Expanding cyclitol structural diversity by biocatalysis and metalocatalysis. A click chemistry approach

The palladium catalyzed cross-coupling reaction of phenyltrifluoroborate with a chemoenzymatically derived bromoazidoconduritol, combined with 1,3-dipolar cycloaddition, with a variety of alkynes is described. Fourteen new compounds were synthesized in moderate to good yields. The click chemistry reaction can be effected by using sodium ascorbate and CuSO(4) center dot 5H(2)O as catalyst in toluene-H(2)O at room temperature.

The Ruthenium Complex cis-(Dichloro)tetraammineruthenium(III) Chloride Presents Selective Cytotoxicity Against Murine B Cell Lymphoma (A-20), Murine Ascitic Sarcoma 180 (S-180), Human Breast Adenocarcinoma (SK-BR-3), and Human T Cell Leukemia (Jurkat) Tumor Cell Lines

The aim of present study was to verify the in vitro antitumor activity of a ruthenium complex, cis-(dichloro)tetraammineruthenium(III) chloride (cis-[RuCl(2)(NH(3))(4)]Cl) toward different tumor cell lines. The antitumor studies showed that ruthenium(III) complex presents a relevant cytotoxic activity against murine B cell lymphoma (A-20), murine ascitic sarcoma 180 (S-180), human breast adenocarcinoma (SK-BR-3), and human T cell leukemia (Jurkat) cell lines and a very low cytotoxicity toward human peripheral blood mononuclear cells. The ruthenium(III) complex decreased the fraction of tumor cells in G0/G1 and/or G2-M phases, indicating that this compound may act on resting/early entering G0/G1 cells and/or precycling G2-M cells. The cytotoxic activity of a high concentration (2 mg mL(-1)) of cis-[RuCl(2)(NH(3))(4)]Cl toward Jurkat cells correlated with an increased number of annexin V-positive cells and also the presence of DNA fragmentation, suggesting that this compound induces apoptosis in tumor cells. The development of new antineoplastic medications demands adequate knowledge in order to avoid inefficient or toxic treatments. Thus, a mechanistic understanding of how metal complexes achieve their activities is crucial to their clinical success and to the rational design of new compounds with improved potency.

Fast and efficient synthesis of pyrano[3,2-c]quinolines catalyzed by niobium(V) chloride

A highly efficient two-step method for the synthesis of pyranoquinoline derivatives from imino-Diels-Alder reactions between aldimines and 3,4-dihydro-2H-pyran using niobium(V) chloride as catalyst under mild conditions is described.

Er(3+) doped phosphoniobate glasses and planar waveguides: structural and optical properties

Phosphoniobate glasses with composition (mol%) (100-x) NaPO(3)-xNb(2)O(5) ( x varying from 11 to 33) were prepared and characterized by means of thermal analysis, Fourier transform infrared spectroscopy, Raman scattering and (31)P nuclear magnetic resonance. The addition of Nb(2)O(5) to the polyphosphate base glass leads to depolymerization of the metaphosphate structure. Different colors were observed and assigned as indicating the presence of Nb(4+) ions, as confirmed by electron paramagnetic resonance measurements. The color was observed to depend on the glass composition and melting temperature as well. Er(3+) containing samples were also prepared. Strong emission in the 1550 nm region was observed. The Er(3+4)I(15/2) emission quantum efficiency was observed to be 90% and the quenching concentration was observed to be 1.1 mol%( 1.45 x 10(20) ions cm(-3)). Planar waveguides were prepared by Na(+)-K(+)-Ag(+) ion exchange with Er(3+) containing samples. Optical parameters of the waveguides were measured at 632.8, 543.5 and 1550 nm by the prism coupling technique as a function of the ion exchange time and Ag(+) concentration. The optimized planar waveguides show a diffusion depth of 5.9 mu m and one propagating mode at 1550 nm.

