Iridium(III)-Catalyzed C-H Cyclization of Sulfoximines with Diazo Meldrum's Acids for the Synthesis of Cyclic Sulfoximines.

Iridium(III)-catalyzed C-H cyclization of sulfoximines with diazo Meldrum's acid provided cyclic sulfoximines with a carbonyl group in good to excellent yields. These compounds were easily converted into unsubstituted and arylated sulfoximines. Moreover, the vinyl triflates obtained from the cyclic sulfoximines underwent palladium(II)-catalyzed cross-coupling reactions with a variety of aryl, arylalkynyl, and heteroatom (N and S) nucleophiles, affording a wide range of monosubstituted sulfoximines in high yields.

Direct and Regioselective Palladium(II)-Catalyzed B(4)-H Monoacyloxylation and B(4,5)-H Diacetoxylation of o-Carborane Acids with Phenyliodonium Dicarboxylates.

A direct B(4)-H monoacyloxylation via a Pd-catalyzed regioselective B(4)-H activation of o-carborane acids with phenyliodonium dicarboxylates was developed, and a series of B(4)-H monoacyloxylated o-carboranes decorated with active groups were synthesized with moderate to good yields as well as excellent selectivity. In addition, a direct B(4,5)-H diacetoxylation from o-carborane acids with phenyliodonium diacetate was demonstrated.

Expansion of Azulenes as Nonbenzenoid Aromatic Compounds for C-H Activation: Rhodium- and Iridium-Catalyzed Oxidative Cyclization of Azulene Carboxylic Acids with Alkynes for the Synthesis of Azulenolactones and Benzoazulenes.

Rhodium-catalyzed oxidative [4 + 2] cyclization reactions through the C-H activation of azulene carboxylic acids as nonbenzenoid aromatic compounds with symmetrical and unsymmetrical alkynes were developed under aerobic conditions, which produced azulenolactone derivatives with a wide substrate scope and excellent functional group tolerance. Interestingly, azulenic acids in reaction with alkynes underwent iridium-catalyzed [2 + 2 + 2] cyclization accompanied by decarboxylation to afford tetra(aryl)-substituted benzoazulene derivatives. The reactivity order for C-H activation reaction is greater toward azulene-6-carboxylic acid, azulene-1-carboxylic acid, and azulene-2-carboxylic acid. For the first time, the expansion of azulenes having directing group as nonbenzenoid aromatic compounds for C-H activation was successful, indicating that nonbenzenoid aromatic compounds can be used as good substrates for the C-H activation reaction. Therefore, the research area of C-H activation will certainly expand to nonbenzenoid aromatic compounds in future.

Iridium-Catalyzed Regioselective B(4)-Alkenylation and B(3,5)-Dialkenylation of o-Carboranes.

Iridium(I)-catalyzed regioselective B(4)-alkenylation has been developed from o-carboranyl sulfoxonium ylides and alkynes through B(4)-H activation. The sequential B(4)- and B(6)-alkenylation afforded B(3,5)-dialkenylated o-carboranyl sulfoxonium ylides in one pot. Eventually, two alkenyl groups, the same or different, were introduced at positions 3 and 5 of the carborane. Sulfoxonium ylide used as a directing group remains available for further functionalization and is converted to B-alkenylated o-carboranyl trichloromethyl ketones.

Regiodivergent metal-catalyzed B(4)- and C(1)-selenylation of o-carboranes.

Regiodivergent transition metal-catalyzed B(4)- and C(1)-selenylation reactions of o-carboranes have been demonstrated. Namely, Ru(ii)-catalysis selectively generated B(4)-selenylated o-carboranes from the reaction of o-carborane acids with arylselenyl bromides with the release of carbon dioxide. In contrast, Pd(ii) catalysis provided exclusively C(1)-selenylated o-carboranes from the decarboxylative reaction of o-carborane acids with diaryl diselenides. In contrast to previous milestones in this area, these reactions demonstrate broad substrate scope with excellent yields. Combination of these methods leads to the formation of B(4)-C(1)-diselenylated o-carboranes. DFT studies revealed the mechanism of the Ru-process, with initial selenylation of the carborane cluster discovered to be essential for an energetically reasonable decarboxylation. This results in selenylation on the B(4) position prior to the decarboxylation event at C(1). This contrasted with the Pd-process in which the ready decarboxylation at C(1) leads to selenylation at C(1).

