Search

A reaction of [Cp*IrCl2]2 {Cp* = η5-C5(CH3)5} and 2-mercaptobenzimidazole (H2bimt) in methanol in a 1:2 molar ratio gave a yellow complex of [Cp*IrCl2(H2bimt)]·CH3OH (1). In compound 1 the H2bimt acts as a monodentately S-donating (κS) ligand. A similar reaction of [Cp*IrCl2]2 and H2bimt in the presence of NaOCH3 (molar ratio of 1:2:2) gave an orange product (2) on addition of excess amount of NH4PF6. Compound 2 was composed of an unsymmetrical dinuclear complex cation, [(Cp*IrCl)2(μ-Hbimt)(μ-H2bimt)]+, a PF6− anion, and water molecules of crystallization. In the complex cation, H2bimt bridges two IrIII centers by S atom in the μ-κS:κS mode, while the monodeprotonated Hbimt− ligand bridges via S and N atoms in the μ-κS:κN1 mode.

Click chemistry is a popular approach to the synthesis of functionalized molecules, and emphasizes the use of practical and reliable reactions. Copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC), which selectively produces anti(1,4)-triazoles in preference to the syn isomer (1,5-triazole), is regarded as a superlative example of click chemistry. The CuAAC reaction can be accelerated by Cu-stabilizing ligands, such as tris[(1-substituted-1H-1,2,3-triazol-4-yl)methyl]amines and tris(2-benzimidazolylmethyl)amines. The catalytic system has received a great deal of use in various fields such as chemical biology and materials science. The 1,3-dipolar cycloaddition of azides with unactivated alkynes occurs much more slowly but is highly chemoselective. This property stimulated the development of “in situ click chemistry” for the field of drug discovery, in which target enzymes are allowed to assemble new inhibitors by linking azides and alkynes that bind to adjacent sites on the protein surface. The linkage reaction does not employ Cu catalysis, but instead relies on acceleration of the otherwise sluggish [3+2] cycloaddition reaction when the reaction partners are held in proximity to each other, often in or near the enzyme active site. In the course of an in situ click chemistry study on histone deacetylase (HDAC), we unexpectedly observed acceleration of the AAC reaction by trace copper associated with the protein in a structurally sensitive manner. Herein we report these findings, which constitute the first example of a Cu-protein complex catalyzing the AAC reaction. HDAC inhibitors are attractive drug candidates for cancer, inflammation, and neurodegenerative disorders. As shown in Figure 1, most HDAC inhibitors consist of a

Mononuclear [Fe(H2LR)2]X2 (R = H, 2-Me, 5-Me, 2-Et-5-Me; X = ClO4, BF4) and dinuclear [Fe2(H2LR)3]X4 complexes containing imidazole-4-carbaldehyde azine (H2LH) and its derivatives prepared by condensation of 4-formylimidazole, 2-methyl- or 5-methyl-4-formylimidazole, or 2-ethyl-4-methyl-5-formylimidazole, with hydrazine in a 2:1 mole ratio in methanol, were prepared and their magnetostructural relationships were studied. In the mononuclear complexes, H2LR acts as an unsymmetrical tridentate ligand with two imidazole nitrogen atoms and one azine nitrogen atom, while in the dinuclear complexes, H2LR acts as a dinucleating ligand employing four nitrogen atoms to form a triple helicate structure. At room temperature, [Fe2(H2LH)3](ClO4)4 and [Fe2(H2L2-Me)3](ClO4)4 were in the high-spin (HS) and low-spin (LS) states, respectively. The results are in accordance with the ligand field strength of H2L2-Me with electron-donating methyl groups being stronger than H2LH, with the order of the ligand field strengths being H2L2-Me > H2LH. However, in the mononuclear [Fe(H2LH)2](ClO4)2 and [Fe(H2L2-Me)2](ClO4)2 complexes, a different order of ligand field strengths, H2LH > H2L2-Me, was observed because [Fe(H2LH)2](ClO4)2 was in the LS state while [Fe(H2L2-Me)2](ClO4)2 was in the HS state at room temperature. X-ray structural studies revealed that the interligand steric repulsion between a methyl group of an H2L2-Me ligand and the other ligand in [Fe(H2L2-Me)2](ClO4)2 is responsible for the observed change in the spin state. The same is true for [Fe(H2L2-Et-5-Me)2](ClO4)2, while [Fe(H2L5-Me)2](ClO4)2 does not involve such a steric congestion and stays in the LS state over the temperature range 5–300 K. Two kinds of crystals (polymorphs) were isolated for [Fe2(H2LH)3](BF4)4 and [Fe2(H2L2-Et-5-Me)3](ClO4)4, and they exhibited different magnetic behaviors.

Background: Glioblastoma (GBM) is associated with poor survival (1 year-34.6% and 5 year-4.75%) and affects approximately 13,000 patients per year. Standard treatment consists of surgical resection, external beam radiation therapy, adjuvant chemotherapy with temozolomide and tumor treating fields. Nonetheless, despite a heavy investment in therapy, all patients eventually succumb to their disease. Hypoxic regions are common in GBM and are implicated in maintenance of glioma stem cells (GSCs), promoting angiogenesis and therapeutic resistance. Recently, we and others have shown that lysine-specific histone demethylase 1A (KDM1A) is overexpressed in GBM and GSCs. However, the role of KDM1A and its functions in hypoxic response remains unknown. The objective of this study is to elucidate the functional role of KDM1A in hypoxia and test the efficacy of novel KDM1A inhibitors on hypoxia-mediated functions in GBM. Methods: The expression of KDM1A following hypoxia induction was determined in vitro by Western blotting and qRT-PCR. The expression of KDM1A in GBM tissue was examined by immunohistochemistry (IHC). KDM1A knockout cells were generated using CRISPR/Cas9 system and knockdown cells were generated using KDM1A shRNA lentiviral particles. The effect of KDM1A knockdown or treatment with KDM1A inhibitors NCL-1 and NCD-38 on stemness and self-renewal of primary patient-derived GBM cells was examined using neurosphere formation and extreme limiting dilution assays. Interaction of KDM1A with hypoxia inducible factor 1α (HIF-1α) was examined by immunoprecipitation (IP). The role of KDM1A on HIF target genes was determined using qRT-PCR and HRE-reporter activity. Mouse orthotopic xenografts models were used for preclinical evaluation of KDM1A inhibitors. Results: Western blot analysis revealed that KDM1A expression is induced in primary GBM cells following hypoxia. IHC analysis demonstrated elevated expression of KDM1A in hypoxic regions in human GBM tissues as well as mouse GBM xenografts. IP analysis demonstrated that KDM1A interacts with HIF-1α. Cell viability assays revealed that NCD-38 is more potent in reducing the cell viability of primary GBM cells compared to other KDM1A inhibitors. KDM1A knockdown or KDM1A inhibitor treatment significantly reduced the HIF- target gene expression including VEGF, PGK, CAIX, and HRE-Luc reporter activity in GBM cells. Further, hypoxia mediated cell proliferation and self-renewal ability of GSCs was compromised in KDM1A knockdown and KDM1A inhibitor-treated cells. Further, knockdown of KDM1A or treatment with KDM1A inhibitor significantly reduced the in vivo tumor growth and improved survival in orthotopic models. Conclusions: Our results demonstrate that KDM1A plays a critical role in hypoxia response and inhibition of KDM1A is a novel therapeutic approach for the treatment of GBM. Citation Format: Gangadhara R. Sareddy, Suryavathi Viswanadhapalli, Mei Zhou, Yiliao Luo, Xiaonan Li, Jinyou Liu, Aleksandra Gruslova, Takayoshi Suzuki, Andrew Brenner. The lysine demethylase KDM1A inhibition attenuates hypoxic responses in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2422.

