A ratiometric substrate for rapid evaluation of transfer hydrogenation efficiency in solution.

A cyclometalated iridium(III) complex bearing a self-immolative quinolinium moiety was developed as a ratiometric substrate for transfer hydrogenation studies. This photoluminescent probe allowed the rapid screening of a variety of Ir catalysts using a microplate reader, offering a convenient method to assess activity using a minimum amount of catalyst sample.

Lewis acid-driven self-assembly of diiridium macrocyclic catalysts imparts substrate selectivity and glutathione tolerance.

Molecular inorganic catalysts (MICs) tend to have solvent-exposed metal centers that lack substrate specificity and are easily inhibited by biological nucleophiles. Unfortunately, these limitations exclude many MICs from being considered for in vivo applications. To overcome this challenge, a strategy to spatially confine MICs using Lewis acid-driven self-assembly is presented. It was shown that in the presence of external cations (e.g., Li+, Na+, K+, or Cs+) or phosphate buffered saline, diiridium macrocycles spontaneously formed supramolecular iridium-cation species, which were characterized by X-ray crystallography and dynamic light scattering. These nanoassemblies selectively reduced sterically unhindered C[double bond, length as m-dash]O groups via transfer hydrogenation and tolerated up to 1 mM of glutathione. In contrast, when non-coordinating tetraalkylammonium cations were used, the diiridium catalysts were unable to form higher-ordered structures and discriminate between different aldehyde substrates. This work suggests that in situ coordination self-assembly could be a versatile approach to enable or enhance the integration of MICs with biological hosts.

Fumarate hydratase functions as a tumor suppressor in endometrial cancer by inactivating EGFR signaling.

Fumarase hydratase (FH) is an enzyme that catalyzes the reversible hydration and dehydration of fumarate to malate in the tricarboxylic acid cycle. The present study addressed the role of FH in endometrial cancer and clinically observed that the expression of FH was significantly lower in endometrial cancer tissues compared with normal endometrial tissues and, furthermore, that the decreased FH expression in endometrial cancer tissues was significantly associated with increased tumor size and lymph node metastasis. Further analysis in in vitro study showed that cell proliferation, migration and invasion abilities were increased when the expression of FH in the endometrial cancer cells was knocked down, but, by contrast, overexpression of FH in endometrial cancer cells decreased cell proliferative, migratory and invasive abilities. Mechanistic studies showed that the expression of vimentin and twist, being two well-studied mesenchymal markers in endometrial cancer cells, were upregulated in fumarate hydratase-knockdowned cells. In addition, phosphokinase array analysis demonstrated that the expression of phospho-EGFR (Y1086), which promotes carcinogenesis in cancers, was increased in endometrial cancer cells when FH was knocked down. In conclusion, the present study suggested that FH is a tumor suppressor and inhibits endometrial cancer cell proliferation and metastasis by inactivation of EGFR. Further studies are required to clarify its role as a prognostic biomarker and therapeutic target for endometrial cancer.

IL17RB expression is associated with malignant cancer behaviors and poor prognosis in oral cancer.

OBJECTIVES: Previously, we demonstrated that IL17RB plays an essential role in lung cancer progression. This study aimed to determine whether IL17RB correlates with oral cancer and promotes oral cancer progression. SUBJECTS AND METHODS: IL17RB expression in oral cancer tissues and normal tissues was determined by immunohistochemistry staining, while the association of IL17RB expression with the clinicopathological characteristics of oral squamous cell carcinoma (OSCC) patients was analyzed and its correlation with progression-free survival and response to radiotherapy and chemotherapy in OSCC patients was also explored. Western blotting was performed to investigate the expression of IL17RB in various OSCC cell lines; moreover, transwell assay was performed to evaluate the effect of IL17RB expression on cell migration ability. RESULTS: In this study, we found that IL17RB was expressed higher in OSCC tissues compared to normal oral mucosa tissues and its expression was positively correlated with tumor size, lymph node metastasis, advanced cancer stage, and poor prognosis. In vitro study showed that IL17RB expression in OSCC cell lines as determined by Western blotting, was positively correlated with their migration ability. CONCLUSION: Clinical and in vitro studies suggest that IL17RB might serve as an independent risk factor and a therapeutic target for oral cancer.

