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Heterobimetallic cages built from Pd and either octahedral Ru or square-planar Pt moieties and bridged by ligands with H bonding-accepting or -donating properties are reported. They showed stimulus-responsive dis- and reassembly, while guest binding was found to be dependent on the complementary properties of the guest to the host in terms of charge, size and H bonding properties.

Enzymes are known for their remarkable catalytic efficiency across a wide range of applications. Here, we present a novel and convenient nanoreactor platform based on zwitterionic polyelectrolyte complex vesicles (PCVs), assembled from oppositely charged homopoly(2-oxazoline)s, facilitating enzyme immobilization. We show remarkable enhancements in catalytic activity and stability by encapsulation of lipase as a model enzyme. Even as the temperature rises, the performance of the lipase remains robust. Further, the structural characteristics of PCVs, including hollow architecture and semipermeable membranes, endow them with unique advantages for enzyme cascade reactions involving glucose oxidase (GOx) and horseradish peroxidase (HRP). A decline in catalytic efficiency is shown when the enzymes are individually loaded and subsequently mixed, in contrast to the coloaded GOx-HRP-PCV group. We demonstrate that the vesicle structures establish confined environments where precise enzyme-substrate interactions facilitate enhanced catalytic efficiency. In addition, the nanoreactors exhibit excellent biocompatibility and efficient anti-tumor activity, which hold significant promise for biomedical applications within enzyme-based technologies.

Metallosupramolecular architectures formed from metal ions and bridging ligands are increasing in popularity due to their range of applications and ease of self-assembly. Many are able to readily change their shape and/or function in response to an external stimulus and have the ability to encapsulate guest molecules within their internal cavities. Ferrocenyl groups (Fc) have been incorporated previously within the bridging ligands of metallosupramolecular structures due to their ideal attributes brought about by the structural and rotational flexiblity of the two cyclopentadienyl (Cp) rings coordinated to the Fe(II) centre. However, the majority of these Fc-based structures contain symmetrically substituted Cp rings. We report the synthesis and characterisation of non-symmetrically functionalised Fc-based ligands incorporating both N , N ' and NHC-donor groups chosen for their differing coordination properties. Both substituents were designed to coordinate to a single metal centre with the dissimilar coordination properties of each donor group facilitating stimulus-induced dissociation/association of one of the substituents as an opening/closing mechanism. Preliminary investigations into the coordination of these Fc-based ligands to a [Ru(η 6 - p -cymene)] 2+ moiety indicated complexation through a mixture of either a bi- or tridentate fashion, as alluded by 1 H NMR spectroscopy and mass spectrometry. Density functional theory (DFT) calculations revealed the Fc-based ligands adopt a syn conformation driven by H-bonding and π-interactions between the two Cp substituents, which facilitate coordination of both donor groups towards the metal centre.

The clinical use of many potent anticancer agents is limited by their non-selective toxicity to healthy tissue. One of these examples is vorinostat (SAHA), a pan histone deacetylase inhibitor, which shows high cytotoxicity with limited discrimination for cancerous over healthy cells. In an attempt to improve tumor selectivity, we exploited the properties of cobalt(III) as a redox-active metal center through stabilization with cyclen and cyclam tetraazamacrocycles, masking the anticancer activity of SAHA and other hydroxamic acid derivatives to allow for the complex to reach the hypoxic microenvironment of the tumor. Biological assays demonstrated the desired low in vitro anticancer activity of the complexes, suggesting effective masking of the activity of SAHA. Once in the tumor, the bioactive moiety may be released through the reduction of the Co III center. Investigations revealed long-term stability of the complexes, with cyclic voltammetry and chemical reduction experiments supporting the design hypothesis of SAHA release through the reduction of the Co III prodrug. The results highlight the potential for further developing this complex class as novel anticancer agents by masking the high cytotoxicity of a given drug, however, the cellular uptake needs to be improved., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Synthesis and biological activity of two series of modified side chain methotrexate (MTX) derivatives are presented, one with a ferrocenyl moiety inserted between the pteroyl and glutamate portions of the molecule and the other with glutamate substituted for short chain amino acids. Ferrocenyl derivatives of MTX turned out to be rather moderate inhibitors of dihydrofolate reductase (DHFR) although molecular modeling suggested more effective interactions between these compounds and the target enzyme. More interestingly, ferrocene-decorated MTX derivatives were able to impede the proliferation of four murine and human cell lines as well as their methotrexate-resistant counterparts, overcoming the multidrug resistance (MDR) barrier. They were also able to directly interact with Abcc1, an MDR protein. Of the amino acid pteroyl conjugates, the γ-aminobutyric acid derivative was an efficient inhibitor of DHFR but had no effect on cell proliferation in the concentration range studied while a taurine conjugate was a poor DHFR inhibitor but able to affect cell viability. We postulate that modification of the methotrexate side chain may be an efficient strategy to overcome efflux-dependent methotrexate resistance., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Modern approaches in metallodrug research focus on compounds that bind protein targets rather than DNA. However, the identification of protein targets and binding sites is challenging. Using intact mass spectrometry and proteomics, we investigated the binding of the antimetastatic agent RAPTA-C to the model proteins ubiquitin, cytochrome c, lysozyme, and myoglobin. Binding to cytochrome c and lysozyme was negligible. However, ubiquitin bound up to three Ru moieties, two of which were localized at Met1 and His68 as [Ru(cym)], and [Ru(cym)] or [Ru(cym)(PTA)] adducts, respectively. Myoglobin bound up to four [Ru(cym)(PTA)] moieties and five sites were identified at His24, His36, His64, His81/82 and His113. Collision-induced unfolding (CIU) studies via ion-mobility mass spectrometry allowed measuring protein folding as a function of collisional activation. CIU of protein-RAPTA-C adducts showed binding of [Ru(cym)] to Met1 caused a significant compaction of ubiquitin, likely from N-terminal S-Ru-N chelation, while binding of [Ru(cym)(PTA)] to His residues of ubiquitin or myoglobin induced a smaller effect. Interestingly, the folded state of ubiquitin formed by His functionalization was more stable than Met1 metalation. The data suggests that selective metalation of amino acids at different positions on the protein impacts the conformation and potentially the biological activity of anticancer compounds., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

A dynamic covalent approach was exploited to generate a family of homometallic [Pt n L 2 n ] 2 n + cage (predominantly [Pt 2 L 4 ] 4+ systems) architectures. The family of platinum(II) architectures were characterized using 1 H nuclear magnetic resonance (NMR) and diffusion ordered spectroscopy (DOSY), electrospray ionization mass spectrometry (ESI-MS) and the molecular structures of two cages were determined by X-ray crystallography.

Mass spectrometry (MS) is an analytical technique for molecule identification that can be used for investigating protein-metal complex interactions. Once the MS data is collected, the mass spectra are usually interpreted manually to identify the adducts formed as a result of the interactions between proteins and metal-based species. However, with increasing resolution, dataset size, and species complexity, the time required to identify adducts and the error-prone nature of manual assignment have become limiting factors in MS analysis. AdductHunter is a open-source web-based analysis tool that  automates the peak identification process using constraint integer optimization to find feasible combinations of protein and fragments, and dynamic time warping to calculate the dissimilarity between the theoretical isotope pattern of a species and its experimental isotope peak distribution. Empirical evaluation on a collection of 22 unique MS datasetsshows fast and accurate identification of protein-metal complex adducts in deconvoluted mass spectra., (© 2024. The Author(s).)