Synthesis, oxygen activation, and DNA-cleaving property of a histidine-pyridine-histidine ligand

A novel metal-chelating system comprising a 4-dimethylamino-　pyridine and two histidine appendages was synthesized. The two histidines were introduced by different manners; one through an amide linkage and other via a secondary amino linkage. ESR spectrum suggested a distorted pentacoordinate configuration of the copper complex of the ligand. The iron complex of the ligand had oxygen-activating property as shown by ESR spin trapping and DNA-cleaving activity as evaluated by experiments using pUC19 DNA

The neutrophil-to-lymphocyte ratio as a novel independent prognostic factor for multiple metastatic lung tumors from various sarcomas

Purpose Sarcomas are among the most refractory malignant tumors and often recur as pulmonary metastasis. Although the presence of a high neutrophil-to-lymphocyte ratio (NLR) has been associated with the prognosis of several malignancies, the relationship between the NLR and sarcoma with pulmonary metastasis is unclear. We investigated the impact of the NLR in patients who underwent surgical resection for metastatic lung tumors from various sarcomas. Methods The subjects of this retrospective study were 158 patients with metastatic lung tumors from various sarcomas, who underwent initial pulmonary metastasectomy between 2006 and 2015. We examined the clinicopathological variables, including the NLR and the characteristics of surgical procedures. Survival was estimated by the Kaplan–Meier method and prognostic factors were evaluated by multivariate analysis. Results Multivariate analysis revealed significantly better survival of the group with an NLR  2 years, and 3 or more pulmonary metastasectomies. Conclusion The NLR immediately before the most recent pulmonary metastasectomy is a novel independent prognostic factor, which may be helpful when considering repeated pulmonary metastasectomy

(5-Fluoro-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-1-ido-κN1)(1,4,8,11-tetraazacyclotetradecane-κ4N)zinc(II) perchlorate

In the structure of the title complex, [Zn(C4H2FN2O2)(C10H24N4)]ClO4, the zinc(II) ion forms coordination bonds with the four nitrogen atoms of cyclam (1,4,8,11-tetraazacyclotetradecane or [14]aneN4) as well as with the nitrogen atom of a deprotonated 5-fluorouracil ion (FU−). Cyclam adopts a trans-I type conformation within this structure. The coordination structure of the zinc(II) ion is a square pyramid with a distorted base plane formed by the four nitrogen atoms of the cyclam. FU− engages in intermolecular hydrogen bonding with neighboring FU− molecules and with the cyclam molecule

Sulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-β-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance

Carbapenem antibiotics are the last resort for control of severe infectious diseases, bloodstream infections, and pneumonia caused by Gram-negative bacteria, including Enterobacteriaceae. However, carbapenem-resistant Enterobacteriaceae (CRE) strains have spread globally and are a critical concern in clinical settings because CRE infections are recognized as a leading cause of increased mortality among hospitalized patients. Most CRE produce certain kinds of serine carbapenemases (e.g., KPC- and GES-type β-lactamases) or metallo-β-lactamases (MBLs), which can hydrolyze carbapenems. Although effective MBL inhibitors are expected to restore carbapenem efficacy against MBL-producing CRE, no MBL inhibitor is currently clinically available. Here, we synthesized 2,5-diethyl-1-methyl-4-sulfamoylpyrrole-3-carboxylic acid (SPC), which is a potent inhibitor of MBLs. SPC is a remarkable lead compound for clinically useful MBL inhibitors and can potentially provide a considerable benefit to patients receiving treatment for lethal infectious diseases caused by MBL-producing CRE.Production of metallo-β-lactamases (MBLs), which hydrolyze carbapenems, is a cause of carbapenem resistance in Enterobacteriaceae. Development of effective inhibitors for MBLs is one approach to restore carbapenem efficacy in carbapenem-resistant Enterobacteriaceae (CRE). We report here that sulfamoyl heteroarylcarboxylic acids (SHCs) can competitively inhibit the globally spreading and clinically relevant MBLs (i.e., IMP-, NDM-, and VIM-type MBLs) at nanomolar to micromolar orders of magnitude. Addition of SHCs restored meropenem efficacy against 17/19 IMP-type and 7/14 NDM-type MBL-producing Enterobacteriaceae to satisfactory clinical levels. SHCs were also effective against IMP-type MBL-producing Acinetobacter spp. and engineered Escherichia coli strains overproducing individual minor MBLs (i.e., TMB-2, SPM-1, DIM-1, SIM-1, and KHM-1). However, SHCs were less effective against MBL-producing Pseudomonas aeruginosa. Combination therapy with meropenem and SHCs successfully cured mice infected with IMP-1-producing E. coli and dually NDM-1/VIM-1-producing Klebsiella pneumoniae clinical isolates. X-ray crystallographic analyses revealed the inhibition mode of SHCs against MBLs; the sulfamoyl group of SHCs coordinated to two zinc ions, and the carboxylate group coordinated to one zinc ion and bound to positively charged amino acids Lys224/Arg228 conserved in MBLs. Preclinical testing revealed that the SHCs showed low toxicity in cell lines and mice and high stability in human liver microsomes. Our results indicate that SHCs are promising lead compounds for inhibitors of MBLs to combat MBL-producing CRE