IL-1RA promotes oral squamous cell carcinoma malignancy through mitochondrial metabolism-mediated EGFR/JNK/SOX2 pathway.

BACKGROUND: Interleukin-1 receptor antagonist (IL-1RA), a member of the IL-1 family, has diverse roles in cancer development. However, the role of IL-1RA in oral squamous cell carcinoma (OSCC), in particular the underlying mechanisms, remains to be elucidated. METHODS: Tumor tissues from OSCC patients were assessed for protein expression by immunohistochemistry. Patient survival was evaluated by Kaplan-Meier curve analysis. Impact of differential IL-1RA expression on cultured OSCC cell lines was assessed in vitro by clonogenic survival, tumorsphere formation, soft agar colony formation, and transwell cell migration and invasion assays. Oxygen consumption rate was measured by Seahorse analyzer or multi-mode plate reader. PCR array was applied to screen human cancer stem cell-related genes, proteome array for phosphorylation status of kinases, and Western blot for protein expression in cultured cells. In vivo tumor growth was investigated by orthotopic xenograft in mice, and protein expression in xenograft tumors assessed by immunohistochemistry. RESULTS: Clinical analysis revealed that elevated IL-1RA expression in OSCC tumor tissues was associated with increased tumor size and cancer stage, and reduced survival in the patient group receiving adjuvant radiotherapy compared to the patient group without adjuvant radiotherapy. In vitro data supported these observations, showing that overexpression of IL-1RA increased OSCC cell growth, migration/invasion abilities, and resistance to ionizing radiation, whereas knockdown of IL-1RA had largely the opposite effects. Additionally, we identified that EGFR/JNK activation and SOX2 expression were modulated by differential IL-1RA expression downstream of mitochondrial metabolism, with application of mitochondrial complex inhibitors suppressing these pathways. Furthermore, in vivo data revealed that treatment with cisplatin or metformin-a mitochondrial complex inhibitor and conventional therapy for type 2 diabetes-reduced IL-1RA-associated xenograft tumor growth as well as EGFR/JNK activation and SOX2 expression. This inhibitory effect was further augmented by combination treatment with cisplatin and metformin. CONCLUSIONS: The current study suggests that IL-1RA promoted OSCC malignancy through mitochondrial metabolism-mediated EGFR/JNK activation and SOX2 expression. Inhibition of this mitochondrial metabolic pathway may present a potential therapeutic strategy in OSCC.

Chemo-, Stereo- and Regioselective Fluoroallylation/Annulation of Hydrazones with gem-Difluorocyclopropanes via Tunable Palladium/NHC Catalysis.

Defluorinative manipulation of polyfluorinated molecules has shown great promise due to its granting of synthetic versatility to inert C-F bonds. The development of chemo-, stereo- and regioselective strategies to realize highly efficient formation of either the linear/branched or E/Z products from gem-difluorocyclopropanes (gem-F2 CPs) is a challenging task. Herein, we have realized palladium/NHC-catalyzed fluoroallylation/annulation of hydrazones with gem-F2 CPs that incorporate the hydrazone N2 moiety into the products. The thermodynamically unstable fluorinated E-allylation products with aryl ketone hydrazones were obtained for the first time, while the di-alkyl ketone hydrazones yielded the monofluorinated products with branched selectivity under similar reaction conditions. With aldehyde hydrazones, two kinds of pyrazoles were obtained via a defluorinative allylation/annulation cascade, in which different carbon atoms of gem-F2 CPs could be incorporated into the pyrazole rings regiospecifically. DFT calculations revealed that the divergent selectivity was kinetically controlled and the final C-C bond formation proceeded through a 7-membered TS.

Taming glutathione potentiates metallodrug action.

Metallodrugs that are redox sensitive or have labile coordination sites are particularly susceptible to inhibition by glutathione (GSH) and other endogenous thiols. Because GSH is an essential antioxidant, strategies to prevent thiol deactivation must consider their potential effects on normal cellular functions. In this short review, we describe general approaches for taming glutathione in metallodrug therapy and discuss their strengths and limitations. We also offer our perspectives on developing practical solutions that are effective and clinically relevant.

