Syntheses,structures, and magnetic properties of heterobimetallic complexes based on tetracyanometallic building blocks

Two tetracyanometalate building blocks, [Fe(5,5′-dmbipy)(CN)₄]^? (2) and [Fe(4,4′-dmbipy)(CN)₄]^? (3) (5,5′-dmbipy = 5,5′-dimethyl-2,2′-bipyridine; 4,4′-dmbipy = 4,4′-dimethyl-2,2′-bipyridine), and two cyano-bridged heterobimetallic complexes, [Cu₂(bpca)₂(H₂O)₂Fe₂(5,5′-dmbipy)₂(CN)₈] · 2[Cu(bpca)Fe(5,5′-dmbipy)(CN)₄] · 4H₂O (4) and [Cu(bpca)Fe(4,4′-dmbipy)(CN)₄]_n (5) (bpca = bis(2-pyridylcarbonyl)amidate), have been synthesized and structurally characterized. Complex 4 contains two dinuclear and one tetranuclear heterobimetallic clusters in an asymmetric unit whereas the structure of complex 5 features a one-dimensional heterobimetallic zigzag chain. The Cu(II) ion is penta-coordinated in the form of a distorted square-based pyramid. Magnetic studies show ferromagnetic coupling between Cu(II) and Fe(III) ions with g = 2.28, J₁ = 2.64 cm^?1, J₂ = 5.40 cm^?1 and TIP = ?2.36 × 10^?3 for complex 4, and g = 2.17, J = 4.82 cm^?1 and zJ′ = 0.029 cm^?1 for complex 5.     

Synthesis,crystal structure and magnetic properties of the spin crossover system [Fe(pq)3]2+

Three new compounds formulated (ClO₄)₂[Fe(pq)₃] (1), (BF₄)₂[Fe(pq)₃] · EtOH (2) and {(ClO₄)[MnCr(C₂O₄)₃][Fe(pq)₂(H₂O)₂]} (3), where pq is 2,2′-pyridylquinoline, have been synthesised and characterised. Despite the different crystal packing exhibited by 1 and 2, the cationic species [Fe(pq)₃]²⁺ are structurally quite similar. At 293 K, the Fe–N bond lengths are characteristic of the iron(II) in the high-spin state. In contrast to 1, 2 undergoes a continuous spin transition. Indeed, at 95 K its structure experiences a noticeable change in the Fe–N bonds and angles, i.e. the Fe–N bonds shorten by 0.194 Å on the average. The magnetic behaviour confirms that 1 is fully high-spin in the 4–300 K temperature range while 2 shows a spin transition centred at T_1/2 = 150 K. The corresponding enthalpy, entropy and interaction parameter are ΔH = 7.49 kJ mol^?1, ΔS = 50 J K^?1 mol^?1and Γ = 1.35 kJ mol^?1. Compound 3 has been obtained as a microcrystalline powder. The magnetic properties of 3 point at the occurrence of ferromagnetic coupling below 100 K and the onset of a ferromagnetic ordering below 10 K (Weiss constant equal to 6.8 K). The Mössbauer spectra of 3 show the occurrence of a magnetic order at T ? 4.2 K.     

Esculentin-2CHa: A host-defense peptide with differential cytotoxicity against bacteria,erythrocytes and tumor cells