Background: Triple-negative breast cancer (TNBC) lacks targeted therapy, exhibits an aggressive clinical course and contributes to a disproportional share of the overall mortality from breast cancer. TNBC is characterized by significant heterogeneity, a high proportion of cancer stem cells (CSCs), and resistance to conventional therapies. CSCs are highly tumorigenic, spared by chemotherapy, sustain the tumor growth and enhance the tumor recurrence after conventional therapies. Therefore, eradication of CSCs is critical for the development of efficient therapeutic strategies for TNBC. The lysine-specific histone demethylase 1A (KDM1A) is highly expressed in TNBC and is essential for maintenance of CSCs. However, the role of KDM1A in CSC function remains unknown. The objective of this study is to examine the role of KDM1A in CSCs and test the utility of KDM1A inhibitors using in vivo models. Methods: We have generated KDM1A knockout cells using the CRISPR/Cas9 system and knockdown cells using KDM1A shRNA lentiviral particles. The effect of KDM1A inhibitors on the cell viability was examined by MTT assays. The effect of KDM1A knockdown and KDM1A inhibition using novel inhibitor NCD-38 on stemness and self-renewal of CSCs was examined using mammosphere formation and extreme limiting dilution assays. Global transcriptional changes modulated by KDM1A inhibition were examined by RNA-sequencing. Mechanistic studies were conducted using Western blot, RT-qPCR, and immunoprecipitation (IP) analysis. Mouse xenograft and patient-derived xenograft models were used for preclinical evaluation of the KDM1A inhibitor. Results: Western blot and RT-qPCR analysis demonstrated that KDM1A is highly expressed in CSCs compared to non-CSCs. Cell viability assays using various KDM1A inhibitors revealed that novel KDM1A inhibitor NCD-38 is highly potent in reducing cell viability of TNBC cells compared to other inhibitors. NCD-38 effectively reduced the cell viability of therapy-sensitive and therapy-resistant TNBC cells. Flow cytometry analysis revealed that KDM1A knockout or KDM1A inhibitor treatment reduced the CSC population on TNBC cells. Further, KDM1A inhibition reduced the cell proliferation, mammosphere formation and self-renewal ability of CSCs. RNA-seq analysis revealed that KDM1A inhibition modulated pathways that are involved in the stemness of TNBC. IP analysis and GST pulldown assays revealed that KDM1A interacts with TLX and KDM1A inhibition modulated TLX target genes. Knockout of KDM1A reduced the in vivo tumor growth in xenograft models and KDM1A inhibitor NCD-38 treatment significantly reduced the tumor growth in patient-derived xenograft (PDX) models. Conclusions: Our results establish KDM1A inhibitors as a novel class of drugs for treating TNBC and contribute to the development of a highly promising therapy that can significantly extend patient survival with minimal toxicity. Citation Format: Mei Zhou, Suryavathi Viswanadhapalli, Mengxing Li, Xiaonan Li, Takayoshi Suzuki, Rajeshwar R. Tekmal, Andrew Brenner, Ratna K. Vadlamudi, Gangadhara R. Sareddy. KDM1A inhibition is effective in reducing stemness and treating triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 146.

Water-soluble [60]fullerene (C 60 ) derivatives were synthesized to examine their bioactivities. PC12 cells were used as a model of nerve cells and the bioactivities of synthesized C 60 derivatives together with some reported ones were tested. Among the compounds tested, C 60 /(γ-CyD) 2 , C 60 -bis(γ-CyD) ( 5 ) containing C 60 -mono(γ-CyD) ( 5′ ), and C 60 /PVP were sufficiently soluble in water and showed an enhancing effect on the neurite outgrowth of NGF-treated PC12 cells.

To identify novel non-nucleoside DNA methyltransferase (DNMT) inhibitors, we designed and synthesized a series of maleimide derivatives. Among this series, compounds 5-8 were found to be more potent DNMT1 inhibitors than RG108, a DNMT1 inhibitor reported previously by Siedlecki et al. The binding mode analysis of compound 5 is also reported.

The "solvent effect" on the solid-state luminescence of a neutral complex, [Ru(dbb)(2)(CN)(2)] (dbb = 4,4'-di-tert-butyl-2,2'-bipyridine), was presented. The crystals of this complex showed a variety of luminescence color from orange to dark-red, depending on the acceptor number of the solvent included in the crystal as a solvent of crystallization. The luminescence change was very similar to the solvatochromism in solution, which was attributed to the local donor-acceptor interaction between the CN group and the solvent molecules. The dynamic shift observed in the transient emission spectrum of the crystalline powder was accounted for by the solvent molecule reorganization. X-ray crystallography of [Ru(dbb)(2)(CN)(2)].3(CH(3))(2)CO showed the complex molecule having an approximate C(2) symmetry and very weak interactions between the acetone molecules and the CN groups. A three-dimensional network constructed by acetone molecules was observed in the hydrophobic space consisting of t-butyl groups in dbb ligands. A thin film of the complex showed vapochromic behavior such that the luminescence changed depending on the solvent of crystallization. This suggests a capability for organic molecule discrimination using the complex in the solid state.

Hydrogen (H) behaviour in materials was investigated in rapidly solidified (RS) foils of pure aluminium (Al), Al-0.4 Cr and Al-0.25 Zr alloys (at %) by means of thermal desorption spectroscopy (TDS). In addition, Al-0.25; 0.3 Zr alloys were examined with respect to microstructure and its instability during the thermal process using SEM and microhardness measurements. The effect of dopes and heating rate on H desorption was summarized. The lowest energy desorption is attributed with significant thermal desorption peak which temperature was found is correlated with sample composition.

Nickel(II) complexes containing P―N-type bidentate hybrid ligands of 2-aminoethylphosphanes (RR'Pea; RR' = Ph 2 or MePh) or 8-quinolylphosphanes (RR'Pqn), namely [Ni(P―N) 2 ]-(BF 4 ) 2 [P―N = Ph 2 Pea (1), MePhPea (2), Ph 2 Pqn (3), or MePhPqn (4)] have been prepared, and their structural, spectroscopic, and electrochemical properties determined. The crystal structure analysis indicates that the 2-aminoethyl-phosphane complexes (1 and 2) have a square-planar coordination geometry around the Ni II center with a cis(P,P) configuration, whereas the 8-quinolylphosphane complexes (3 and 4) exhibit a severe tetrahedral distortion because of the steric repulsion between the ortho-H atoms in the mutually cis-positioned quinolyl rings. Complexes 1 and 2 maintain their diamagnetic square-planar four-coordinate structure on acetonitrile solution, whereas complexes 3 and 4 show paramagnetic behavior. Spectroscopic and electrochemical measurements suggest that the ligand-field strengths of these four P-N-type ligands increase in the order Ph 2 Pqn (3) < MePhPqn (4) < Ph 2 Pea (1) < MePhPea (2). The Ph 2 Pqn complex 3 is readily reduced by Zn powder to afford the corresponding nickel(I) complex [Ni(Ph 2 Pqn) 2 ]BF 4 (5). The crystal structure of complex 5 reveals that the Ni I ion adopts a distorted tetrahedral coordination geometry with slightly longer (= 0.05 A) Ni-P and Ni―N bond lengths than those in the corresponding Ni II complex 3.

