Simple mimetics of a nuclear localization signal (NLS)

[reaction: see text] Molecular modeling was used to design mimetics of the HIV-1 matrix protein nuclear localization signal (NLS) in which a scaffold of two resorcinol units joined by a diamide linker presents 3-aminopropyl ethers in place of lysine side chains. Prospective mimetics with linkers of 6, 8, 10, or 12 atoms were synthesized and compared in a competition assay for binding to the nuclear import receptor subunit karyopherin alpha, showing the 10-atom linker to be best and shorter ones ineffective.     

The inverted cucurbit[n]uril family

We report the isolation, characterization, and recognition behavior of iCB[6] and iCB[7], which are diastereomers of CB[6] and CB[7], respectively, containing a single inverted glycoluril unit. Product resubmission experiments establish that these inverted CB[n] are intermediates in the mechanism of CB[n] formation. As a consequence of the inverted glycoluril ring, these inverted cucurbiturils possess a permanent dipole moment, are slightly smaller than their diastereomers, show distinctive selectivity in their recognition behavior, and report directly on the contents of their hydrophobic cavity.     

Synthesis and Cytotoxicity Evaluation of Metal‐Chelator‐Bearing Flavone,Carbazole, Dibenzofuran,Xanthone, and Anthraquinone

2‐(Aryloxymethyl)‐5‐benzyloxy‐1‐methyl‐1H‐pyridin‐4‐ones 8a – 8g , 2‐(aryloxymethyl)‐5‐hydroxy‐4H‐pyran‐4‐ones 9a – 9g , and 2‐(aryloxymethyl)‐5‐hydroxy‐1‐methyl‐1H‐pyridin‐4‐ones 10a – 10g were prepared from the known 5‐benzyloxy‐2‐(hydroxymethyl)pyran‐4‐one ( 3 ) in a good overall yield. These compounds were evaluated in vitro against a three‐cell lines panel consisting of MCF7 (breast), NCI‐H460 (lung), and SF‐268 (CNS), and the active compounds passed on for evaluation in the full panel of 60 human tumor cell lines derived from nine cancer cell types. The results indicated that 5‐hydroxy derivatives are more favorable than their corresponding 5‐benzyloxy precursors ( 10a – 10g vs. 8a – 8g ), and 1‐methyl‐1H‐pyridin‐4‐ones are more favorable than their corresponding pyran‐4(1H)‐ones ( 10a – 10g vs. 9a – 9g ). Among these three types of compounds, 2‐(aryloxymethyl)‐5‐hydroxy‐1‐methyl‐1H‐pyridin‐4‐ones 10a – 10g were the most cytotoxic; they inhibited the growth of almost all the cancer cells tested. On the contrary, compound 8a (a mean GI₅₀=27.8 μM ), 8b (38.5), 8d (11.0), and 8e (30.5) are especially active against the growth of SK‐MEL‐5 (a melanoma cancer cell) with a GI₅₀ of <0.01, 5.65, 0.55, and 0.03 μM , respectively (cf. Table 2).     

Seasonal variation and activity size distribution of <Superscript>7</Superscript>Be in ambient air

The seasonal variation of the ⁷Be activities in air and the size distribution of the ⁷Be aerosols were studied by using a continuous air sampler and a five stage cascade impactor. The mean monthly activity level of ⁷Be at the Korea Atomic Energy Research Institute (KAERI) site varied from 0.5 to 4.8 Bq·m⁻³ and revealed a seasonal variation, in which the ⁷Be activity levels were high in winter and low in summer. The mass size distribution showed a bi-modal distribution with a higher peak around 0.49 μm and a smaller peak between 3 μm and 7.2 μm. The activity median aerodynamic diameter (AMAD) decreased with increasing ambient ⁷Be concentrations. The mean residence times by using a mean growth rate of 0.004 μm·h⁻¹ were estimated to be 2.5–6.4 days. The AMAD has an increasing tendency with higher relative humidity. It seemed that the high humidity condition facilitated the growth of the aerosol, resulting in increased deposition rates of the aerosols and the low ⁷Be content in the surface air. The AMAD of the ⁷Be aerosols increased with an increasing temperature, but the temperature dependency of AMAD should be explained with geological and meteorological conditions.     

