Synthesis, Structural Characterization, and Optical Properties of Benzene-Fused Tetracyclic and Pentacyclic Stiboles.

The expectation that antimony (Sb) compounds should display phosphorescence emissions based on the "heavy element effect" prompted our interest in the introduction of antimony to a biaryl as the bridging atom in a fused heterole system. Herein, the synthesis, molecular structures, and optical properties of novel benzene-fused heteroacenes containing antimony or arsenic atoms are described. The stiboles and arsole were prepared by the condensation of dibromo(phenyl)stibane or dichloro(phenyl)arsine with dilithium intermediates derived from the corresponding dibromo compounds. Nuclear magnetic resonance (NMR) spectroscopy and X-ray crystal analysis revealed that the linear pentacyclic stibole was highly symmetric in both the solution and crystal states. In contrast, the curved pentacyclic stibole adopted a helical structure in solution, and surprisingly, only M helical molecules were crystallized from the racemate. All synthesized compounds produced very weak or no emissions at room temperature or in the solid state. In contrast, the linear penta- and tetracyclic stiboles exhibited clear phosphorescence emissions in the CHCl3 frozen matrix at 77 K under aerobic conditions.

Cytobrush cytology patterns of early postpartum dairy cows.

Endometrial cytobrush cytology has been recommended as a reliable method for determining the percentage of polymorphonuclear leukocytes (PMN%) in cattle smears to diagnose cytological endometritis (CE). In this study, the clarity of cytobrush　cytological smears and the influence of different sample evaluation methods (number　and types of cells counted) on CE diagnosis were evaluated. Samples from 28 lactating　Holstein cows were collected weekly between 3 and 7 weeks postpartum. Smear clarity,　based on cell density, quality of cell morphology, and red blood cell contamination,　was significantly poorer at 3 weeks than between 5 and 7 weeks postpartum. Five　different cell counting methods (C100, C200, C300, C400, and C500) were used,　where 100-500 nucleated cells (endometrial epithelial cells, PMN consisting of neutrophils, eosinophils and basophils, lymphocytes, and macrophages) were counted. Agreement of diagnostic results for CE between C300 and C500 and between C400 and C500 was excellent at all observation times. In calculations of the PMN% based on whether the number of lymphocytes and macrophages were or were not excluded in the denominator, exclusion of these cells in the calculations did not affect the diagnosis of CE. While reduced clarity in earlier stage samples might interfere with the accuracy of cytobrush cytology, C300 can be recommended to determine the endometrial PMN%.

Overall Shape Constraint of Alternating α/ß-Hybrid Peptides Containing Bicyclic ß-Proline.

Our NMR, IR/Raman, CD spectroscopic, and X-ray crystallographic studies, as well as accelerated molecular dynamics simulations, showed that alternating hybrid α/ß-peptides containing a bicyclic ß-proline surrogate form unique extended curved folds, regardless of the peptide length and solvent environment. It is suggested that extended ß/PPII structures are preferred in the insulating α-alanine moieties between the rigid bicyclic ß-proline structures. These hybrid peptides inhibit p53-MDM2 and p53-MDMX protein-protein interactions.

Robust trans-amide helical structure of oligomers of bicyclic mimics of ß-proline: impact of positional switching of bridgehead substituent on amide cis-trans equilibrium.

Because homooligomers of 7-azabicyclo[2.2.1]heptane-2-endo-carboxylic acid, a bridged ß-proline analogue with a substituent installed at the remote C4-bridgehead position, completely biased the amide cis-trans equilibrium to the cis-amide structure, we expected that introduction of a substituent at the C1-bridgehead position adjacent to the carboxylic acid moiety, rather than the remote C4-bridgehead position, would tip the cis-trans amide equilibrium toward trans-amide structure without the aid of hydrogen bonding. Thus, in this work we established an efficient synthetic route to an optically active bicyclic analogue of 1,1-disubstituted ß-proline, bearing a substituent at the C1-bridgehead position. Crystallographic, spectroscopic, and computational studies showed that indeed oligomers of this analogue take a consistent helical structure involving all-trans-amide linkages, independently of the number of residues, from the dimer up to the octamer. Oligomers composed of (R)-ß-amino acid units form an extended left-handed helix with about 2.7 residues per turn and an approximately 4.0 Å rise per residue, characterized by complete lack of main-chain hydrogen bonding. This unique helical structure shows some similarity in shape to the trans-amide-based polyproline II (PPII) helix. The present helix was stable in various kinds of solvents such as alcohols. The present work provided a fundamental structural basis for future applications.