An ultrasensitive and highly selective determination method for quinones by high-performance liquid chromatography with photochemically initiated luminol chemiluminescence.

Quinones are a class of compounds of substantial toxicological and pharmacological interest. An ultrasensitive and highly selective chemiluminescence (CL) method was newly developed for the determination of quinones based on the utility of photochemically initiated luminol CL. The method involved ultraviolet (UV) irradiation of quinones to generate reactive oxygen species (ROS) through the unique photosensitization reaction accompanied with the photolytical generation of 3,6-dihydroxyphthalic acid (DHPA) from quinones. The photoproducts were detected by luminol CL reaction. Interestingly, it was noticed that DHPA had enhancement effect for the luminol CL. The generation of the enhancer (DHPA) in association with the oxidant (ROS) in the photochemical reaction greatly increases the sensitivity and selectivity of the proposed luminol CL method. In order to elucidate the type of ROS produced by the photosensitizaion reaction in relation to the proposed CL reaction, we investigated the quenching effect of selective ROS scavengers in the luminol CL. Although several ROS were generated, superoxide anion was the most effective ROS for the generated CL. Moreover, the enhancement mechanism of DHPA for luminol CL was confirmed. The enhancement was found to be through the formation of stabilized semiquinone anion radical that provided long-lived CL. The generation of the semiquinone radical was confirmed by electron spin resonance technique. Furthermore, we developed an HPLC method with on-line photochemical reaction followed by the proposed CL detection for the determination of four quinones. A luminol analogue, L-012, was used for its high sensitivity. The detection limits for quinones obtained with the proposed method (S/N=3) were in the range 1.5-24 fmol that were 10-1000 times more sensitive compared with the previous methods. Finally, the developed HPLC-CL system was successfully applied for the determination of quinones in airborne particulate samples collected at Nagasaki city

Aqua{μ-1,4-bis[(1,4,7,10-tetraazacyclododecan-1-yl)methyl]benzene}(nitrato-κO)dicopper(II) tris(nitrate) trihydrate

In the title dinuclear CuII complex, [Cu2(NO3)(C24H46N8)(H2O)](NO3)3·3H2O, the two CuII molecules both have a square-pyramidal geometry, but the ligands in the axial positions are different: a water molecule and a nitrate ion. All nitrate ions, water molecules, and N—H groups are involved in an intermolecular hydrogen-bond network

Structure of AmpC β-lactamase (AmpCD) from an Escherichia coli clinical isolate with a tripeptide deletion (Gly286-Ser287-Asp288) in the H10 helix

The structure of AmpC β-lactamase (AmpCD) from E. coli with a tripeptide deletion (Gly286-Ser287-Asp288) is reported