The host-defense peptide, esculentin-2CHa (GFSSIFRGVA¹⁰KFASKGLGK D²⁰LAKLGVDLVA³⁰ CKISKQC) shows potent (MIC ≤ 6 μM) growth inhibitory activity against clinical isolates of multidrug-resistant strains of Staphylococcus aureus, Acinetobacter baumannii, and Stenotrophomonas maltophilia and differential cytotoxic activity against human erythrocytes (LC₅₀ = 150 μM) and human non-small cell lung adenocarcinoma A549 cells (LC₅₀ = 10 μM). Esculentin-2CHa significantly (P < 0.01) stimulates the release of the anti-inflammatory cytokine IL-10 by mouse lymphoid cells and elevates its production after stimulation with concanavalin A and significantly (P < 0.05) stimulates TNF-α production by peritoneal macrophages. Effects on IL-6 and IL-1β production were not significant. Removal of the hydrophobic N-terminal hexapeptide (GFSSIF) from esculentin-2CHa results in abolition of growth inhibitory activity against S. aureus and cytotoxic activity against erythrocytes and A549 cells as well as a marked (≥16-fold) reduction in potency against A. baumannii and S. maltophilia. The primary structure of esculentin-2 has been poorly conserved between frog species but evolutionary pressure has acted to maintain the hydrophobic character of this N-terminal hexapeptide sequence. Removal of the cyclic C-terminal domain (CKISKQC) and replacement of the Cys³¹ and Cys³⁷ residues by serine resulted in appreciable decreases in cytotoxicity against all microorganisms and against mammalian cells. The more cationic [D20K, D27K] analog showed a modest increase in potency against all microorganisms (up to 4-fold) but a marked increase in cytotoxicity against erythrocytes (LC₅₀ = 11 μM) and A549 cells (LC₅₀ = 3 μM).     

Development of a microfluidic device for determination of cell osmotic behavior and membrane transport properties

An understanding of cell osmotic behavior and membrane transport properties is indispensable for cryobiology research and development of cell-type-specific, optimal cryopreservation conditions. A microfluidic perfusion system is developed here to measure the kinetic changes of cell volume under various extracellular conditions, in order to determine cell osmotic behavior and membrane transport properties. The system is fabricated using soft lithography and is comprised of microfluidic channels and a perfusion chamber for trapping cells. During experiments, rat basophilic leukemia (RBL-1 line) cells were injected into the inlet of the device, allowed to flow downstream, and were trapped within a perfusion chamber. The fluid continues to flow to the outlet due to suction produced by a Hamilton Syringe. Two sets of experiments have been performed: the cells were perfused by (1) hypertonic solutions with different concentrations of non-permeating solutes and (2) solutions containing a permeating cryoprotective agent (CPA), dimethylsulfoxide (Me₂SO), plus non-permeating solute (sodium chloride (NaCl)), respectively. From experiment (1), cell osmotically inactive volume (V_b) and the permeability coefficient of water (L_p) for RBL cells are determined to be 41% [n = 18, correlation coefficient (r²) of 0.903] of original/isotonic volume, and 0.32 ± 0.05 μm/min/atm (n = 8, r² > 0.963), respectively, for room temperature (22 °C). From experiment (2), the permeability coefficient of water (L_p) and of Me₂SO (P_s) for RBL cells are 0.38 ± 0.09 μm/min/atm and (0.49 ± 0.13) × 10⁻³ cm/min (n = 5, r² > 0.86), respectively. We conclude that this device enables us to: (1) readily monitor the changes of extracellular conditions by perfusing single or a group of cells with prepared media; (2) confine cells (or a cell) within a monolayer chamber, which prevents imaging ambiguity, such as cells overlapping or moving out of the focus plane; (3) study individual cell osmotic response and determine cell membrane transport properties; and (4) reduce labor requirements for its disposability and ensure low manufacturing costs.     

Shear stress-induced Ca2+ mobilization in MDCK cells is ATP dependent,no matter the primary cilium

Primary cilium has emerged as mechanosensor to subtle flow variations in epithelial cells, but its role in shear stress detection remains controversial. To probe the function of this non-motile organelle in shear stress detection by cells, we compared calcium signalling responses induced by shear stress in ciliated and unciliated MDCK cells. Cytosolic free Ca²⁺ ([Ca²⁺]_i) was measured using Fura-PE3 video imaging fluorescence microscopy in response to shear stress due to laminar flow (385 μl s^?1). Our results show that both unciliated and ciliated MDCK cells are shear stress sensitive via ATP release and autocrine feedback through purinergic receptors. However, purinergic calcium signals differed in response intensity and receptor subtypes. In unciliated cells, shear stress-induced elevation in [Ca²⁺]_i was predominantly mediated through P2X receptors (P2XR). In contrast, calcium mobilization in ciliated MDCK cells resulted from P2YRs and store-operated Ca²⁺-permeable channels besides P2XRs. These findings lend support to the hypothesis that ATP release in response to shear stress is independent of the primary cilium and that transduction of mechanical strain into a specific biochemical responses stems on the mobilization of different sets of purinergic receptors.     