Synthesis and characterization of trans-[Ru(NO)Cl(L)(4)](PF(6))(2) (L = isonicotinamide; 4-acetylpyridine) and related species

The trans-[RUCl(2)(L)(4)], trans-[Ru(NO)Cl (L)(4)](PF(6))(2) (L = isonicotinamide and 4-acetylpyridine) and trans-[Ru(NO)(OH)(py)(4)]Cl(2) (py = pyridine) complexes have been prepared and characterized by elemental analysis, UV-visible, infrared, and (1)H NMR spectroscopies, and cyclic voltammetry. The MLCT band energies of trans-[RUCl(2)(L)(4) increase in the order 4-acpy < isn < py. The reduction potentials of trans-[RuCl(2)(L)(4)] and trans-[Ru(NO)Cl(L)(4)](2+) increase in the order py < isn < 4-acpy. The stretching band frequency. v(NO), of the nitrosyl complexes ranges from 1913 to 1852 cm(-1) indicating a nitrosonium character for the NO ligand. Due to the large pi-acceptor ability of the equatorial ligands, the coordinated water is much more acidic in the water soluble trans-[Ru(NO)(H(2)O)(py)(4)](3+) than in trans-[Ru(NO)(H(2)O)(NH(3))(4)](3+) (C) 2009 Elsevier B.V. All rights reserved.

Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial

Background Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial. Methods The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48.4 months (IQR 42.0-56.5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11. Findings The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78.6%) compared with the observation group (4-year disease-free survival 72.2%; hazard ratio [HR] 0.76; 95% CI 0.66-0.87; p<0.0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89.3% vs 87.7%, respectively; HR 0.85; 95% CI 0.70-1.04; p=0.11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22.8 months (range 4.5-52.7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0.68; 95% CI 0.51-0.90; p=0.0077). Higher incidences of grade 3-4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea. Interpretation Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort.

FibroTest is an independent predictor of virologic response in chronic hepatitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPIC(3) program

Background & Aims: EPIC-3 is a prospective, international study that has demonstrated the efficacy of PEG-IFN alfa-2b plus weight-based ribavirin in patients with chronic hepatitis C and significant fibrosis who previously failed any interferon-alfa/ribavirin therapy. The aim of the present study was to assess FibroTest (FT), a validated non-invasive marker of fibrosis in treatment-naive patients, as a possible alternative to biopsy as the baseline predictor of subsequent early virologic (EVR) and sustained virologic response (SVR) in previously treated patients. Methods: Of 2312 patients enrolled, 1459 had an available baseline FT, biopsy, and complete data. Uni- (UV) and multi-variable (MV) analyses were performed using FT and biopsy. Results: Baseline characteristics were similar as in the overall population; METAVIR stage: 28% F2, 29% F3, and 43% F4, previous relapsers 29%, previous PEG-IFN regimen 41%, high baseline viral load (BVL) 64%. 506 patients (35%) had undetectable HCV-RNA at TW12 (TW12neg), with 58% achieving SVR. The accuracy of FT was similar to that in naive patients: AUROC curve for the diagnosis of F4 vs F2 = 0.80 (p<0.00001). Five baseline factors were associated (p<0.001) with SVR in UV and MV analyses (odds ratio: UV/MV): fibrosis stage estimated using FT (4.5/5.9) or biopsy (1.5/1.6), genotype 2/3 (4.5/5.1), BVL (1.5/1.3), prior relapse (1.6/1.6), previous treatment with non-PEG-IFN (2.6/2.0). These same factors were associated (p <= 0.001) with EVR. Among patients TW12neg, two independent factors remained highly predictive of SVR by MV analysis (p <= 0.001): genotype 2/3 (odds ratio = 2.9), fibrosis estimated with FT (4.3) or by biopsy (1.5). Conclusions: FibroTest at baseline is a possible non-invasive alternative to biopsy for the prediction of EVR at 12 weeks and SVR, in patients with previous failures and advanced fibrosis, retreated with PEG-IFN alfa-2b and ribavirin. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

The broad effects of the functional IL-10 promoter-592 polymorphism: modulation of IL-10, TIMP-3, and OPG expression and their association with periodontal disease outcome

