Hexanuclear Ln6L6 Complex Formation by using an Unsymmetric Ligand

Multinuclear, self‐assembled lanthanide complexes present clear opportunities as sensors and imaging agents. Despite the widely acknowledged potential of this class of supramolecule, synthetic and characterization challenges continue to limit systematic studies into their self‐assembly restricting the number and variety of lanthanide architectures reported relative to their transition metal counterparts. Here we present the first study evaluating the effect of ligand backbone symmetry on multinuclear lanthanide complex self‐assembly. Replacement of a symmetric ethylene linker with an unsymmetric amide at the centre of a homoditopic ligand governs formation of an unusual Ln6L6 complex with coordinatively unsaturated metal centres. The choice of triflate as a counterion, and the effect of ionic radii are shown to be critical for formation of the Ln6L6 complex. The atypical Ln6L6 architecture is characterized using a combination of mass spectrometry, luminescence, DOSY NMR and EPR spectroscopy measurements. Luminescence experiments support clear differences between comparable Eu6L6 and Eu2L3 complexes, with relatively short luminescent lifetimes and low quantum yields observed for the Eu6L6 structure indicative of non‐radiative decay processes. Synthesis of the Gd6L6analogue allows three distinct Gd···Gd distance measurements to be extracted using homo‐RIDME EPR experiments

Mutual stabilisation between M II 4 L 6 tetrahedra and M II X 4 2− metallate guests

A series of [MIIX4]2− ⊂ MII4L6 host–guest complexes are formed through the mutual stabilisation of the host and guest complexes; neither the host nor guest is stable in the absence of the other.</p

Repair shielding of platinum-DNA lesions in testicular germ cell tumors by high-mobility group box protein 4 imparts cisplatin hypersensitivity

Cisplatin is the most commonly used anticancer drug for the treatment of testicular germ cell tumors (TGCTs). The hypersensitivity of TGCTs to cisplatin is a subject of widespread interest. Here, we show that high-mobility group box protein 4 (HMGB4), a protein preferentially expressed in testes, uniquely blocks excision repair of cisplatin-DNA adducts, 1,2-intrastrand cross-links, to potentiate the sensitivity of TGCTs to cisplatin therapy. We used CRISPR/Cas9-mediated gene editing to knockout the HMGB4 gene in a testicular human embryonic carcinoma and examined cellular responses. We find that loss of HMGB4 elicits resistance to cisplatin as evidenced by cell proliferation and apoptosis assays. We demonstrate that HMGB4 specifically inhibits repair of the major cisplatin-DNA adducts in TGCT cells by using the human TGCT excision repair system. Our findings also reveal characteristic HMGB4-dependent differences in cell cycle progression following cisplatin treatment. Collectively, these data provide convincing evidence that HMGB4 plays a major role in sensitizing TGCTs to cisplatin, consistent with shielding of platinum-DNA adducts from excision repair

Repair shielding of platinum-DNA lesions in testicular germ cell tumors by high-mobility group box protein 4 imparts cisplatin hypersensitivity

Cisplatin is the most commonly used anticancer drug for the treatment of testicular germ cell tumors (TGCTs). The hypersensitivity of TGCTs to cisplatin is a subject of widespread interest. Here, we show that high-mobility group box protein 4 (HMGB4), a protein preferentially expressed in testes, uniquely blocks excision repair of cisplatin-DNA adducts, 1,2-intrastrand cross-links, to potentiate the sensitivity of TGCTs to cisplatin therapy. We used CRISPR/Cas9-mediated gene editing to knockout the HMGB4 gene in a testicular human embryonic carcinoma and examined cellular responses. We find that loss of HMGB4 elicits resistance to cisplatin as evidenced by cell proliferation and apoptosis assays. We demonstrate that HMGB4 specifically inhibits repair of the major cisplatin-DNA adducts in TGCT cells by using the human TGCT excision repair system. Our findings also reveal characteristic HMGB4-dependent differences in cell cycle progression following cisplatin treatment. Collectively, these data provide convincing evidence that HMGB4 plays a major role in sensitizing TGCTs to cisplatin, consistent with shielding of platinum-DNA adducts from excision repair.National Cancer Institute (U.S.) (Grant CA034992

Design of lanthanide based metal-organic polyhedral cages for application in catalysis, sensing, separation and magnetism

Lanthanide organic polyhedral cage complexes are a class of supramolecular compounds that present exciting opportunities in applications ranging from sensing to catalysis and magnetism. Metal organic polyhedra incorporating transition metal vertices bridged by organic ligands have been extensively studied. By contrast analogous lanthanide complexes, which present additional benefits beyond those of their transition metal counterparts, remain an underrepresented class of supramolecule. One unique property of lanthanide organic cages is the luminescence properties bestowed by the metal ions which offer interesting opportunities in imaging applications, whilst the large ionic radii of the trivalent ions enables the formation of novel structures with opportunities to incorporate ancillary ligands not possible for transition metal structures. This review summarizes the key developments in synthesis and characterization of lanthanide metal organic cages, allowing general structural trends to emerge and highlights the exciting applications already demonstrated for these complexes

Nucleotide Binding Preference of the Monofunctional Platinum Anticancer-Agent Phenanthriplatin

The monofunctional platinum anticancer agent phenanthriplatin generates covalent adducts with the purine bases guanine and adenine. Preferential nucleotide binding was investigated by using a polymerase stop assay and linear DNA amplification with a 163-base pair DNA double helix. Similarly to cisplatin, phenanthriplatin forms the majority of adducts at guanosine residues, but significant differences in both the number and position of platination sites emerge when comparing results for the two complexes. Notably, the monofunctional complex generates a greater number of polymerase-halting lesions at adenosine residues than does cisplatin. Studies with 9-methyladenine reveal that, under abiological conditions, phenanthriplatin binds to the N1 or N7 position of 9-methyladenine in approximately equimolar amounts. By contrast, comparable reactions with 9-methylguanine afforded only the N7-bound species. Both of the 9-methyladenine linkage isomers (N1 and N7) exist as two diastereomeric species, arising from hindered rotation of the aromatic ligands about their respective platinum–nitrogen bonds. Eyring analysis of rate constants extracted from variable-temperature NMR spectroscopic data revealed that the activation energies for ligand rotation in the N1-bound platinum complex and the N7-linkage isomers are comparable. Finally, a kinetic analysis indicated that phenanthriplatin reacts more rapidly, by a factor of eight, with 9-methylguanine than with 9-methyladenine, suggesting that the distribution of lesions formed on double-stranded DNA is kinetically controlled. In addition, implications for the potent anticancer activity of phenanthriplatin are discussed herein.National Cancer Institute (U.S.) (NCI. Grant Number: CA034992