Iridium(III)-Catalyzed Regioselective B(4)-H Amination of o-Carboranes with Sufilimines.

Iridium(III)-catalyzed regioselective B(4)-H amination is developed from the reaction of o-carborane acids with sulfilimines without any oxidants under mild conditions, which leads to a wide range of B(4)-H aminated o-carboranes in good yields with a broad substrate scope. Moreover, the selective B(3,6)-diamination reaction of the o-carborane acid was achieved. The present reaction is attractive from a practical point of view because dibenzothiophene is quantitatively recovered and reused.

Synthesis of o-Carborane-Fused Pyrazoles through Sequential C-N Bond Formation.

Transition-metal-free synthetic method for o-carborane-fused pyrazoles as a new scaffold has been developed from the reaction of B(4)-acylmethyl or B(3,5)-diacylmethyl o-carborane with 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP) in the presence of DBU in acetonitrile through sequential diazotization and cyclization reaction in one pot, consequently allowing twofold C-N bond formation under extremely mild conditions and high functional group tolerance.

Iridium-Catalyzed Cage B(4)-Amidation Reaction of o-Carboranes with Dioxazolones: Selective Synthesis of Amidated o-Carboranes and Amidated and Methoxycarbonylated nido-Carboranes.

Described is the Ir-catalyzed cage B(4)-amidation of o-carboranes with dioxazolones by carboxylic acid-assisted B(4)-H bond activation under extremely mild conditions, affording amidated o-carboranes and amidated and methoxycarbonylated nido-carboranes through sequential B(4)-amidation, O-methylation, and B(3)-deboronation in one pot. Carboxylic acid used as a directing group after the cage B(4)-amidation is efficiently trapped by trimethylsilyldiazomethane instead of undergoing decarboxylation. Mechanism studies demonstrated that the O-methylation through trapping of acid occurred first, followed by the B(3)-deboronation.

Rhodium(III)-Catalyzed Sequential C-H Activation and Cyclization from N-Methoxyarylamides and 3-Diazooxindoles for the Synthesis of Isochromenoindolones.

An efficient synthetic method for structurally various isochromenoindolones has been demonstrated through Rh(III)-catalyzed C-H activation followed by a cyclization reaction of N-methoxyarylamides with 3-diazooxindoles. The sequential reaction involves the streamlined formation of C-C and C-O bonds in one pot. The present method provides a broad range of isochromenoindolones as a new privileged scaffold in moderate to good yields with the release of methoxyamine and molecular nitrogen and has the benefits of a broad substrate scope and good functional group tolerance.

Iridium(III)-Catalyzed Sequential C(2)-Arylation and Intramolecular C-O Bond Formation from Azulenecarboxylic Acids and Diaryliodonium Salts Access to Azulenofuranones.

Described herein is the iridium-catalyzed sequential C(2)-arylation reaction and intramolecular C-O bond formation from azulenecarboxylic acids and diaryliodonium salts, leading to the formation of 3-arylazulenofuranones. The sequential reaction proceeded smoothly through generation of 2-arylazulene-1-carboxylic acids derived from the iridium-catalyzed regioselective C(2)-arylation reaction without the decarboxylation reaction.

Electrical property of organic thin films for power device.

Monolayers of lipid on a water surface have attracted much interest as models of biological membranes, but also as precursors of multilayer systems promising many technical applications. Until now, many methodologies have been developed in order to gain a better understanding of the relationship between the structure and function of the monolayers. Maxwell displacement current (MDC) measurement has been employed to study the dielectric property of Langmuir-films. MDC flowing across monolayers is analyzed using a rod-like molecular model. A linear relationship between the monolayer compression speed alpha and the molecular area A(m). Compression speed alpha was about 30, 40, 50 mm/min. Langmuir-Blodgett (LB) layers of Arachidic acid deposited by LB method were deposited onto slide glass as Y-type film. The structure of manufactured device is Au/Arachidic acid/Al (MIM), the number of accumulated layers are 9-21. Also, we then examined of the Metal-Insulator-Metal (MIM) device by means of I-V. I-V characteristics of the device are measured from -3 to +3 [V]. The insulation property of a thin film is better as the distance between electrodes is larger.

