowing for observation of nuclear and mitochondrial morphology with excellent spatial resolution, and gold element maps comparable to the data obtained with NanoSIMS. Following 2 h treatment with 1, the subcellular distribution of gold was associated with sulfur-rich regions in the nucleus and cytoplasm, supporting the growing evidence for the the mechanism of action of Au(I) compounds based on inhibition of thiol-containing protein families, such as the thioredoxin system. The combination of NanoSIMS and EFTEM has broader applicability for studying the subcellular distribution of other types of metal-based drugs.

There are increasing reports of novel metal-based chemotherapeutics that have either improved cancer cell selectivity, or alternative mechanisms of action, to existing anticancer drugs, and techniques are required for determining their sub-cellular molecular targets. Imaging methods offer many distinct advantages over destructive fractionation techniques, including the preservation of useful morphological information; however, mapping the intracellular distribution of metal ions inside tumour cells still remains challenging. Recent advances in three modes of imaging are discussed in this review, with a particular focus on the application to metal-based cancer chemotherapy – fluorescence microscopy, electron microscopy (including energy-filtered transmission electron microscopy (EFTEM)), and a new technique, Nano-scale secondary ion mass spectrometry (NanoSIMS).

We have synthesized a new series of azolium cyclophanes and used them as precursors of inherently luminescent dinuclear Au(i)-N-heterocyclic carbene (NHC) complexes. The azolium cyclophanes contained two azolium groups (either imidazolium or benzimidazolium), an o-xylyl group, and an alkyl linker chain (either C2, C3 or C4). All of the azolium cyclophanes were characterised by X-ray diffraction studies and VT NMR studies, and all were fluxional in solution on the NMR timescale. The C3- and C4-linked azolium cyclophanes served as precursors of Au2L2(2+) complexes (L is a cyclophane bis(NHC) ligand). Due to the unsymmetrical nature of the azolium cyclophanes, the Au2L2(2+) complexes each existed as cis and trans isomers. X-ray diffraction studies showed that the Au2L2(2+) complexes had short intramolecular AuAu distances, in the range 2.9-3.3 Å, suggestive of an aurophilic attraction, presumably as a consequence of the geometrical constraints imposed by the cyclophane bis(NHC) ligands. The complexes having the shortest AuAu distances (i.e., those based on C3-linked cyclophanes) exhibited intense luminescence in solution. The uptake of one of the dinuclear Au-NHC complexes by tumorigenic cells, and its subsequent distribution and toxicity in the cells, was monitored by luminescence microscopy over 6 h and proliferation measurements, respectively.

Gold weist den Weg: Ein zweizähniges N‐heterocyclisches Cyclophan‐Carben ist der Ligand im neuen zweikernigen AuI‐Komplex der Formel [Au2L2]2+. Der durch den starren Cyclophanliganden erzwungene kleine Au⋅⋅⋅Au‐Abstand hat ein rotverschobenes Lumineszenzprofil zur Folge, was den Komplex zu einer geeigneten Lumineszenzsonde für Verteilungsstudien an einzelnen lebenden Krebszellen macht.

Fluorescence and X-ray absorption spectroscopy were used to investigate the anion binding properties of a luminescent, dinuclear Au(I) N-heterocyclic carbene (NHC) complex ([1](2+)) with a short Au(I)···Au(I) contact. The addition of Br(-) ions to a DMSO solution of [1](PF(6))(2) caused a red-shift in the fluorescence emission band from 396 nm to 496 nm. Similarly, the addition of Br(-) ions to [1](PF(6))(2) caused a decrease in the energy of the Au L(3)-edge in the X-ray absorption spectrum, consistent with the formation of an association complex between the cation [1](2+) and Br(-) ions. Solution-based structural studies of the association complex were carried out using extended X-ray absorption fine structure (EXAFS) modelling of the Au(I)···Au(I) core of the cation. These studies indicate that the association complex results from Au(I)···Br(-) interactions, with the Br(-) ions occupying two partially occupied sites at ~2.9 and 3.9 Å from the Au(I) atoms.

Review: 145 refs.