Bioreactor leaching of uranium from a low grade Indian silicate ore

Bio-leaching studies were carried out in a 2 L bioreactor- BIOSTAT-B^® equipped with a PLC based controller at 20–40% (w/v) pulp density using enriched culture of A.ferrooxidans for Turamdih uranium ore (Jharkhand, India). With the enriched culture of A.ferrooxidans adapted on Fe(II) at pH 2.0, 35 °C and 20% (w/v) pulp density, a 98.3% uranium recovery was recorded in 14 days. The leaching of uranium in the bioreactor improved the dissolution rate by reducing the time from 40 days in shake flask as per our earlier studies to 14 days. While investigating the importance of biogenic Fe(III) in the bio-leaching process a maximum recovery of 84.7% U₃O₈ was observed at pH 2.0 and 20% (w/v) pulp density in 10 h as compared to the uranium leaching of 38.3% in the control experiments. On raising the pulp density to 30%, uranium bio-recovery increased to 87.6% in 10 h at pH 2.0 with <76 μm size material. This showed a distinct advantage because of better mixing of slurry in the bioreactor with auto-controlled conditions that improved the kinetics.     

Crystal structure,magnetic and thermal properties of the one-dimensional complex [Nd(pzam)3(H2O)Mo(CN)8] · H2O

The new d–f cyanido-bridged 1D assembly [Nd(pzam)₃(H₂O)Mo(CN)₈] · H₂O was prepared by self-assembly of pyrazine-2-carboxamide (pzam), Nd(NO₃) · nH₂O and (Bu₃NH)₃[Mo(CN)₈] · 4H₂O in acetonitrile. X-ray crystallographic studies indicate that the complex comprises chains of alternating, cyanido-bridged [Nd(pzam)₃(H₂O)]³⁺ and Mo(CN)₈]^3? fragments. The magneto-structural properties have been studied by field-dependent magnetization and specific heat measurements at low temperatures (?0.3 K). Below ≈10 K the Nd(III) moment is well approximated by an effective spin S = 1/2, with anisotropic g-tensor. The exchange coupling between the Nd(III) and the Mo(V) spins S = 1/2 along the structural chains is found to be ferromagnetic, with J/k_B = 1.8 ± 0.2 K and approximately XY (planar) anisotropy. No evidence for 3D interchain magnetic ordering is found. A comparison with magneto-structural data of other cyanido-bridged complexes involving the Nd(III) ion is presented.     

Intramolecular electron transfer in the mixed-valence [Co(3,5-DTBCat)(3,5-DTBSQ)(bpy)] complex: Beyond valence tautomerism

The series of complexes [Co(Q)₂(bpy)]ⁿ (n = ?1, 0, +1) that can be derived by partial reduction or oxidation of complex 1, ls-Co(III) has been synthesized and studied. The results support the theoretical calculations which pointed to an intervalence transfer (IT) from the Cat^2? to the SQ^? ligand rather than a LMCT transition as the origin for the low-energy band transition centered at 2500 nm observed for 1, ls-Co(III).     

Arsenic accumulation by aquatic macrophyte coontail (Ceratophyllum demersum L.) exposed to arsenite,and the effect of iron on the uptake of arsenite and arsenate