Metabolic studies of methenolone acetate in horses

Methenolone acetate (17β-acetoxy-1-methyl-5α-androst-1-en-3-one), a synthetic anabolic steroid, is frequently abused in human sports. It is preferred for its therapeutic efficiency and lower hepatic toxicity compared with its 17α-alkylated analogs. As with other anabolic steroids, methenolone acetate may be used to enhance performance in racehorses. Metabolic studies on methenolone acetate have been reported for humans, whereas little is known about its metabolic fate in horses. This paper describes the investigation of in vitro and in vivo metabolism of methenolone acetate in racehorses.Studies on the in vitro biotransformation of methenolone acetate with horse liver microsomes were carried out. Methenolone (M1, 1-methyl-5α-androst-1-en-17β-ol-3-one) and seven other metabolites (M2-M8) were detected in vitro. They were 1-methyl-5α-androst-1-ene-3,17-dione (M2), 1-methyl-5α-androst-1-en-6-ol-3,17-dione (M3) and two stereoisomers of 1-methylen-5α-androstan-2-ol-3,17-dione (M4 and M5), 1-methyl-5α-androst-1-en-16-ol-3,17-dione (M6) and monohydroxylated 1-methyl-5α-androst-1-en-17-ol-3-one (M7 and M8). After oral administration of Primobolan^® (80 tablets × 5 mg of methenolone acetate each) to two thoroughbred geldings, the parent steroid ester was not detected in the post-administration urine samples. However, seven metabolites, namely M1, M6-M8, two stereoisomers of M7 (M9 and M10) and 1-methyl-5α-androst-1-en-17α-ol-3-one (M11), could be detected. The metabolic pathway for methenolone acetate is postulated. This study has shown that metabolite M1 could be targeted for controlling the abuse of methenolone acetate in horses.     

Oxidation-Induced Structural Alterations and Its Effect on Chaperone Function of Rat Lens α-Crystallin

An ascorbate-FeCl₃-EDTA-H₂O₂ system was used to oxidize rat lens α-crystallins. Under this oxidative insult, the chaperone activity of α-crystallin toward γ-crystallin was shown to decrease significantly, which is quite different from the result reported by Wang and Spector. (Invest. Ophthalmol. Vis. Sci. 1995 , 36, 311-321.) Fluorescence spectroscopy and circular dichroism were employed to characterize the structural changes of oxidized α-crystallin. It was found that fluorescence intensity of l-anilinonaphthalene-8-sul-phonate (ANS) bound to oxidized α-crystallin increased comparing to that bound to normal α-crystallin, suggesting oxidation causes the exposure of more hydrophobic regions. Further, α-crystallin's fluorescence intensity in response to tryptophan residues showed a pseudo first order decline. Amino acid analysis of normal versus oxidized α-crystallin confirmed actual decline in tryptophan levels, showing about 80% of tryptophan being modified after 10-hour oxidation. Circular dichroism showed both changes in the secondary and tertiary structures of oxidized α-crystallin, characterized by a large loss of aromatic-type amino acid interactions and a large loss of β-sheet structure. In conclusion, modified tryptophan, secondary and tertiary structural changes of α-crystallin correlate best with the reduction of chaperone function, the curves all showing a linear slope for 10 hours, then plateauing. These results indicate that the decrease of α-crystallin chaperone activity is attributed to the structural changes.     