Mononuclear [Fe(H2L2-Et-5-Me)2]2+ and dinuclear [Fe2(H2L2-Et-5-Me)3]4+ complexes, where H2L2-Et-5-Me denotes 2-ethyl-5-methylimidazole-4-carbaldehyde azine, were prepared and isolated as the perchl...

Objectives: Recent reports have shown significant associations between organopshophorus pesticide (OP) exposure and decreased sperm motility in workers and laboratory animals. However, the notion that OPs possess spermatotoxicity has yet to be established. The aim of this study was to clarify the effects of OP exposure on detailed sperm toxicity markers, i.e., motility, morphology and sperm adenine nucleotide contents, and the histopathology of the testis and epididymis. Methods: Ten-week-old Wistar rats were divided into 4 groups (n=10) and orally administered corn oil, dichlorvos (DDVP; 5, 10 mg/kg) or diazinon (DZN; 3 mg/kg) 6 days a week for 9 wk. Sperm motility and morphology markers were analyzed with a computer-assisted sperm analysis (CASA) system. Results: In addition to a significant decrease in acetylcholinesterase (AChE) activities and a significant increase in urinary OP metabolites, DDVP and DZN significantly reduced sperm motility, but they did not influence sperm adenine nucleotide contents. The OPs also significantly increased the percentage of broken sperm, and DDVP significantly increased the percentage of cytoplasmic droplets. Importantly, both OPs significantly increased cytoplasmic vacuolation and nuclear shrinkage in the epithelial cells of the ductus epididymis, whereas the testes did not show significant histopathological changes. Conclusions: The broken sperm and cytoplasmic droplets as well as reduced sperm motility were the relevant spermatotoxicity makers of DDVP and DZN. To our knowledge, this is the first report to suggest that the above-mentioned OP-induced spermatotoxicity is related to histopathological impairment of the caput epididymis.

Normalizing the critical resolved shear stress (CRSS) by the shear modulus G and the temperature by Gb 3 / k B ( b : the strength of the Burgers vector) in the temperature dependence of CRSS vs. the temperature plots for {1 1 0}〈1 1 0〉 slip in eleven NaCl type crystals reported previously, it is found that there exist two groups of NaCl type crystals for {1 1 0}〈1 1 0〉 slip, i.e., the high Peierls stress group with the normalized Peierls stress of 0.0014 ± 0.0002 and the low Peierls stress group with the normalized Peierls stress of 0.0004 ± 0.0001. The origin of the presence of the two groups for {1 1 0}〈1 1 0〉 slip has been discussed based on the possible slight splitting of the dislocation core. On the other hand, the normalized CRSS vs. the temperature plots for {0 0 1}〈1 1 0〉 slip in seven NaCl type crystals fall in a single zone. Kink pair energies for the dislocations of the two slip systems have been estimated based on the line tension approximation from the estimated Peierls stress and also from the critical temperature at which the steep temperature dependence of the CRSS vanishes. The reported activation energies of the Bordoni peak in NaCl type crystals have been compared with the above estimated kink pair energies.

Mononuclear [Fe(H(2)L(R))(2)](2+) and dinuclear [Fe(2)(H(2)L(R))(3)](4+) (R = H, 2-Me, 5-Me) complexes containing the new imidazole-4-carbaldehyde azine ligand (H(2)L(H)) and its derivatives (H(2)L(2-Me) and H(2)L(5-Me)) prepared from the condensation reaction of 4-formylimidazole or 2-methyl- or 5-methyl-4-formylimidazole with hydrazine (2:1) were prepared, and their magnetostructural relationships were studied. In the mononuclear complexes, H(2)L(R) acts as an unsymmetrical tridentate ligand with two imidazole nitrogen atoms and one azine nitrogen atom, while in the dinuclear complexes, H(2)L(R) acts as a dinucleating ligand employing four nitrogen atoms to form a triple helicate. At room temperature, [Fe(2)(H(2)L(H))(3)](ClO(4))(4) and [Fe(2)(H(2)L(2-Me))(3)](ClO(4))(4) were in the high-spin (HS) and low-spin (LS) states, respectively. The results are in accordance with the ligand field strength of H(2)L(2-Me) with electron-donating methyl groups being stronger than H(2)L(H), with the order of the ligand field strengths being H(2)L(2-Me)H(2)L(H). However, in the mononuclear [Fe(H(2)L(H))(2)](ClO(4))(2) and [Fe(H(2)L(2-Me))(2)](ClO(4))(2) complexes, a different order of ligand field strengths, H(2)L(H)H(2)L(2-Me), was observed because [Fe(H(2)L(H))(2)](ClO(4))(2) was in the LS state while [Fe(H(2)L(2-Me))(2)](ClO(4))(2) was in the HS state at room temperature. X-ray structural studies revealed that the interligand steric repulsion between a methyl group of an H(2)L(2-Me) ligand and the other ligand in [Fe(H(2)L(2-Me))(2)](ClO(4))(2) is responsible for the observed change in the spin state. Two kinds of crystals, needles and blocks, were isolated for [Fe(2)(H(2)L(H))(3)](BF(4))(4), and both exhibited a sharp spin transition, [LS-HS]--[HS-HS]. The spin transition of the block crystals is more abrupt with a hysteresis, T(c) upward arrow = 190 K and T(c) downward arrow = 183 K with DeltaT = 7 K.

To report wavy horizontal artifacts on optical coherence tomography (OCT) monitor images.Tokyo Dental College Suidobashi Hospital, Department of Ophthalmology, Tokyo, Japan.The line-scanning ophthalmoscopy images from an OCT device of eyes that had uneventful cataract extraction with implantation of a diffractive multifocal intraocular lens (IOL) were evaluated. The images were compared with those of eyes that had cataract surgery with implantation of a monofocal IOL.The study evaluated 38 eyes of 19 patients with a diffractive multifocal IOL and 29 eyes of 18 patients with a monofocal IOL. Wavy horizontal artifacts were seen in all eyes with a multifocal IOL but not in any image of eyes with a monofocal IOL (P.0001, Fisher exact probability test). The OCT images, fundoscopic photographs, and scanning-laser ophthalmoscopy images were unaffected by the multifocal IOLs.The aberrations in the images from line-scanning ophthalmoscopy may have been caused by the optical design of the diffractive multifocal IOLs.