Periodontal diseases are infectious diseases, in which periodontopathogens trigger chronic inflammatory and immune responses that lead to tissue destruction. It occurs through the generation of metalloproteinases and the activation of bone resorption mechanisms. Anti-inflammatory cytokines such as IL-10 seem to attenuate periodontal tissue destruction through the induction of tissue inhibitors of metalloproteinases (TIMPs) and the inhibitor of osteoclastogenesis osteoprotegerin (OPG). A high individual variation in levels of IL-10 mRNA is verified in periodontitis patients, which is possibly determined by genetic polymorphisms. In this study, the IL-10 promoter -592C/A single nucleotide polymorphism ( SNP), which is associated with a decrease in IL-10 production, was analyzed by RFLP in 116 chronic periodontitis (CP) patients and 173 control (C) subjects, and the IL-10, TIMPs, and OPG mRNA expression levels in diseased gingival tissues were determined by real-time-PCR. The IL-10-592 SNP CA (P=0.0012/OR=2.4/CI:1.4-4.1), AA (P=0.0458/OR=2.3/CI:1.1-4.9), and CA+AA (P=0.0006/OR=2.4/CI: 1.4-3.4) genotypes and the allele A (P=0.0036/OR=1.7/CI:1.2-2.4) were found to be significantly more prevalent in the CP group when compared with control subjects. Both CA and AA genotypes were associated with lower levels of IL-10, TIMP-3, and OPG mRNA expression in diseased periodontal tissues and were also associated with disease severity as mean pocket depth. Taken together, the results presented here demonstrate that IL10-592 SNP is functional in CP, being associated with lower levels of IL-10 mRNA expression, which is supposed to consequently decrease the expression of the downstream genes TIMP-3 and OPG, and influence periodontal disease outcome. J. Leukoc. Biol. 84: 1565-1573; 2008.

Microbicidal Action of Indole-3-Acetic Acid Combined with Horseradish Peroxidase on Prototheca zopfii from Bovine Mastitis

We investigated the toxic effect of indole-3-acetic acid (IAA) combined with horseradish peroxidase (HRP) on Prototheca zopfii from bovine mastitis. P. zopfii isolates were identified and characterized by morpho-physiological parameters; presences of P. zopfii genotype 2 were also investigated. Subsequently, P. zopfii was incubated in the absence (control) or presence of IAA/HRP and examined for: (i) cell viability; (ii) colonies number formation; (iii) antioxidant enzyme activity; and (iv) DNA integrity. Significance of differences was calculated using ANOVA and Tukey`s test (P a parts per thousand currency sign 0.05). As evidenced by Trypan blue exclusion and colony formation in Sabouraud dextrose agar, IAA/HRP addition to the culture reduced respective P. zopfii viability and P. zopfii colony formation in a concentration- and time-dependent manner. IAA/HRP specifically reduced cell viability in 10, 15, 20, 25, and 32% after 4, 6, 8, 10, and 12 h of incubation, respectively, compared with the control at the same time. The number of colony formation was inhibited (45, 82, and 88%) by IAA/HRP after 4, 6, and 9 h of incubation, respectively, compared with the control at the same time. In addition, P. zopfii antioxidant activity increased measurably in the presence of IAA/HRP (6 h); superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase increased by 90, 120, 150% and 3.4 times, compared with the controls. IAA/HRP did not appear to effect P. zopfii DNA integrity when examined by electrophoresis. In conclusion, IAA/HRP appears to function as a microbicidal mechanism on P. zopfii genotype 2 from bovine mastitis.

Experimental evidence of the spin-glass transition in the diluted magnetic semiconductor Zn(1-x)Mn(x)In(2)Se(4)

This work reports on magnetic measurements of the quasi-two-dimensional (quasi-2D) system Zn(1-x)Mn(x)In(2)Se(4), with 0.01 <= x <= 1.00. For x > 0.67, the quasi-2D system seems to develop a spin-glass behaviour. Evidence of a true phase transition phenomenon is provided by the steep increase of the nonlinear susceptibility chi(nl) when approaching T(C) from above. The static scaling of chi(nl) data yields critical exponents delta = 4.0 +/- 0.2, phi = 4.37 +/- 0.17 and TC = 3.4 +/- 0.1 K for the sample with x = 1.00 and similar values for the sample with x = 0.87. These critical exponents are in good agreement with values reported for other spin-glass systems with short-range interactions.