A novel organobismuth compound, 1-[(2-di-p-tolylbismuthanophenyl)diazenyl]pyrrolidine, induces apoptosis in the human acute promyelocytic leukemia cell line NB4 via reactive oxygen species.

A novel organobismuth compound, 1-[(2-di-p-tolylbismuthanophenyl)diazenyl]pyrrolidine (4), which has 1-(phenyldiazenyl)pyrrolidine (1) substituent in a benzene ring of tri(p-tolyl)bismuthane (2), was synthesized and tested for biological activity toward human tumor cell lines. 4 had a potent anti-proliferative effect on human cancer cell lines, although both 1 and 2 exhibited only weak activity. The sensitivity of leukemic cell lines to 4 was relatively high; IC(50) values for the human leukemia cell line NB4 and cervical cancer cell line HeLa were 0.88 µM and 5.36 µM, respectively. Treatment of NB4 cells with 4 induced apoptosis, loss of mitochondrial membrane potential (ΔΨ(mt)) and the generation of cellular reactive oxygen species (ROS). 1 and 2 did not induce apoptosis and had only a marginal effect on ΔΨ(mt) and the generation of ROS. N-acetyl cysteine (NAC) reduced the generation of ROS and conferred protection against 4-induced apoptosis, indicating a role for oxidative stress. 4 did not inhibit the polymerization of tubulin in vitro. 1-[2-(di-p-tolylstibanophenyl)diazenyl]pyrrolidine (3), which has the same chemical structure as 4 but contains antimony in place of bismuth, did not show any cytotoxic activity. The results suggest that the conjugated structure of the diazenylpyrrolidine moiety and bismuth center are key to the bioactivity of 4.

Linderolides A-F, eudesmane-type sesquiterpene lactones and linderoline, a germacrane-type sesquiterpene from the roots of Lindera strychnifolia and their inhibitory activity on NO production in RAW 264.7 cells in vitro.

From the roots of Lindera strychnifolia, seven sesquiterpenes, named linderolides A-F and linderoline, were isolated together with six known compounds. The structures of linderolides A-F were elucidated to be eudesmane-type sesquiterpenes and linderoline was found to be a derivative of a germacrane-type sesquiterpene. Their structures were elucidated by means of spectroscopic evidence and that of linderolide A was confirmed by X-ray analysis. The inhibitory activity toward NO production was assayed using RAW264.7 cells with evaluating the cell growth by MTT method, linderolides C, D and F being found to be moderately active.

Zierane sesquiterpene lactone, cembrane and fusicoccane diterpenoids, from the Tahitian liverwort Chandonanthus hirtellus.

Cembrane-type diterpenoids, 13,18,20-epi-iso-chandonanthone (1) and (8E)-4alpha-acetoxy-12alpha,13alpha-epoxycembra-1(15),8-diene (2), two fusicoccane-type diterpenoids, fusicoauritone 6alpha-methyl ether (3) and 6beta,10beta-epoxy-5beta-hydroxyfusicocc-2-ene (4) and a zierane sesquiterpene gamma-lactone, chandolide (5) were isolated from the Tahitian liverwort Chandonanthus hirtellus (Web.) Mitt., together with eight known diterpenoids, chandonanthine (6), fusicogigantone A (7), fusicogigantone B (8), fusicogigantepoxide (9), anadensin (10), fusicoauritone (11), ent-verticillol (12) and ent-epi-verticillol (13). Their structures were established by a combination of extensive NMR spectroscopy and/or X-ray crystallographic analyses. Compounds 1, 5 and 10 showed weak cytotoxic activity against HL-60. Compound 3 also indicated weak cytotoxic activity against KB cell lines.