Several (azido)iridium(III) complexes having a pentamethylcyclopentadienyl (Cp∗) group, [Cp∗Ir(N3)2(Ph2Ppy-κP)] (1: Ph2Ppy = 2-diphenylphosphinopyridine), [Cp∗Ir(N3)(Ph2Ppy-κP,κN)]CF3SO3 (2), [Cp∗Ir(N3)(dmpm)]PF6 (3: dmpm = bis(dimethylphosphino)methane), [Cp∗Ir(N3)(Ph2Pqn)]PF6 · CH3OH (4 · CH3OH: Ph2Pqn = 8-diphenylphosphinoquinoline), and [Cp∗Ir(N3)(pybim)] (5: Hpybim = 2-(2-pyridyl)benzimidazole) have been prepared and their crystal structures have been analyzed by X-ray diffraction. In complex 1, the Ph2Ppy ligand is only coordinated via the P atom (-κP), while in 2 it acts as a bidentate ligand through the P and N atoms (-κP,κN) to form a four-membered chelate ring. Comparing the structural parameters of the chelate ring in 2 with those of a similar five-membered chelate ring formed by Ph2Pqn in 4, it became apparent that the angular distortion in the Ph2Ppy-κP,κN ring was remarkable, although the Ir–P and Ir–N bonds in the Ph2Ppy-κP,κN ring were not elongated very much from the corresponding bonds in the Ph2Pqn-κP,κN ring. In the pybim complex 5, the five-membered chelate ring was coplanar with the pyridine and benzimidazolyl rings. With the related (azido)iridium(III) complexes analyzed previously, comparison of the structural parameters of the Ir–N3 moiety in [Cp∗IrIII(N3)(L–L′)]+/0 complexes reveals an anomalous feature of the 2,2′-bipyridyl (bpy) complex, [Cp∗Ir(N3)(bpy)]PF6.

A new type of small-molecular sirtuin inhibitor was designed on the basis of the proposed catalytic mechanism for deacetylation of acetylated lysine substrates by sirtuins. Among the compounds thus designed and synthesized, we found that 2k, which contains an ethoxycarbonyl group at the alpha position to the acetamide of acetylated lysine substrate analogue 1, showed potent inhibitory activity in an in vitro assay using recombinant SIRT1, with high selectivity over SIRT2 and SIRT3. Mechanistic study by means of kinetic analysis, mass spectroscopy, and computation indicated that the enol form of compound 2k nucleophilically attacks NAD(+) in the active site of SIRTs to afford the stable compound 2k-ADP-ribose conjugate 5, leading to inhibition of the enzyme activity. Compound 2k also caused a dose-dependent increase of p53 acetylation in human colon cancer HCT116 cells, indicating inhibition of SIRT1 in the cells. These results have implications for the development of selective sirtuin inhibitors by means of mechanism-based drug design.

Lanthanide complexes are of great importance for their prospective applications in wide range of science and technology. Chiral lanthanide complexes can constitute stereo-discriminating probes in biological media, owing to the luminescent properties of the rare-earth ions. Sensitized emission with narrow bandwidth, having fast radiation rate and high emission quantum efficiency are the main perspective for synthesizing the complexes. Attention has been given on remarkable chirality with high dissymmetry factors (g = Δeext/emax) of the complexes. For this purpose, beta-diketonato ligands with chiral BINAPO (1,1′-binapthyl phosphine oxide) ligand were chosen to achieve the goal. The complexes [Ln(TFN)3(S-BINAPO)](TFN = 4,4,4-trifluoro-1(2-napthyl)-1,3-butanedione), [Ln(HFT)3(S-BINAPO)] (HFT = 4,4,5,5,6,6,6-heptafluoro-1-(2-thienyl)-1,3-hexanedione) and [Ln(HFA)3(S-BINAPO)](hfa = hexafluoroacetylacetonate) (where Ln = Yb, Eu) were synthesized. The complex, [Eu(TFN)3(S-BINAPO)] gives strong red emission at 615 nm with narrow emission band (

A 78 year old man suffering from anaphylactoid purpura complained of abdominal pain and bloody stools. Combined therapy with Prednisolone and cyclophosphamide had been given against nephrotic syndrome caused by purpura nephritis. Severe abdominal pain with symptoms and signs of pan-peritonitis necessitated laparotomy. Rectosigmoid perforation due to necrotizing angiitis (phlebitis) was also demonstrated histologically. The patient died of septicemia 18 days after surgery. Perforation of the alimentary tract rarely occurs in anaphylactoid purpura. Twenty similar cases were briefly reviewed from the Japanese literature.

The success of viral and nonviral gene delivery relies on the ability of DNA-based vectors to traverse the cytoplasm and reach the nucleus. We, as well as other researchers, have shown that plasmids utilize the microtubule network and its associated motor proteins to traffic toward the nucleus. While disruption of microtubules with nocodazole was shown to greatly inhibit cytoplasmic plasmid trafficking, it did not abolish it. It has been demonstrated that a pool of stabilized post-translationally acetylated microtubules exists in cells, and that this acetylation may play a role in protein trafficking. In order to determine whether this modification could account for the residual DNA trafficking in nocodazole-treated cells, we inhibited or knocked down the levels of the tubulin deacetylase, histone deacetylase 6 (HDAC6), thereby generating higher levels of acetylated microtubules. Electroporation of plasmids into cells with inhibited or silenced HDAC6 resulted in increased gene transfer. This increased transfection efficiency was not because of increased transcriptional activity, but rather, because of increased cytoplasmic trafficking. When plasmids were cytoplasmically microinjected into HDAC6-deficient cells, they entered the nucleus within 5 minutes of injection, almost 10 times faster than in wild-type cells. Taken together, these results suggest that modulation of HDAC6 and the microtubule network can increase the efficiency of gene transfer.

The structure, spectroscopic, and electrochemical properties of [Co{(BA)2pn}(L)2]ClO4 complexes, where (BA)2pn = N,N′-bis(benzoylacetone)-1,3-propylenediimine dianion and the two ancillary ligands (L) are pyridine, py (1), and 4-methylpyridine, 4-Mepy (2), have been investigated. These complexes have been characterized by elemental analyses, IR, UV–Vis and 1H-NMR spectroscopy. The crystal structure of [Co{(BA)2pn}(py)2]ClO4 (1) has been determined by X-ray diffraction. The coordination geometry around cobalt(III) is best described as a distorted octahedron. The electrochemical reduction of these complexes at a glassy carbon electrode in acetonitrile solution indicates that the first reduction process corresponding to CoIII–CoII is electrochemically irreversible, which is accompanied by the dissociation of the axial N(py)–cobalt bonds. This process becomes quasi-reversible upon the addition of excess py ligands. The second reduction step of CoII/I shows reversible behavior and is not influenced by the nature of the axial ligands.

Human mesenchymal stem cells (hMSCs) are multipotent cells that differentiate into several cell types, and are expected to be a useful tool for cellular therapy. Although the hMSCs differentiate into osteogenic cells during early to middle stages, this differentiation capacity decreases during the late stages of cell culture. To test a hypothesis that there are biomarkers indicating the differentiation potential of hMSCs, we performed microarray analyses and profiled the gene expression in six batches of hMSCs (passages 4-28). At least four genes [necdin homolog (mouse) (NDN), EPH receptor A5 (EPHA5), nephroblastoma overexpressed gene (NOV) and runt-related transcription factor 2 (RUNX2)] were identified correlating with the passage numbers in all six batches. The results showed that the osteogenic differentiation capacity of hMSCs is down-regulated in the late stages of cell culture. It seemed that adipogenic differentiation capacity was also down-regulated in late stage of the culture. The cells in late stage are oligopotent and the genes identified in this study have the potential to act as quality-control markers of the osteogenic differentiation capacity of hMSCs.