Fabrication of protein chip by magnetic force.

This research describes a new immobilizing method of many kinds of biomaterials (enzyme, antibody, and DNA) on a transducer array using magnetic force interaction as the short-range force. The method composes two immobilizing steps. In the first step, same biomaterials are immobilized on metal particles. In the second step, the particles are arranged by the fluidic self-assembly method at random on an array. An array immobilized many kinds of the particles become multichannel biosensor. The biosensor can apply to DNA chip, protein chip, multienzyme electrode, and so on. The metal particles and the array were fabricated by micromachining manufacture. The metal particles were multilayer structure (gold, titanium, and nickel). In the array case, sidewalls of patterning nickel dots on an array were covered by thick negative photoresist (SU-8), and the array was magnetized. The array and the particles were mixed in buffer solution, and were arranged by magnetic force interaction. A quarter of total nickel dots were covered by the particles. The binding direction of the particles was controllable, and condition of particles was almost with gold surface on top. The immobilization of the biomaterials to metal particles was able to materialize it by using 3-CPD. This confirmed an activity by the luminol radiation.

Antiplatelet activity of [5-(2-methoxy-5-chlorophenyl)furan-2-ylcarbonyl]guanidine (KR-32570), a novel sodium/hydrogen exchanger-1 and its mechanism of action.

The antiplatelet effects of a novel guanidine derivative, KR-32570 ([5-(2-methoxy-5-chlorophenyl) furan-2-ylcarbonyl]guanidine), were investigated with an emphasis on the mechanisms underlying its inhibition of collagen-induced platelet aggregation. KR-32570 significantly inhibited the aggregation of washed rabbit platelets induced by collagen (10 microg/mL), thrombin (0.05 U/mL), arachidonic acid (100 microM), a thromboxane (TX) A2 mimetic agent U46619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F2, 1 microM) and a Ca2+ ATPase inhibitor thapsigargin (0.5 microM) (IC50 values: 13.8 +/- 1.8, 26.3 +/- 1.2, 8.5 +/- 0.9, 4.3 +/- 1.7 and 49.8 +/- 1.4 microM, respectively). KR-32570 inhibited the collagen-induced liberation of [3H]arachidonic acid from the platelets in a concentration dependent manner with complete inhibition being observed at 50 microM. The TXA2 synthase assay showed that KR-32570 also inhibited the conversion of the substrate PGH2 to TXB2 at all concentrations. Furthermore, KR-32570 significantly inhibited the [Ca2+]i mobilization induced by collagen at 50 microM, which is the concentration that completely inhibits platelet aggregation. KR-32570 also decreased the level of collagen (10 microg/mL)-induced secretion of serotonin from the dense-granule contents of platelets, and inhibited the NHE-1-mediated rabbit platelet swelling induced by intracellular acidification. These results suggest that the antiplatelet activity of KR-32570 against collagen-induced platelet aggregation is mediated mainly by inhibiting the release of arachidonic acid, TXA2 synthase, the mobilization of cytosolic Ca2+ and NHE-1.

An antithrombotic agent, NQ301, inhibits thromboxane A2 receptor and synthase activity in rabbit platelets.