In this study, the aquatic macrophyte Ceratophyllum demersum L. (coontail or hornwort) was tested for its efficiency of arsenic (As) uptake under laboratory conditions. Our results revealed that the solution pH had a significant effect on As accumulation by C. demersum (p < 0.001). The accumulation was highest at pH 5 and decreased as pH values increased. Plants that were exposed to various concentrations of arsenite (As(III)) for 24 and 48 h, exhibited tolerance and toxic responses, respectively. As accumulation by C. demersum depended on the concentrations of As(III) and the duration of exposure (p < 0.001). At 40 μM after 24 h, plants accumulated 227.5 μg As g⁻¹ dw and showed no visible symptoms of toxicity. However, after 48 h, As level reached 302.4 μg g⁻¹ dw and biomass production decreased significantly. Toxic effects were evident by plant necrosis and negative biomass production, leading to a decrease in the amount of accumulated As. Also, the addition of iron (Fe) into the nutrient solutions (0.18 mM) had contrasting effects on the uptake of 2 As species – the uptake of As(III) was enhanced by the presence of Fe, but the uptake of arsenate (As(V)) was considerably inhibited.     

Synthesis,X-ray structures,and magnetic properties of heterometal dinuclear Cr(III)–M(II) complexes

New 3,5-bis(2-pyridyl)pyrazolato (bpypz) bridged heterometal dinuclear complexes [(nta)Cr(μ-bpypz)M^II(picen)]⁺ (M = Mn(II), Ni(II)) and [(acac)₂Cr(μ-bpypz)Ni^II(picen)]²⁺ (nta = nitrilotriacetate, picen = N,N′-bis(2-pyridylmethyl)ethylenediamine, acac = acetylacetate) were synthesized and characterized by the X-ray analysis, ESI-MS and the magnetic measurements, and/or ²H NMR spectra. The molecular structures were compared from a viewpoint of the conformation of the picen depending on M^II ionic radii or different modes of hydrogen bonds. The picen in [(nta)Cr(μ-bpypz)Mn^II(picen)]BF₄ takes an abnormal conformation with intramolecular bifurcated three-center hydrogen bonds between two carboxylate oxygens of nta and an amine proton of the picen as found for the previously reported corresponding Fe(II) complex [K. Ni-iya, A. Fuyuhiro, T. Yagi, S. Nasu, K. Kuzushita, S. Morimoto, S. Kaizaki, Bull. Chem. Soc. Jpn. 74 (2001) 1891]. On the other hand, for both Ni(II)-nta and Ni(II)-acac complexes, the picen takes a normal conformation with only a two-center hydrogen bond between non-bridging ligands. The magneto-structural relation is discussed for the Cr(III)–Ni(II) complexes in connection with the orthogonality or orbital overlap arising from the difference in distortion around Cr(III) moiety.     

Evaluation of hexavalent chromium reduction by chromate-resistant moderately halophile,Nesterenkonia sp. strain MF2

A Gram-positive moderately halophilic chromate reducing bacterial strain was isolated from effluents of tanneries, and identified as Nesterenkonia sp. strain MF2 by phenotypic characterization and 16S rRNA analysis. The strain could tolerate up to 600 mM of chromate and completely reduced 0.2 mM highly toxic and soluble Cr(VI) (as CrO₄²⁻) into almost non-toxic and insoluble Cr(III) in 24 h under aerobic condition.The maximum chromate removal was exhibited in 1.5 M NaCl at 35 °C and pH 8.0. Initial Cr(VI) concentration until 0.4 mM did not have a significant effect on Cr(VI) reduction. The isolate was capable of chromate reduction in the presence of various concentrations of salts. The chromate reduction corresponded with growth of bacteria and reached a maximum level at the end of exponential phase.     

Effect of arsenic on visible symptom and arsenic concentration in hydroponic Japanese mustard spinach