The crystal structures of mononuclear (azido)(pentamethylcyclopentadienyl)iridium(III) complexes bearing 2- or 8-quinolinethiolate ( n -Sqn − ), [Cp ∗ Ir(N 3 )( n -Sqn)] { n = 2 ( 1 ) or 8 ( 2 ); Cp ∗ = η 5 -C 5 Me 5 } have been determined by X-ray analysis. The 2-Sqn complex, 1 , acquires severe steric strains in the four-membered κ 2 N , S chelate ring, while the 8-Sqn isomer, 2 , forms a strain-free five-membered planar κ 2 N , S chelate ring. It has also been revealed that the corresponding benzimidazole-2-thiolate (Hbimt − ) complex, which was obtained similarly to the above n -Sqn complexes from [Cp ∗ Ir(N 3 ) 2 ] 2 and Na(Hbimt), takes an unsymmetrical dinuclear structure bridged by two Hbimt − ligands with different bonding modes, [Cp ∗ Ir(N 3 ){ μ ( S : N 1 )-Hbimt}{ μ ( S : S )-Hbimt}Ir(N 3 )Cp ∗ ] · MeOH ( 3 ).

The X-ray crystal structure of tetrakis (+)-hfbc Pr(III) complex, Na[Pr((+)-hfbc)4]·CH3CN, was compared with that of the corresponding Na–La complex with a pseudo-achiral dodecahedron, and the solution CD spectra were also discussed in the 4f–4f transition in consideration of the exciton CD couplet showing Δ-SAPR-8 configuration in CHCl3.

Background: Idiopathic thrombocytopenic purpura (ITP) is associated with the cytokine response and dysregulation of the cytokine network. Gene polymorphisms of proinflammatory cytokines are associated with several diseases including ITP. Recently, the successful eradication of Helicobacter pylori has been reported to improve the platelet counts in some patients with ITP. The aim of this study was to elucidate the relationship between cytokine gene polymorphisms and platelet recovery in ITP patients after the eradication of H. pylori. Materials and Methods: Gastric H. pylori infection was confirmed using a culture method or specific IgG antibodies against H. pylori in the serum. Thirty-six adult H. pylori-positive ITP patients received antibiotic therapy for H. pylori. The response to treatment was defined as complete response (CR) if the platelet count was above 150 × 103/µl and partial response (PR) if the platelet count increased by more than 50 × 103/µl above the pretreatment count. Genomic DNA was extracted from peripheral blood and polymorphisms in IL-1B (–31, –511), IL-1RN (long or short), TNFA (–308) and TNFB (+252) were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: Of the 36 ITP patients, twenty patients (responders) exhibited a platelet response after successful H. pylori eradication therapy, but the other patients (nonresponders) did not. There were no statistical differences in the frequencies of polymorphisms in IL-1B, IL-1RN and TNFA genes between responders and nonresponders. In contrast, the frequency of responders in ITP patients with the TNFB G/G or G/A genotype was significantly higher (69.6%) than that with the TNFB A/A genotype (30.8%). Conclusion: The TNFB (+252) G/G or G/A genotype may therefore be a good predictor of platelet recovery in ITP patients after the eradication of H. pylori.

Although triacylglycerol, the major component for lipid storage, is essential for normal physiology, its excessive accumulation causes obesity in adipose tissue and is associated with organ dysfunction in nonadipose tissue. Here, we focused on theDrosophilamodel to develop therapeutics for preventing obesity. The brummer (bmm) gene inDrosophila melanogasteris known to be homologous with human adipocyte triglyceride lipase, which is related to the regulation of lipid storage. We established aDrosophilamodel for monitoringbmmexpression by introducing the green fluorescent protein (GFP) gene as a downstream reporter of thebmmpromoter. The third-instar larvae ofDrosophilashowed the GFP signal in all tissues observed and specifically in the salivary gland nucleus. To confirm the relationship betweenbmmexpression and obesity, the effect of oral administration of glucose diets onbmmpromoter activity was analyzed. TheDrosophilaflies given high-glucose diets showed higher lipid contents, indicating the obesity phenotype; this was suggested by a weaker intensity of the GFP signal as well as reducedbmmmRNA expression. These results demonstrated that the transgenicDrosophilamodel established in this study is useful for screening antiobesity agents. We also report the effects of oral administration of histone deacetylase inhibitors and some vegetables on thebmmpromoter activity.

We previously reported that CD31(bright) cells, which were sorted from cultured AC133(+) cells of adult peripheral blood cells, differentiated more efficiently into endothelial cells than CD31(+) cells or CD31(-) cells, suggesting that CD31(bright) cells may be endothelial precursor cells. In this study, we found that CD31(bright) cells have a strong ability to release cytokines. The mixture of vascular endothelial growth factor (VEGF), thrombopoietin (TPO), and stem cell factor stimulated ex vivo expansion of the total cell number from cultured AC133(+) cells of adult peripheral blood cells and cord blood cells, resulting in incrementation of the adhesion cells, in which endothelial nitric oxide synthase and kinase insert domain-containing receptor were positive. Moreover, the mixture of VEGF and TPO increased the CD31(bright) cell population when compared with VEGF alone or the mixture of VEGF and stem cell factor. These data suggest that TPO is an important growth factor that can promote endothelial precursor cells expansion ex vivo.

To find effective antiprion compounds, we synthesized and evaluated various pyrazolone derivatives. Seven of 19 compounds showed inhibition of PrP-res accumulation and the remarkably active compound 13 showed an IC50 value of 3 nM in both ScN2a and F3 cell lines. Findings from studies on physicochemical and biochemical properties suggest that the action mechanism of these compounds does not correlate with any antioxidant activities, any of hydroxyl radical scavenging activities, or any SOD-like activities.

The magnetic interactions in a new series of isostructural imino nitroxide radical lanthanide(III) complexes, [Ln(hfac)3(IM2py)] (Ln = Gd–Yb: IM2py = 2-(2′-pyridyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazoline-1-oxy; hfac = 1,1,1,5,5,5-hexafluoro-2,4-pentanedione), are examined by considering the intrinsic paramagnetic contribution of the Ln(III) ion from the corresponding [Ln(hfac)3(pybzim)] with a diamagnetic pybzim(2-(2-pyridyl)benzimidazole) ligand; the Ln(III)–IM2py interaction being antiferromagnetic for the 4f7 to 4f13 Ln(III) complexes and negligibly small for the other complexes. This series is the first example reverse to the previous cases for the series of Ln–Cu or Ln–aminoxyl(NIT) radical (4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazoline-3-oxide-1-oxy) complexes, other than only a few examples of semiquinone Ln complexes. This reverse nature of the magnetic interaction, as compared with the NIT complexes, validates the empirical approach by O. Kahn et al. [Inorg. Chem. 38 (1999) 3692; J. Am. Chem. Soc. 122 (2000) 3413] in the spin-coupled systems for a series of Ln(III) complexes.

To find novel PPARdelta-selective agonists, we designed and synthesized phenylpropanoic acid derivatives bearing 6-substituted benzothiazoles. Optimization of this series led to the identification of a potent and selective PPARdelta agonist 17. Molecular modeling suggested that compound 17 occupies the Y-shaped pocket of PPARdelta appropriately.