Absolute configuration of (+)-pinoresinol 4-O-[6''-O-galloyl]-beta-D-glucopyranoside, macarangiosides E, and F isolated from the leaves of Macaranga tanarius.

A lignan glucoside, (+)-pinoresinol 4-O-[6''-O-galloyl]-beta-D-glucopyranoside (1), and two megastigmane glucosides, named macarangiosides E and F (2,3), together with 15 known compounds (4-18) were isolated from leaves of Macaranga tanarius (L.) Müll.-Arg. (Euphorbiaceae). Their structures were elucidated by spectroscopic and chemical analyses. In addition, the absolute stereochemistry of macarangiosides B and C isolated previously from the same plant was also determined for the first time. Compounds 1 and 2 were galloylated on glucose and possessed potent DPPH radical-scavenging activity.

Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity.

Retinoid X receptor (RXR) ligands are attractive candidates for clinical application because of their activity against tamoxifen-resistant breast cancer, taxol-resistant lung cancer, metabolic syndrome, and allergy. Though several RXR ligands, especially RXR antagonists, have been reported, the rational molecular design of such compounds is not well advanced. 4-[N-Methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)amino]nicotinic acid (5a) is a moderately RXRalpha-preferential agonist, and we examined the feasibility of replacing the methyl group on the sulfonamide with a longer alkyl chain or an aromatic ring as an approach to produce new RXR antagonists. Several of the resulting benzenesulfonanilide-type compounds showed RXR antagonist activity. This design strategy should be a useful approach for addressing the lack of structure diversity of RXR antagonists.

Novel oxime and oxime ether derivatives of 12,14-dichlorodehydroabietic acid: design, synthesis, and BK channel-opening activity.

Oxime ether derivatives of the benzylic ketone of 12,14-dichlorodehydroabietic acid (diCl-DHAA, 4b) were synthesised, and their BK channel-opening activity was evaluated in an assay system of CHO-K1 cells expressing hBKalpha channels. Oxime ether structure on the B ring of diCl-DHAA significantly increased the BK channel-opening activity.

Optical resolution of (+/-)-1,2-Bis(2-methylphenyl)ethylene-1,2-diamine as a chiral framework for 2-iminoimidazolidine with 2-methylphenyl pendant and the guanidine-catalyzed asymmetric michael reaction of tert-butyl diphenyliminoacetate and ethyl acrylate.

(+/-)-1,2-Bis(2-methylphenyl)ethylene-1,2-diamine, prepared from benzil and ammonium acetate, was optically resolved as a chiral framework for 2-(1-benzyl-2-hydroxyethyl)imino-1,3-dimethylimidazolidine with 2-methylphenyl pendants at the 4,5-positions. Catalysis ability of the 1,3-dimethyl-4,5-bis(2-methylphenyl)imidazolidine and the related 1,3-dibenzyl-4,5-diphenylimidazolidine was examined in the asymmetric Michael reaction of t-butyl diphenyliminoacetate and ethyl acrylate.

Design, synthesis, and biological activity of folate receptor-targeted prodrugs of thiolate histone deacetylase inhibitors.

Aiming to develop selective anticancer drugs, we designed and synthesized three disulfides bearing a folic acid moiety as candidate folate receptor (FR)-targeted prodrugs of thiolate histone deacetylase inhibitors. Among them, compound 1 displayed growth-inhibitory activity toward folate receptor-positive MCF-7 breast cancer cells. The activity of 1 was significantly reduced by free folic acid, suggesting that cellular uptake of 1 is mediated by FR.

ent-halimane diterpenes and a guaiane sesquiterpene from Cladogynos orientalis.

Four new ent-halimane diterpenes (1-4) and one new guaiane sesquiterpene (5) were isolated from the CHCl(3) extract of the roots of Cladogynos orientalis, together with six known compounds. The structures of compounds 1-5 were established using spectroscopic methods, and the stereochemistry of chettaphanin I (6) was confirmed by X-ray crystallography.