Responses of Japanese mustard spinach (JM-spinach; Brassica rapa L. var. pervirdis) were investigated at elevated levels of arsenic (As). Plants were grown hydroponically in the greenhouse under 0, 6.7, 33.5 and 67 μM As (equal to 0, 0.5, 2.5 and 5 mg L^?1 As, respectively) for 14 days. Arsenic was used as sodium meta-arsenite (NaAsO₂). Toxicity symptom was solely shown as shoot growth repression at 33.5 and 67 μM As exposures. Dry weight (DW) enhanced by 19.4% in shoot and 38.9% in root in the 6.7 μM As level as compared to control but decreased by 48.1% and 72.1% DW in shoot and 24.1% and 61.1% DW in root in the 33.5 and 67 μM As levels, respectively. This result indicated that As at lower concentration might have slight stimulating effect on JM-spinach growth, but toxicity increased with increasing As. Based on the regression lines between growth and As concentration in the plant tissues, the critical toxicity level (CTL) of As in JM-spinach shoot was 7.85 μg g^?1 DW considering 10% DW reduction. The CTL for the root was almost 2110 μg As g^?1 DW, indicating that shoot of JM-spinach was more sensitive to As-toxicity than that of root. Arsenic concentrations increased in plant parts with increasing As in the medium. Arsenic concentrations were also compared in DW and fresh weight (FW) basis. The JM-spinach concentrated unaccepted level of As in shoots for human consumption in the higher As levels without showing visible toxicity symptom. In spite of decreasing iron (Fe) concentration in shoot in the highest As level, chlorophyll index did not decrease accordingly. Phosphorus (P) concentration also decreased. Phosphorus concentration decreased much more than Fe concentration. Low P might help to mobilize Fe in shoots, resulting in higher chlorophyll index at 67 μM As level. Phosphorus might compete with Fe in shoot tissues of As-stressed JM-spinach.     

Foliage type specific susceptibility to ozone in Picea abies,Pinus cembra and Larix decidua at treeline: A synthesis

Cumulative ozone uptake (COU, mmol m⁻²) and O₃ flux (FO₃, nmol m⁻² s⁻¹) were related to physiological, morphological and biochemical characteristics of field-grown mature evergreen Norway spruce [Picea abies (L.) Karst.], Cembran pine [Pinus cembra L.], and deciduous European larch [Larix decidua Mill.] trees at treeline. The threshold COU causing a statistically significant decline in photosynthetic capacity (A_max) ranged between 19.6 mmol m⁻² in current-year needles of evergreen conifers and 22.0 6 mmol m⁻² in short-shoot needles of deciduous L. decidua subjected to exposure periods of ≥84 and ≥43 days, respectively. The higher O₃ sensitivity of deciduous L. decidua than of evergreen P abies and P. cembra was associated with differences in FO₃ and specific leaf area (SLA), both being significantly higher in L. decidua. FO₃ was 5.9 nmol m⁻² s⁻¹ in L. decidua and 2.7 nmol m⁻² s⁻¹ in evergreen conifers. Species-dependent differences were also related to detoxification capacity expressed through total surface area based concentrations of reduced ascorbate and α-tocopherol that both increased with SLA. Findings suggest that differences in O₃ sensitivity between evergreen and deciduous conifers can be attributed to foliage type specific differences in SLA, the latter determining physiological and biochemical characteristics of the treeline conifers.     

Trispyrazolylmethane piano stool complexes of iron(II) and cobalt(II)

A series of cationic trispyrazolylmethane complexes of the general form [Tm^RM(CH₃CN)₃]²⁺ (Tm = tris(pyrazolyl)methane, 1, R = 3,5-Me₂, M = Fe(II); 2, R = 3-Ph, M = Fe(II); 3, R = 3,5-Me₂, M = Co(II); 4, R = 3-Ph, M = Co(II)) with ‘piano-stool’ structures was prepared by the reaction of the N₃tripodal ligands (Tm^R)with [(CH₃CN)₆M](BF₄)₂ in a 1:1 stoichiometric ratio. Magnetic susceptibility measurements indicate that all four complexes with BF₄⁻ counter anions are paramagnetic, high-spin systems in the solid state with μ_eff at high temperatures of 5.2 (1, S = 2), 5.4 (2, S = 2), 4.9 (3, S = 3/2) and 4.6 (4, S = 3/2) BM, respectively. Comparisons of bond lengths from the metal centre to the Tm^R nitrogen donors, and from the metal centre to the acetonitrile nitrogen donors indicate that the neutral tripodal ligands appear to be more weakly coordinated to the metal centre than are the acetonitrile ligands. Reactions of these tripodal complexes with bidentate phosphine ligands, such as 1,2-diphosphinoethane or 1,2-bis(diallylphosphino)ethane leads to displacement of the tripodal ligand, or to the formation of more thermally stable bis-ligand complexes M(Tm^R)₂ (R = 3,5-dimethyl).     