Potassium bromate (KBrO(3)) is strongly carcinogenic in rodents and mutagenic in bacteria and mammalian cells in vitro. The proposed genotoxic mechanism for KBrO(3) is oxidative DNA damage. KBrO(3) can generate high yields of 8-hydroxydeoxyguanosine (8OHdG) DNA adducts, which cause GC>TA transversions in cell-free systems. In this study, we investigated the in vitro genotoxicity of KBrO(3) in human lymphoblastoid TK6 cells using the comet (COM) assay, the micronucleus (MN) test, and the thymidine kinase (TK) gene mutation assay. After a 4h treatment, the alkaline and neutral COM assay demonstrated that KBrO(3) directly yielded DNA damages including DNA double strand breaks (DSBs). KBrO(3) also induced MN and TK mutations concentration-dependently. At the highest concentration (5mM), KBrO(3) induced MN and TK mutation frequencies that were over 30 times the background level. Molecular analysis revealed that 90% of the induced mutations were large deletions that involved loss of heterozygosity (LOH) at the TK locus. Ionizing-irradiation exhibited similar mutational spectrum in our system. These results indicate that the major genotoxicity of KBrO(3) may be due to DSBs that lead to large deletions rather than to 8OHdG adducts that lead to GC>TA transversions, as is commonly believed. To better understand the genotoxic mechanism of KBrO(3), we analyzed gene expression profiles of TK6 cells using Affymetrix Genechip. Some genes involved in stress, apoptosis, and DNA repair were up-regulated by the treatment of KBrO(3). However, we could not observe the similarity of gene expression profile in the treatment of KBrO(3) to ionizing-irradiation as well as oxidative damage inducers.

A series of bis(4,4,4-trifluoro-1-R-1,3-butanedinato) Co(II) complexes with imino nitroxide radical(IM2py), [Co(Rtfc)2(IM2py)] (R = trifluoromethyl, phenyl, naphthyl, thienyl), was prepared and characterized by the X-ray analysis which demonstrated the stereospecific formation of the trans(CF3)-isomer with the trans disposition of the CF3 groups. The significant substituents effect on the UV–Vis spectra and magnetic properties were discussed in consideration of the inversion of the dπ(t2g) orbital levels leading to the orbital orthogonality or overlap with the SOMOπ∗ of IM2py in terms of the AOM parametrizations or spin-paring energy.

Until the development of wireless capsule endoscopy (CE) and double-balloon enteroscopy (DBE), it was extremely difficult to examine the entire small intestine. To assess the usefulness of DBE for diagnosing suspected small intestinal bleeding, we retrospectively compared the diagnoses and treatments of cases before and after its introduction at one hospital. Between September 2003 and December 2005, 21 consecutive patients with suspected small intestinal bleeding underwent DBE at Tokai University Hospital (group A), and subsequently 2 were excluded from the study after being diagnosed with bleeding from a diverticulum and an angiodysplasia in the ascending colon, respectively. For comparison, inpatients who were negative for gastrointestinal bleeding on colonoscopy and gastroscopy between May 1998 and August 2003 were reviewed and 27 consecutive patients who had not undergone DBE were selected as the control group (group B). All patients had been diagnosed negative for a source of bleeding on more than one colonoscopy and gastroscopy. There were no significant differences between the two groups in terms of age, gender, history of blood transfusion, blood hemoglobin value on admission, or symptoms. The diagnostic yield of DBE in identifying the source of bleeding was 78.9%: six cases of small intestinal ulcers, five cases of angiodysplasia, two cases of hard submucosal tumor (SMT), one case of small pulsating SMT, and one case of small intestinal cancer. DBE was also used to successfully treat three cases of angiodysplasia with argon plasma coagulation. In the control group, conventional investigations, including enteroclysis, angiography, Meckel scan, scintigraphy with technetium-labeled red blood cells, and/or push enteroscopy, were performed in 88.9%, 29.6%, 29.6%, 55.6%, and 25.9%, respectively. The overall diagnostic yield of the conventional approaches was only 11.1% (P < 0.01), comprising a Meckel's diverticulum, a polyp, and an angiodysplasia. We conclude that DBE can be used to diagnose suspected small intestinal bleeding and to treat some cases, such as angiodysplasia.

Oxidative stress affecting lipid membranes is considered to be closely related to cardiovascular disease and brain ischemia. In this study, we designed and synthesized membrane-localizing TEMPO derivatives and demonstrated that one of these synthesized probes, compound 1, localized and detected oxidative stress in the cell membrane in an endotoxic model of a mouse macrophage-like cell line. Compound 1 is therefore a potentially useful probe for evaluating oxidative stress at the cell membrane.

To identify prodrugs of a thiolate histone deacetylase inhibitor NCH-31 that show potent antiproliferative activity and are stable in human plasma, we synthesized several candidate prodrugs of NCH-31. Among these compounds, S-2-methyl-3-phenylpropanoyl compound 2 showed more potent antiproliferative activity and higher stability in human plasma than S-isobutyryl compound NCH-51.

Quinoline and four monofluorinated derivatives of quinoline (FQ's) were tested for their clastogenicity in a Chinese hamster lung (CHL) cell line using chromosomal aberration (CA) and micronucleus (MN) tests. Quinoline and all the fluoroquinolines, 3-, 5-, 6-, and 8-FQ, induced CA in the presence of the metabolic activation system. However, the clastogenic property was altered by fluorine-substitution. 3-FQ showed reduced cytotoxicity and clastogenicity. It was positive only at a higher dose than the other compounds. 6-FQ was as cytotoxic and clastogenic as quinoline when tested in the lower dose range (less than 0.075 mg/ml). 5-FQ and 8-FQ were only moderately clastogenic in the CA test although their toxicity was similar to that of quinoline. The MN test showed almost the same tendency in clastogenicity as the CA test, except that 8-FQ showed a negative result. These results demonstrate that fluorine-substitution can modify the clastogenicity of quinoline, probably through interference of the metabolic activation.

Induction of micronucleated liver cells (MN-liver cells) was examined with the hepatocarcinogenic quinoline and its fluorinated derivatives, 3-fluoroquinoline (3-FQ) and 5-fluoroquinoline (5-FQ), using non-hepatectomized rats and mice. Male F344 rats or ICR mice were given each test chemical at a daily dose of 0.5 mmol/kg for three consecutive days by i.p. injection, and sacrificed at six or eleven days after the final treatment. The data may suggest that the induction frequencies of MN-liver cells by the quinoline derivatives correlate with the magnitudes of both their medium-term carcinogenicity and bacterial mutagenicity. Thus, the potently hepatocarcinogenic/mutagenic 5-FQ caused significantly higher levels of induction of MN-liver cells than the vehicle in both rats and mice. The non-hepatocarcinogenic/non-mutagenic 3-FQ showed no appreciable differences in MN-liver cell induction from the control group in rats and mice. Quinoline showed a slight and statistically insignificant increase of MN-liver cells in mice, but there was not such increase in rats. These findings may suggest the utility of the micronucleus test using hepatocytes from non-hepatectomized animals, although its sensitivity may be low as compared with hepatectomized animals.