In previous studies we have reported that NQ301, a synthetic 1,4-naphthoquinone derivative, displays a potent antithrombotic activity, and that this might be due to antiplatelet effect, which was mediated by the inhibition of cytosolic Ca(2+) mobilization in activated platelets. In the present study, the effect of NQ301 on arachidonic acid cascade in activated platelets has been examined. NQ301 concentration-dependently inhibited washed rabbit platelet aggregation induced by collagen (10 microg/ml), arachidonic acid (100 microM) and U46619 (1 microM), a thromboxane A2 receptor agonist, with IC50 values of 0.60+/-0.02, 0.78+/-0.04 and 0.58+/-0.04 microM, respectively. NQ301 also produced a shift to the right of the concentration-effect curve of U46619, indicating a competitive type of antagonism on thromboxane A2/prostaglandin H2 receptor. NQ301 slightly inhibited collagen-induced arachidonic acid liberation. In addition, NQ301 potently suppressed thromboxane B2 formation by platelets that were exposed to arachidonic acid in a concentration-dependent manner, but had no effect on the production of prostaglandin D2, indicating an inhibitory effect on thromboxane A2 synthase. This was supported by thromboxane A2 synthase activity assay that NQ301 concentration-dependently inhibited thromboxane B2 formation converted from prostaglandin H2. Moreover, NQ301 concentration-dependently inhibited 12-hydroxy-5,8,10,14-eicosatetraenoic acid formation by platelets that were exposed to arachidonic acid. Taken together, these results suggest that NQ301 has a potential to inhibit thromboxane A2 synthase activity with thromboxane A2/prostaglandin H2 receptor blockade, and modulate arachidonic acid liberation as well as 12-hydroxy-5,8,10,14-eicosatetraenoic acid formation in platelets. This may also be a convincing mechanism for the antithrombotic action of NQ301.

Inhibition of human endothelial cell proliferation by Gami--Jeonggi--San (Jiawei--Zhenqi--San) is accompanied by transcriptional up-regulation of p53 and Waf1 tumor suppressor genes.

The effects of Gami-Jeonggi-San (GJS) on proliferation of human endothelial cell (HUV-EC-C) were investigated using a flow cytometry and a quantitative RT-PCR analysis of gene expression. An accumulation of cells at G(1) phase of the cell cycle was found at 72 h after treatment (10 microl/ml) while no detectable reduction of PCNA expression was recognized. To elucidate that the cell cycle inhibitory effect of GJS stems from its capability of transcriptional regulation of the cell cycle-controlling genes, we investigated mRNA expression of p53, Waf1, PCNA, Cyclin D1, Cdc2, Histone H3, c-Myc, and c-Fos. Significantly elevated mRNA levels of the p53 tumor suppressor gene and its down-stream mediator gene, Waf1, whose increased expressions were known to trigger G(1) cell cycle arrest, were observed. In contrast, a marked reduction of two early G(1)-specific, cell cycle stimulating genes, c-Myc and c-Fos, were found at 24h after treatment, while there were no detectable changes in expressions of G(1)-S or G(2)-M transition-related genes, indicating the G(1) specificity of GJS effect on the cell cycle. These results suggest that the pharmacological effects of GJS might be derived in part from inhibition of cellular proliferation of human endothelial cells, and that GJS inhibition of the cell cycle might stem from its regulatory capability on the transcription of the cell cycle-controlling genes, including p53 and Waf1 tumor suppressor genes.

Fecal metabolic activities of herbal components to bioactive compounds.

The herbal components should be transformed to bioactive compounds by the intestinal bacteria and then expressed the pharmacological action of herbal medicines. Human fecal enzyme activities related to the metabolism of herbal components were measured. The metabolic activities of puerarin, poncirin, glycyrrhizin, ginsenoside Rb1 and ginsenoside Rb2 to their bioactive compounds were 3.5 +/- 1.18, 333.1 +/-183.64, 95.7 +/- 107.1, 28.6 +/- 10.32 and 20.8 +/- 13.3 micromol/ h/g, respectively. The profile of these metabolic activities of glycyrrhizin and ginsenosides were not changed even if herbal extracts, water extract of Glycyrrhizae Radix and Ginseng Radix, instead of the isolated compounds were used. All the enzyme activities tested were not different between male and female, and between ages. However, the difference of these enzyme activities in individuals was significant. These results suggest that the metabolic activity of herbal components to bioactive compounds may be a factor of constitutional classification, and could be available for constitutional classifications, if the constitutional herbal medicines were used.

Hepatoprotective activity of reduohanxiao-tang (yuldahanso-tang) is related to the inhibition of beta-glucuronidase.