Effect of changing electrophilic center from C=O to C=S on rates and mechanism: pyridinolyses of O-2,4-dinitrophenyl thionobenzoate and its oxygen analogue

Second-order rate constants have been measured spectrophotometrically for the reactions of O-2,4-dinitrophenyl thionobenzoate (1) and 2,4-dinitrophenyl benzoate (2) with a series of substituted pyridines in 80 mol % H(2)O/20 mol % DMSO at 25.0 +/- 0.1 degrees C. The Br?nsted-type plots obtained are nonlinear with beta(1) = 0.26, beta(2) = 1.07, and pK(a) degrees = 7.5 for the reactions of 1 and beta(1) = 0.40, beta(2) = 0.90, and pK(a) degrees = 9.5 for the reactions of 2, suggesting that the pyridinolyses of 1 and 2 proceed through a zwiterionic tetrahedral intermediate T(+/-) with a change in the rate-determining step at pK(a) degrees = 7.5 and 9.5, respectively. The thiono ester 1 is more reactive than its oxygen analogue 2 except for the reaction with the strongest basic pyridine studied (pK(a) = 11.30). The k(1) value is larger for the reactions of 1 than for those of 2 in the low pK(a) region, but the difference in the k(1) value becomes negligible with increasing the basicity of pyridines. On the other hand, 1 exhibits slightly larger k(2)/k(-1) ratio than 2 in the low pK(a) region but the difference in the k(2)/k(-1) ratio becomes more significant with increasing the basicity of pyridines. Pyridines are more reactive than alicyclic secondary amines of similar basicity toward 2 in the pK(a) above ca. 7.2 but less reactive in the pK(a) below ca. 7.2. The k(1) value is slightly larger, but the k(2)/k(-1) ratio is much smaller for the reactions of 2 with pyridines than with isobasic secondary amines in the low pK(a) region, which is responsible for the fact that the weakly basic pyridines are less reactive than isobasic secondary amines.     

Relaxation processes in semidilute solutions of polymers in liquid crystal solvents

We investigate the relaxation phenomena in a polymer (polystyrene)/liquid crystal (4-cyano-4'-n-octyl-biphenyl) system, in its homogeneous isotropic phase near the isotropic-isotropic, isotropic-nematic, and isotropic-smectic coexistence curve, using both polarized and depolarized photon correlation spectroscopy (PCS). We study this system for different polystyrene molecular weights (4750, 12 500, and 65 000 g/mol), different compositions (50, 40, 30, and 10% polystyrene (PS) by weight), and different temperatures close to phase boundaries. First of all, we determine the phase diagrams of this system for the different molecular weights. The shape of the phase diagrams strongly depends on the molecular weight. However, in all cases, at low temperatures, these systems separate into an almost pure liquid crystalline (LC) phase and polystyrene-rich phase. PCS measurements show that the relaxation processes in the homogeneous phase are not affected by the proximity of the nematic, or smectic, boundaries (even at a temperature of 0.1 degrees C above the phase separation in two phases). In polarized PCS experiments, we always see three relaxation processes well separated in time: one, very fast, with a relaxation time of the order of 10(-5) s; a second one with a relaxation time within the range 10(-2)-10(-3) s; and a last one, very slow, with a relaxation time of the order of 1 s. Both the fast and slow modes are independent of the wave vector magnitude, while the intermediate relaxation process is diffusive. In depolarized PCS experiments, the intermediate mode disappears and only the fast and slow relaxation processes remain, and they are independent of the magnitude of the wave vector. The diffusive mode is the classical diffusive mode, which is associated with the diffusion of polymer chains in all polymer solutions. The fast mode is due to the rotational diffusion of 4-cyano-4'-n-octyl-biphenyl (8CB) molecules close to polystyrene chains (transient network). Finally, we assign the slowest mode to reorientational processes of small aggregates of PS chains that are not dissolved in 8CB.     