Several new cobalt(III) complexes containing (3-aminopropyl)dimethylphosphine (pdmp) have been prepared, and their molecular structures have been determined. A dichloro complex of trans(Cl,Cl)-cis(P,P)-[CoCl(2)(pdmp)(2)]PF(6) (1) was prepared from trans-[CoCl(2)(py)(4)]Cl.6H(2)O and pdmp. X-Ray crystallography confirmed the (C(2))-chair(2) conformation of two six-membered pdmp chelate rings in 1, while the analogous 1,3-bis(dimethylphosphino)propane (dmpp) complex trans-[CoCl(2)(dmpp)(2)]ClO(4) (3) exhibited the (D(2d))-twist(2) conformation. Substitution reactions of 1 for ethane-1,2-diamine (en), pentane-2,4-dionate (acac), and N,N-dimethyldithiocarbamate (dtc) gave the mixed-ligand tris(chelate)-type complexes of [Co(en)(2)(pdmp)]Cl(2)(PF(6)) (5), [Co(acac)(pdmp)(2)](PF(6))(2) (7), and [Co(dtc)(3-n)(pdmp)(n)](PF(6))(n) [n = 1 (9) or 2 (10)], respectively. The conformer of the complex cation in 5 was assigned as lel.ob.chair by X-ray analysis. In the case of the acac complex 7, both trans(P,N) (7a) and trans(N,N) (7b) isomers were isolated, and the complex cations were characterized as syn-chair(2) and anti-chair(2) conformers, respectively, with respect to the six-membered pdmp chelate rings. These conformers coincide with the most stable ones anticipated by the DFT optimum geometry calculations. In the crystal structure of trans(P,N)-[Co(dtc)(pdmp)(2)](BPh(4))(2) (10') one of the pdmp chelate rings adopted a skew-boat (twist) conformation, which reduced the intramolecular steric ring-ring interaction effectively. The DFT optimized geometries for several isomers and/or conformers of [CoCl(2)(pdmp)(2)](+) were compared.

The density of the Co and Ni 3d states of a decagonal quasicrystal Al72Co16Ni12 has been investigated by Co and Ni 2p–3d resonance photoemission spectroscopy (XPS) and soft X-ray emission spectroscopy (XES) with synchrotron radiation as an excitation source. The valence-band photoemission spectrum recorded at the high excitation photon energy shows a single 3d band at the binding energy of 2 eV, which is higher than that obtained at the low excitation photon energy. This implies that the bulk 3d electronic states are different from the surface ones. The present resonance XPS and XES spectra also show that the Ni 3d-derived band is located at slightly higher binding energy than the Co 3d-derived one, in contrast with results reported so far. Comparison with the electronic structure calculated for a cluster simulating the local columnar atomic arrangement of the decagonal quasicrystal suggests rather random occupation of the transition metal sites by Co and Ni atoms.

Inhibition of lysine-specific demethylase 1 (LSD1), a flavin-dependent histone demethylase, has recently emerged as a new strategy for treating cancer and other diseases. LSD1 interacts physically with SNAIL1, a member of the SNAIL/SCRATCH family of transcription factors. This study describes the discovery of SNAIL1 peptide-based inactivators of LSD1. We designed and prepared SNAIL1 peptides bearing a propargyl amine, hydrazine, or phenylcyclopropane moiety. Among them, peptide 3, bearing hydrazine, displayed the most potent LSD1-inhibitory activity in enzyme assays. Kinetic study and mass spectrometric analysis indicated that peptide 3 is a mechanism-based LSD1 inhibitor. Furthermore, peptides 37 and 38, which consist of cell-membrane-permeable oligoarginine conjugated with peptide 3, induced a dose-dependent increase of dimethylated Lys4 of histone H3 in HeLa cells, suggesting that they are likely to exhibit LSD1-inhibitory activity intracellularly. In addition, peptide 37 decreased the viability of HeLa cells. We believe this new approach for targeting LSD1 provides a basis for development of potent selective inhibitors and biological probes for LSD1.

Lysine-specific demethylase 2 (LSD2) demethylates mono- and dimethylated Lys-4 of histone H3 (H3K4me1 and H3K4me2). NPAC protein is known to interact with LSD2 and promote its H3K4 demethylase activity. In this study, we established a demethylation assay system that utilizes recombinant LSD2 in the presence of a synthetic NPAC peptide. Several phenylcyclopropylamine (PCPA)-based inhibitors were examined for their LSD2 inhibitory activity in the LSD2 enzymatic assay with the NPAC peptide. The assay results showed that the PCPA derivatives, including NCD41, selectively inhibited LSD1 in preference to LSD2.

We reported a case of sigmoid colonic high grade tubular adenomas associated with deposited ova of Schistosoma japonicum. A 76-year-old Japanese man was referred to our colonoscopy due to a positive fecal occult blood test. He had a medical history of schistosomiasis japonica. The colonoscopy revealed that there were two sigmoid colon polyps, approximately 8 mm in diameter. These were removed by endoscopic mucosal resection (EMR). Pathological examination revealed high grade tubular adenomas and deposited some ova of Schistosoma japonicum with severe fibrotic change and granuloma formation in the submucosal layer. Colonic schistosomiasis is a probable independent risk factor for the development of colorectal carcinogenesis.

Herein we report the discovery of a series of new KDM5A inhibitors. A three-dimensional (3D) structure model of KDM5A jumonji domain was firstly established based on homology modeling. Molecular docking-based virtual screening was then performed against commercial chemical databases. A number of hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the most active hit compound, 9 (IC50: 2.3 μM), which led to the discovery of several new KDM5A inhibitors. Among them, compound 15e is the most potent one with an IC50 value of 0.22 μM against KDM5A. This compound showed good selectivity for KDM5A and considerable ability to suppress the demethylation of H3K4me3 in intact cells. Compound 15e could be taken as a good lead compound for further studies.

We prepared hydrazone-palladium(II) complexes of [PdCl2(HL(n))] and [PdCl(L(n))] (n = 1-3) by the reaction of [PdCl2(cod)] or [PdCl2(PhCN)2] and the hydrazone ligands of HL(n) {N'-(pyridin-2-ylmethylene)picolinohydrazide (HL(1)), N'-[1-(pyridin-2-yl)ethylidene]picolinohydrazide (HL(2)), and N'-[(6-methylpyridin-2-yl)methylene]picolinohydrazide (HL(3))}. The structures of the complexes were determined by X-ray analysis. The hydrazone ligands had κN(py1),κN(imine) and κN(amidate),κN(py2) bidentate coordination modes in [PdCl2(HL(n))] (1, n = 1; 2, n = 2) and in [PdCl2(HL(3))] (3), respectively. In contrast, tridentate coordination modes of κN(py1),κN(imine),κN(py2) and κN(py1),κN(amidate),κN(py2) were observed in [PdCl(L(n))] (4, n = 1; 5, n = 2) and in [PdCl(L(n))] (6, n = 1; 7, n = 2; 8, n = 3). Thermal conversion of complexes 1-3 to complexes 6-8 proceeded in acetonitrile. Complexes 4 and 5 were obtained from complexes 1 and 2, respectively, in a basic acetonitrile solution under dark conditions. Complex 4 reverted immediately to complex 1 in an acidic acetonitrile solution that included hydrochloric acid. However, under room light, in the basic acetonitrile solution that included trimethylamine, complex 4 converted photochemically to complex 6. The thermochromic or vapochromic structure conversion of these complexes also occurred in the solid state. On heating at 180 °C, the color of the crystals of complexes 1, 2, and 3 changed from yellow to orange in the solid state. (1)H NMR and/or UV-vis absorption spectroscopy confirmed that the orange complexes 6-8 were produced. The reddish-orange crystals of complexes 4 and 5 were exposed to hydrogen chloride vapor to yield the yellow products of complexes 1 and 2, respectively.