Customizing Polymers by Controlling Cation Switching Dynamics in Non-Living Polymerization.

Controlling the chain growth process in non-living polymerization reactions is difficult because chain termination typically occurs faster than the time it takes to apply an external trigger. To overcome this limitation, we have developed a strategy to regulate non-living polymerizations by exploiting the chemical equilibria between a metal catalyst and secondary metal cations. We have prepared two nickel phenoxyphosphine-polyethylene glycol variants, one with 2-methoxyphenyl (Ni1) and another with 2,6-dimethoxyphenyl (Ni2) phosphine substituents. Ethylene polymerization studies using these complexes in the presence of alkali salts revealed that chain growth is strongly dependent on electronic effects, whereas chain termination is dependent on both steric and electronic effects. By adjusting the solvent polarity, we can favor polymerizations via non-switching or dynamic switching modes. For example, in a 100:0.2 mixture of toluene/diethyl ether, reactions of Ni1 and both Li+ and Na+ cations in the presence of ethylene yielded bimodal polymers with different relative fractions depending on the Li+/Na+ ratio used. In a 98:2 mixture of toluene/diethyl ether, reactions of Ni2 and Cs+ in the presence of ethylene generated monomodal polyethylene with dispersity <2.0 and increasing molecular weight as the amount of Cs+ added increased. Solution studies by NMR spectroscopy showed that cation exchange between the nickel complexes and alkali cations in 98:2 toluene/diethyl ether is fast on the NMR time scale, which supports our proposed dynamic switching mechanism.

Fluorescent half-sandwich iridium picolinamidate complexes for in-cell visualization.

In this work, we report on the development of fluorescent half-sandwich iridium complexes using a fluorophore attachment strategy. These constructs consist of pentamethylcyclopentadienyl (Cp*) iridium units ligated by picolinamidate donors conjugated to green-emitting boron-dipyrromethene (bodipy) dyes. Reaction studies in H2O/THF mixtures showed that the fluorescent Ir complexes were active as catalysts for transfer hydrogenation, with activities similar to that of their non-fluorescent counterparts. The iridium complexes were taken up by NIH-3T3 mouse fibroblast cells, with 50% inhibition concentrations ranging from ~20-70 µM after exposure for 3 h. Visualization of the bodipy-functionalized Ir complexes in cells using fluorescence microscopy revealed that they were localized in the mitochondria and lysosome but not the nucleus. These results indicate that our fluorescent iridium complexes could be useful for future biological studies requiring intracellular catalyst tracking.

A Cerium-Containing Metal-Organic Framework: Synthesis and Heterogeneous Catalytic Activity toward Fenton-Like Reactions.

A cerium-based metal-organic framework, namely MOF-589, was synthesized using benzoimidephenanthroline tetracarboxylic acid (H4 BIPA-TC) as an organic linker. Full characterization including single-crystal and powder X-ray diffraction analysis, thermogravimetrical analysis, scanning electron microscopy, and N2 adsorption measurements at low pressure and 77 K were carried out. The material was employed as an efficient heterogeneous catalyst for decomposition of methylene blue (MB) dye (40 ppm) in the presence of H2 O2 in 15 minutes. Interestingly, comparison studies showed that the activity of MOF 589 was higher than that of other iron-based heterogeneous and cerium-based catalysts. Further experiments to clarify the MOF 589 activity indicated that the BIPA-TC linker might have an important impact through a cooperative effect on the metal cluster. Control studies confirmed that the presence of catalyst was necessary for the reaction to occur and the catalyst recyclability. In particular, catalysis from leached cerium in the reaction filtrate is unlikely and the solid material could be reused at least eight times without a remarkable loss in activity.

Minimum energy surface required by quantum memory devices.

We address the question of what physical resources are required and sufficient to store classical information. While there is no lower bound on the required energy or space to store information, we find that there is a nonzero lower bound for the product P = of these two resources. Specifically, we prove that any physical system of mass m and d degrees of freedom that stores S bits of information will have a lower bound on the product P that is proportional to d2/m(exp(S/d) - 1)2. This result is obtained in a nonrelativistic, quantum mechanical setting, and it is independent of earlier thermodynamical results such as the Bekenstein bound on the entropy of black holes.