Synthesis, characterisation, crystal structures, reactivity, and electrochemistry of ruthenium-nitrido, ruthenium-cobalt-imido and ruthenapyrrolidone carbonyl clusters containing alkyne ligands

Thermolysis of [Ru3(CO)9(mu3-NOMe)(mu3-eta2-PhC2Ph)] (1) with two equivalents of [Cp*Co(CO)2] in THF afforded four new clusters, brown [Ru5(CO)8(mu-CO)3(eta5-C5Me5)(mu5-N)(mu4-eta2-PhC2Ph)] (2), green [Ru3Co2(CO)7(mu3-CO)(eta5-C5Me5)2(mu3-NH)[mu4-eta8-C6H4-C(H)C(Ph)]] (3), orange [Ru3(CO)7(mu-eta6-C5Me4CH2)[mu-eta3-PhC2(Ph)C(O)N(OMe)]] (4) and pale yellow [Ru2(CO)6[mu-eta3-PhC2(Ph)C(O)N(OMe)]] (5). Cluster 2 is a pentaruthenium mu5-nitrido complex, in which the five metal atoms are arranged in a novel "spiked" square-planar metal skeleton with a quadruply bridging alkyne ligand. The mu5-nitrido N atom exhibits an unusually low frequency chemical shift in its 15N NMR spectrum. Cluster 3 contains a triangular Ru2Co-imido moiety linked to a ruthenium-cobaltocene through the mu4-eta8-C6H4C(H)C(Ph) ligand. Clusters 4 and 5 are both metallapyrrolidone complexes, in which interaction of diphenylacetylene with CO and the NOMe nitrene moiety were observed. In 4, one methyl group of the Cp* ring is activated and interacts with a ruthenium atom. The "distorted" Ru3Co butterfly nitrido complex [Ru3Co(CO)5(eta5-C5Me5)(mu4-N)(mu3-eta2-PhC2Ph)(mu-I)2I] (6) was isolated from the reaction of 1 with [Cp*Co(CO)I2] heated under reflux in THF, in which a Ru-Ru wing edge is missing. Two bridging and one terminal iodides were found to be placed along the two Ru-Ru wing edges and at a hinge Ru atom, respectively. The redox properties of the selected compounds in this study were investigated by using cyclic voltammetry and controlled potential coulometry. 15N magnetic resonance spectroscopy studies were also performed on these clusters.     

Self‐Assembly,Spectroscopic and Electrochemical Studies of Nickel(II)‐4,8‐Diazaundecanediamide Complex

The self‐assembly of NiCl₂·6H₂O with a diaminodiamide ligand 4,8‐diazaundecanediamide (L‐2,3,2) gave a [Ni(C₉H₂₀N₄O₂)(Cl)(H₂O)] Cl·2H₂O ( 1 ). The structure of 1 was characterized by single‐crystal X‐ray diffraction analysis. Structural data for 1 indicate that the Ni(II) is coordinated to two tertiary N atoms, two O atoms, one water and one chloride in a distorted octahedral geometry. Crystal data for 1: orthorhombic, space group P 21nb, a = 9.5796(3) Å, b = 12.3463(4) Å, c = 14.6305(5) Å, Z = 4. Through NH···Cl–Ni (H···Cl 2.42 Å, N···Cl 3.24 Å, NH···Cl 158°) and OH···Cl–Ni contacts (H···Cl 2.36 Å, O···Cl 3.08 Å, OH···Cl 143°), each cationic moiety [Ni(C₉H₂₀N₄O₂) (Cl)(H₂O)]⁺ in 1 is linked to neighboring ones, producing a charged hydrogen‐bonded 1D chainlike structure. Thermogrametric analysis of compound 1 is consistent with the crystallographic observations. The electronic absorption spectrum of Ni(L‐2,3,2)²⁺ in aqueous solution shows four absorption bands, which are assigned to the ³A_2g → ³T_2g, ³T_2g → ¹Eg, ³T_2g → ³T_1g, and ³A_2g → ³T_1g transitions of triplet‐ground state, distorted octahedral nickel(II) complex. The cyclic volammetric measurement shows that Ni²⁺ is more easily reduced than Ni(L‐2,3,2)²⁺ in aqueous solution.