Objective: We sought to evaluate the efficacy and feasibility of superselective intra-arterial infusion of high-dose cisplatin with concomitant radiotherapy (hereafter RADPLAT) for head and neck squamous cell cancer (hereafter HNSCC) patients with retropharyngeal lymph node (hereafter RPLN) metastasis. Study Design: Retrospective case series review. Setting: University medical center in Japan. Subjects and Methods: Ten HNSCC patients with RPLN metastasis treated by RADPLAT were analyzed. Results: The ascending pharyngeal artery was targeted for the treatment of RPLN metastasis in 9 patients. The median total dose of cisplatin was 26.6 mg/m2 (mean, 31.5 mg/m2; range, 11.7-87.9 mg/m2). In the remaining patient, the RPLN was supplied by the ascending palatine artery. As grade 3 and 4 adverse effects, leukopenia was observed in three, mucositis in four and nausea in one patient. No neurological complications were observed in any patients. Metastatic RPLNs were evaluated as a complete response in all patients. There was no recurrence of RPLN metastasis in any patients. Four patients remain alive without any evidence of disease and six patients died of disease. The 5-year overall survival rate was 50%. Conclusions: We have shown that superselective intra-arterial cisplatin infusion for RPLNs was a feasible and effective approach for HNSCC patients with RPLN metastasis.

Six-coordinate [Cu(pdt)2(H2O)2](2+) and four-coordinate [Cu(pdt)2](+) complexes were synthesized and the cross redox reactions were studied in acetonitrile (pdt = 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine). Single crystal analyses revealed that [Cu(pdt)2(H2O)2](BF4)2 was of pseudo-D2h symmetry with two axial water molecules and two symmetrically coordinated equatorial pdt ligands, while the coordination structure of [Cu(pdt)2]BF4 was a squashed tetrahedron (dihedral angle = 54.87°) with an asymmetric coordination by two pdt ligands: one pdt ligand was coordinated to Cu(i) through pyridine-N and triazine-N2 while another pdt ligand was coordinated through pyridine-N and triazine-N4, and a stacking interaction between the phenyl ring on one pdt ligand and the triazine ring on another pdt ligand caused the squashed structure and non-equivalent Cu-N bond lengths. The cyclic voltammograms for [Cu(pdt)2(H2O)2](2+) and [Cu(pdt)2](+) in acetonitrile were identical to each other and quasi-reversible. The reduction of [Cu(pdt)2(H2O)2](2+) by decamethylferrocene and the oxidation of [Cu(pdt)2](+) by [Co(2,2'-bipyridine)3](3+) in acetonitrile revealed that both cross reactions were sluggish through a gated process (the structural change took place prior to the electron transfer) accompanied by slow direct electron transfer processes. It was found that the triazine ring of the coordinated pdt ligand rotates around the C-C bond between the triazine and pyridine rings with the kinetic parameters k = 51 ± 5 s(-1) (297.8 K), ΔH(‡) = 6.2 ± 1.1 kJ mol(-1) and ΔS(‡) = -192 ± 4 J mol(-1) K(-1). The electron self-exchange process was directly measured using the line-broadening method: kex = (9.9 ± 0.5) × 10(4) kg mol(-1) s(-1) (297.8 K) with ΔH(‡) = 44 ± 7 kJ mol(-1) and ΔS(‡) = 0.2 ± 2.6 J mol(-1) K(-1). By comparing this rate constant with the self-exchange rate constants estimated from the cross reactions using the Marcus cross relation, the non-adiabaticity (electronic) factors, κel, for the direct electron transfer processes between [Cu(pdt)2](+/2+) and non-copper metal (Fe(2+) and Co(3+)) complexes were estimated as ca. 10(-7), indicating that the electronic coupling between the d orbitals of copper and of non-copper metals is very small.

Aim. The study assessed the usefulness of a recently developed method for respiratory rate (RR) monitoring in patients undergoing endoscopic submucosal dissection (ESD) under deep sedation.Methods. Study subjects comprised 182 consecutive patients with esophageal cancer or gastric cancer undergoing ESD. The usefulness of acoustic RR monitoring was assessed by retrospectively reviewing the patients’ records for age, gender, height, weight, past history, serum creatinine, RR before ESD, and total dose of sedative.Results. Respiratory suppression was present in 37.9% of (69/182) patients. Continuous monitoring of RR led to detection of respiratory suppression in all these patients. RR alone was decreased in 24 patients, whereas both RR and blood oxygen saturation were decreased in 45 patients. Univariate analysis showed female gender, height, weight, and RR before treatment to be significantly associated with respiratory suppression. Multivariate analysis showed RR before treatment to be the only significant independent predictor [odds ratio (OR) 0.83, 95% confidence interval (CI) 0.73–0.95, andP=0.006] of respiratory suppression.Conclusion. In this study, the difference in RR before treatment between patients with and without respiratory suppression was subtle. Therefore, we suggest that acoustic RR monitoring should be considered in patients undergoing ESD under sedation to prevent serious respiratory complications.

Currently, the creation of class- and isoform-selective modulators of biologically important targets is a particularly challenging problem because different isoforms within a protein family often show striking similarity in spatial quaternary structure, especially at the catalytic sites or binding pockets. Therefore, an understanding of both the precise three-dimensional structure of the target protein and the mechanisms of action of modulators is important for developing more effective and selective agents. In this Perspective, we discuss currently available rational design strategies for obtaining class- and isoform-selective inhibitors and we illustrate these strategies with the aid of specific examples from the recent literature. The strategies covered include: (1) target-derived (-dependent) de novo drug discovery methodologies, and (2) follow-on derivatization approaches from initially identified active molecules (hit-to-lead and lead-to-candidate efforts). We also comment on prospects for further development and integration of strategies to achieve target-specific or isoform-selective inhibition.

Adult T-cell leukaemia/lymphoma (ATL) is an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukaemia virus (HTLV)-1. The identification of new molecular targets for ATL prevention and treatment is desired. SIRT1, a nicotinamide adenine dinucleotide+ -dependent histone/protein deacetylase, plays crucial roles in various physiological processes, including aging and apoptosis. We previously reported that ATL patients had significantly higher SIRT1 protein levels than healthy controls. Here, we demonstrate that two novel small-molecule SIRT1 inhibitors, NCO-01/04, reduced cell viability and enhanced apoptotic cells in peripheral blood monocyte cells of patients with acute ATL, which has a poor prognosis. NCO-01/04 also reduced the cell viability with DNA fragmentation, Annexin V-positive cells and caspase activation. However, a caspase inhibitor did not inhibit this caspase-dependent cell death. NCO-01/04 enhanced the endonuclease G level in the nucleus with loss of the mitochondrial transmembrane potential, which can promote caspase-independent death. Interestingly, NCO-01/04 increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation as well as autophagy. Thus, NCO-01/04 simultaneously caused caspase activation and autophagy. These results suggest that NCO-01/04 is highly effective against ATL cells in caspase-dependent or -independent manners with autophagy and that its clinical application might improve the prognosis of patients with this fatal disease.