Microbial processes and bacterial populations associated to anaerobic treatment of sulfate-rich wastewater

A pilot-scale (1.2 m³) anaerobic sequencing batch biofilm reactor (ASBBR) containing mineral coal for biomass attachment was fed with sulfate-rich wastewater at increasing sulfate concentrations. Ethanol was used as the main organic source. Tested COD/sulfate ratios were of 1.8 and 1.5 for sulfate loading rates of 0.65–1.90 kgSO₄²⁻/cycle (48 h-cycle) or of 1.0 in the trial with 3.0 gSO₄²⁻ l⁻¹. Sulfate removal efficiencies observed in all trials were as high as 99%. Molecular inventories indicated a shift on the microbial composition and a decrease on species diversity with the increase of sulfate concentration. Beta-proteobacteria species affiliated with Aminomonas spp. and Thermanaerovibrio spp. predominated at 1.0 gSO₄²⁻ l⁻¹. At higher sulfate concentrations the predominant bacterial group was Delta-proteobacteria mainly Desulfovibrio spp. and Desulfomicrobium spp. at 2.0 gSO₄²⁻ l⁻¹, whereas Desulfurella spp. and Coprothermobacter spp. predominated at 3.0 gSO₄²⁻ l⁻¹. These organisms have been commonly associated with sulfate reduction producing acetate, sulfide and sulfur. Methanogenic archaea (Methanosaeta spp.) was found at 1.0 and 2.0 gSO₄²⁻ l⁻¹. Additionally, a simplified mathematical model was used to infer on metabolic pathways of the biomass involved in sulfate reduction.     

Comparative serum albumin interactions and antitumor effects of Au(III) and Ga(III) ions

In the present study, interactions of Au(III) and Ga(III) ions on human serum albumin (HSA) were studied comparatively via spectroscopic and thermal analysis methods: UV–vis absorbance spectroscopy, fluorescence spectroscopy, Fourier transform infrared (FT-IR) spectroscopy and isothermal titration calorimetry (ITC). The potential antitumor effects of these ions were studied on MCF-7 cells via Alamar blue assay. It was found that both Au(III) and Ga(III) ions can interact with HSA, however; Au(III) ions interact with HSA more favorably and with a higher affinity. FT-IR second derivative analysis results demonstrated that, high concentrations of both metal ions led to a considerable decrease in the α-helix content of HSA; while Au(III) led to around 5% of decrease in the α-helix content at 200 μM, it was around 1% for Ga(III) at the same concentration. Calorimetric analysis gave the binding kinetics of metal–HSA interactions; while the binding affinity (K_a) of Au(III)–HSA binding was around 3.87 × 10⁵ M⁻¹, it was around 9.68 × 10³ M⁻¹ for Ga(III)–HSA binding. Spectroscopy studies overall suggest that both metal ions have significant effects on the chemical structure of HSA, including the secondary structure alterations. Antitumor activity studies on MCF7 tumor cell line with both metal ions revealed that, Au(III) ions have a higher antiproliferative activity compared to Ga(III) ions.     

Purification and characterization of α-l-rhamnosidase from Penicillium corylopholum MTCC-2011

An extracellular α-l-rhamnosidase has been purified to electrophoretic homogeneity from the culture filtrate of Penicillium corylopholum MTCC-2011 using a simple procedure consisting of concentration by ultrafiltration and cation exchange column chromatography on carboxymethyl cellulose. The sodium dodesyl sulphate polyacrylamide gel electrophoresis analysis of the purified enzyme gave a single protein band corresponding to the molecular mass of 67.0 kDa. The native – polyacrylamide gel electrophoresis analysis also gave a single protein band confirming the purity of the enzyme and also showing that the enzyme is a monomer in the native state. The K_m and k_cat values of the enzyme were 0.42 mM and 35.7 s^?1, respectively, using p-nitrophenyl α-l-rhamnopyranoside as the substrate. The pH and temperature optima of the enzyme were 6.5 and 57.0 °C, respectively. The purified enzyme preparation successfully hydrolyzed naringin and rutin to prunin and quercetin glucoside, respectively. Thus it can be used for the preparation of these pharmaceutically important compounds.     