Heterobimetallic compounds [Ru(eta(5)-Cp)(dppf)X] (X = Cl, Br, I and N(3)): synthesis, electrochemical analysis, and the crystal structure of [Ru(eta(5)-Cp)(dppf)I] [dppf=1,1`-bis(diphenylphosphino)ferrocene]

A series of new ruthenium-iron based derivatives [Ru(eta(5)-Cp)(dppf)Cl] (1), [Ru(eta(5)-Cp)(dppf)Br] (2), [Ru(eta(5)-Cp)(dppf)I] (3) and [Ru(eta(5)-Cp)(dppf)N(3)] (4) were obtained by reactions of [Ru(eta(5)-Cp)(PPh(3))(2)Cl] with 1,1`-bis(diphenylphosphino) ferrocene (dppf) and characterized by IR, NMR ((1)H, (13)C and (31)P), (57)Fe Mossbauer spectroscopy and cyclic voltammetry. Additionally, the compound (3) was structurally characterized by X-ray crystallography, and the results were as follows: orthorhombic, Pbca, a = 18.2458(10), b = 20.9192(11), c = 34.4138(19) a""<<, alpha = beta = gamma = 90A degrees, V = 13135.3(12) a""<<(3) and Z = 16.

Dithiocarbazate complexes with the [M(PPh(3))](2+) (M=Pd or Pt) moiety Synthesis, characterization and anti-Tripanosoma cruzi activity

New neutral Pd(II) and Pt(II) complexes of the type [M(L)(PPh(3))] (M Pd or Pt) were prepared in crystalline form in high-yield synthesis with the S-benzyldithiocarbazates and S-4-nitrobenzyldithiocarbazates derivatives from 2-hydroxyacetophenone, H(2)L(1a) and H(2)L(1b), and benzoylacetone, H(2)L(2a) and H(2)L(2b). The new complexes [Pt(L(1a))(PPh(3))] (1), [Pd(L(1a))(PPh(3))] (2), [Pt(L(1b))(PPh(3))] (3), [Pd(L(1b))(PPh(3))] (4), [Pt(L(2a))(PPh(3))] (5), [Pd(L(2a))(PPh(3))] (6), [Pt(L(2b))(PPh(3))] (7) and [Pd(L(2b))(PPh(3))] (8) were characterized on the basis of elemental analysis, conductivity measurements, UV-visible, IR, electrospray ionization mass spectrometry (ESI-MS), NMR ((1)H and (31)P) and by X-ray diffraction studies. The studies showed that differently from what was observed for the H(2)L(1a) and H(2)L(1b) ligands, H(2)L(2a) and H(2)L(2b) assume cyclic forms as 5-hydroxypyrazolinic. Upon coordination, H2L2a and H2L2b suffer ring-opening reaction, coordinating in the same manner as H(2)L(1a) and H(2)L(1b), deprotonated and in O,N,S-tridentate mode to the (MPPh(3))(2+) moiety. All complexes show a quite similar planar fourfold environment around the M(II) center. Furthermore, these complexes exhibited biological activity on extra and intracellular forms of Trypanosoma cruzi in a time- and concentration-dependent manner with IC(50) values ranging from 7.8 to 18.7 mu M, while the ligand H(2)L(2a) presented a trypanocidal activity on trypomastigote form better than the standard drug benznidazole. (C) 2010 Elsevier Inc. All rights reserved.

An insight into the beginning stage of the aqueous ring opening metathesis polymerization of exo,exo-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid with Ru(III) compounds: the consumption of Ru(III) species in the presence of carboxylic acids monitored by ESR spectroscopy

The presence of paramagnetic species in the aqueous ring opening metathesis polymerizations of the exo,exo-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid monomer with RuCl(3) and K(2)[RuCl(5)H(2)O] compounds was studied using ESR techniques. It was observed that the intensities of the Ru(III) signals in the ESR spectra decrease on the time scale of the induction period so that the ROMP can take place. The intensity of the Ru(III) signal almost disappeared 50 min after reacting with K(2)[RuCl(5)H(2)O] and after 100 mm in the case of RuCl(3). Reactions of the cis-[Ru(NH(3))(4)(H(2)O)(2)](tfms)(3) and [Ru(NH(3))(5)H(2)O](tfms)(3) complexes with the monomer and different organic compounds representing the organic functions in the monomer (furan, norbornene, but-2-ene-1,4-diol and formic, acetic, oxalic and maleic acids) were also monitored by ESR and UV/vis spectra. It was deduced that the organic acids provide the disappearance of the Ru(III) signal. The proton NMR relaxation times of the residual water in D(2)O for reactions with oxalic acid suggested that the presence of paramagnetic ions in the solution decreases along with