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A strategy for the generation of heterotrimetallic double cavity (DC) cages [Pd n Pt m L 4 ] 6+ (DC1: n=1, m=2; and DC2: n=2, m=1) is reported. The DC cages were generated by combining an inert platinum(II) tetrapyridylaldehyde complex with a suitably substituted pyridylamine and Pd II ions. 1 H and DOSY nuclear magnetic resonance spectroscopy (NMR) and electrospray ionization mass spectrometry (ESIMS) data were consistent with the formation of the DC architectures. DC1 and DC2 were shown to interact with several different guest molecules. The structure of DC1, which features two identical cavities, binding two 2,6-diaminoanthraquinone (DAQ) guest molecules was determined by single-crystal X-ray crystallography. In addition, DC1 was shown to bind two molecules of 5-fluorouracil (5-FU) in a statistical (non-cooperative) manner. In contrast, DC2, which features two different cage cavities, was found to interact with two different guests, 5-FU and cisplatin, selectively., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Metal complexes can be considered a "paradigm of promiscuity" when it comes to their interactions with proteins. They often form adducts with a variety of donor atoms in an unselective manner. We have characterized the adducts formed between a series of isostructural N-heterocyclic carbene (NHC) complexes with Ru, Os, Rh, and Ir centers and the model protein hen egg white lysozyme by X-ray crystallography and mass spectrometry. Distinctive behavior for the metal compounds was observed with the more labile Ru and Rh complexes targeting mainly a surface l-histidine moiety through cleavage of p-cymene or NHC co-ligands, respectively. In contrast, the more inert Os and Ir derivatives were detected abundantly in an electronegative binding pocket after undergoing ligand exchange of a chlorido ligand for an amino acid side chain. Computational studies supported the binding profiles and hinted at the role of the protein microenvironment for metal complexes eliciting selectivity for specific binding sites on the protein., (© 2021 Wiley-VCH GmbH.)

The combination of more than one bioactive moiety in a multitargeted anticancer agent may result in synergistic activity of its components. Using this concept, bioorganometallic compounds were designed to feature a metal center, a 2-pyridinecarbothioamide (PCA), and a hydroxamic acid, which is found in the anticancer drug vorinostat (SAHA). The organometallics showed inhibitory activity in the nanomolar range against histone deacetylases (HDACs) as the key target for SAHA. In particular, the Rh complex was a potent inhibitor of HDAC6 over HDAC1 and HDAC8. Whereas this complex was highly cytotoxic in human cancer cells, it showed low toxicity in hemolysis studies and zebrafish, demonstrating the role of the metal center. For this complex a slightly reduced expression of vascular endothelial growth factor receptor 2 (VEGFR2) was established, which was upregulated by SAHA. This finding indicates that the new organometallics display different modes of action than their bioactive components., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A strategy is presented that enables the quantitative assembly of a heterobimetallic [PdPtL 4 ] 4+ cage. The presence of two different metal ions (Pd II and Pt II ) with differing labilities enables the cage to be opened and closed selectively at one end upon treatment with suitable stimuli. Combining an inert Pt II tetrapyridylaldehyde complex with a suitably substituted pyridylamine and Pd II ions led to the assembly of the cage. 1 H and DOSY NMR spectroscopy and ESI mass spectrometry data were consistent with the quantitative formation of the cage, and the heterobimetallic structure was confirmed using single-crystal X-ray crystallography. The structure of the host-guest adduct with a 2,6-diaminoanthraquinone guest molecule was determined. Addition of N,N'-dimethylaminopyridine (DMAP) resulted in the formation of the open-cage [PtL 4 ] 2+ compound and [Pd(DMAP) 4 ] 2+ complex. This process could then be reversed, with the reformation of the cage, upon addition of p-toluenesulfonic acid (TsOH)., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Organometallic metal(arene) anticancer agents require ligand exchange for their anticancer activity and this is generally believed to confer low selectivity for potential cellular targets. However, using an integrated proteomics-based target-response profiling approach as a potent hypothesis-generating procedure, we found an unexpected target selectivity of a ruthenium(arene) pyridinecarbothioamide (plecstatin) for plectin, a scaffold protein and cytolinker, which was validated in a plectin knock-out model in vitro. Plectin targeting shows potential as a strategy to inhibit tumor invasiveness as shown in cultured tumor spheroids while oral administration of plecstatin-1 to mice reduces tumor growth more efficiently in the invasive B16 melanoma than in the CT26 colon tumor model., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)