Identification of a marine NADPH-dependent aldehyde reductase for chemoselective reduction of aldehydes

A putative aldehyde reductase gene from Oceanospirillum sp. MED92 was overexpressed in Escherichia coli. The recombinant protein (OsAR) was characterized as a monomeric NADPH-dependent aldehyde reductase. The kinetic parameters K_m and k_cat of OsAR were 0.89 ± 0.08 mM and 11.07 ± 0.99 s⁻¹ for benzaldehyde, 0.04 ± 0.01 mM and 6.05 ± 1.56 s⁻¹ for NADPH, respectively. This enzyme exhibited high activity toward a variety of aromatic and aliphatic aldehydes, but no activity toward ketones. As such, it catalyzed the chemoselective reduction of aldehydes in the presence of ketones, as demonstrated by the reduction of 4-acetylbenzaldehyde or the mixture of hexanal and 2-nonanone, showing the application potential of this marine enzyme in such selective reduction of synthetic importance.     

Design,synthesis, antiviral and cytostatic activity of ω-(1H-1,2,3-triazol-1-yl)(polyhydroxy)alkylphosphonates as acyclic nucleotide analogues

The efficient synthesis of a new series of polyhydroxylated dibenzyl ω-(1H-1,2,3-triazol-1-yl)alkylphosphonates as acyclic nucleotide analogues is described starting from dibenzyl ω-azido(polyhydroxy)alkylphosphonates and selected alkynes under microwave irradiation. Selected O,O-dibenzylphosphonate acyclonucleotides were transformed into the respective phosphonic acids. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses and for cytostatic activity against murine leukemia L1210, human T-lymphocyte CEM and human cervix carcinoma HeLa cells. Compound (1S,2S)-16b exhibited antiviral activity against Influenza A H3N2 subtype (EC₅₀ = 20 μM—visual CPE score; EC₅₀ = 18 μM—MTS method; MCC >100 μM, CC₅₀ >100 μM) in Madin Darby canine kidney cell cultures (MDCK), and (1S,2S)-16k was active against vesicular stomatitis virus and respiratory syncytial virus in HeLa cells (EC₅₀ = 9 and 12 μM, respectively). Moreover, compound (1R,2S)-16l showed activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC₅₀ = 2.9 and 4 μM, respectively) and feline herpes virus in CRFK cells (EC₅₀ = 4 μM) but at the same time it exhibited cytotoxicity toward uninfected cell (MCC ⩾ 4 μM). Several other compounds have been found to inhibit proliferation of L1210, CEM as well as HeLa cells with IC₅₀ in the 4–50 μM range. Among them compounds (1S,2S)- and (1R,2S)-16l were the most active (IC₅₀ in the 4–7 μM range).     

Synthesis and biological activity of aminophthalazines and aminopyridazines as novel inhibitors of PGE2 production in cells

This Letter reports the synthesis and biological evaluation of a collection of aminophthalazines as a novel class of compounds capable of reducing production of PGE₂ in HCA-7 human adenocarcinoma cells. A total of 28 analogs were synthesized, assayed for PGE₂ reduction, and selected active compounds were evaluated for inhibitory activity against COX-2 in a cell free assay. Compound 2xxiv (R¹ = H, R² = p-CH₃O) exhibited the most potent activity in cells (EC₅₀ = 0.02 μM) and minimal inhibition of COX-2 activity (3% at 5 μM). Furthermore, the anti-tumor activity of analog 2vii was analyzed in xenograft mouse models exhibiting good anti-cancer activity.