Beta-glucuronidase-inhibitory and hepatoprotective effects of Reduohanxiao-tang (Yuldahanso-tang), which has been used for liver diseases and stroke, on carbon tetrachloride (CCl4)-induced hepatotoxicity of rats were investigated. Reduohanxiao-tang potently inhibited beta-glucuronidases. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactic acid dehydrogenase (LDH) levels of the CCl4 group orally treated with Reduohanxiao-tang (100 mg/kg) were lowered to 54%, 71.5% and 66.1% of the CCl4-treated control group, respectively. Among the ingredients of the Reduohanxiao-tang, the rhizomes of Pueraria thunbergiana and Scutellaria baicalensis potently inhibited beta-glucuronidases and protected against CCl4-induced liver injury. Orally administered puerarin, which is a main component of Pueraria thunbergiana, showed potent hepatoprotective activity, but did not inhibit beta-glucuronidase. However, daidzein, which is produced from puerarin by human intestinal bacteria, potently inhibited beta-glucuronidase. These results suggest that beta-glucuronidase inhibition by herbal medicines may protect against CCl4-induced liver injury.

Effect of Uwhangchungsimwon on expression of nitric oxide synthase and vascular cell adhesion molecule-1 in human endothelial cells.

For molecular biological characterization of the effects of Uwhangchungsimwon (UC) on the expression of nitric oxide synthase (NOS) gene and cell adhesion-regulating gene, vascular cell adhesion molecule-1 (VCAM-1), the human endothelial cell line (ECV304) was treated with the extract of UC and transcription of genes was examined using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. UC showed a transcription-activating effect on the NOS gene and a suppressing effect on the VCAM-1 gene in human endothelial cells, and these effects were found in a dose- and time-dependent manner. Down-regulation of VCAM-1 expression by UC was directly mediated by increased nitric oxide (NO) production, which was associated with increased NOS gene transcription. This study strongly suggests that the clinical effects of UC on stroke might be derived at least in part from its ability to induce NOS expression, which was followed by significant reduction of VCAM-1 expression.

Anti-platelet activity of KR-32560, a novel sodium/hydrogen exchanger-1 inhibitor.

We investigated the anti-platelet effect of a newly synthesized guanidine derivative KR-32560, a sodium/hydrogen exchanger-1 (NHE-1) inhibitor, together with the elucidation of the possible mode of action. KR-32560 concentration dependently inhibited the aggregation of washed rabbit platelets induced by collagen (10 microg mL(-1)) and arachidonic acid (AA; 100 microM), with IC50 values of 25 and 46 microM, respectively. Whereas, KR-32560 showed weaker potency against aggregation induced by thrombin (0.05 UmL(-1)) and U46619 (1 microM), and had no effect on thapsigargin (0.5 microM)- or A23187 (5 microM)-induced platelet aggregation up to 50 microM. KR-32560 inhibited the collagen-induced [3H]AA liberation in a concentration-dependent manner. In addition, KR-32560 significantly suppressed TXB2 formation in AA-exposed platelets, but had no effect on production of PGD2, indicating an inhibitory effect on TXA2 synthase. This finding was supported by a TXA2 synthase assay that KR-32560 inhibited the conversion of PGH2 into TXB2 with a similar magnitude to suppression of TXB2 formation. Furthermore, KR-32560 significantly inhibited the collagen-induced [Ca2+]i mobilization and serotonin secretion. Taken together, these observations suggest that the anti-platelet activity of KR-32560 may be mediated by the inhibition of cytoplasmic Ca2+ mobilization and AA liberation.

Antiplatelet activity of J78 (2-Chloro-3-[2'-bromo, 4'-fluoro-phenyl]-amino-8-hydroxy-1,4-naphthoquinone), an antithrombotic agent, is mediated by thromboxane (TX) A2 receptor blockade with TXA2 synthase inhibition and suppression of cytosolic Ca2+ mobilization.

We previously reported that J78 (2-chloro-3-[2'-bromo, 4'-fluoro-phenyl]-amino-8-hydroxy-1,4-naphthoquinone), a newly synthesized 1,4-naphthoquinone derivative, exhibited a potent antithrombotic effect, which might be due to antiplatelet rather than anticoagulation activity. In the present study, possible anti-platelet mechanism of J78 was investigated. J78 concentration-dependently inhibited rabbit platelet aggregation induced by collagen (10 microg/ml), thrombin (0.05 U/ml), arachidonic acid (100 microM), and U46619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F(2); 1 microM), a thromboxane (TX) A(2) mimic, with IC(50) values of 0.32 +/- 0.01, 0.44 +/- 0.02, 0.50 +/- 0.04, and 0.36 +/- 0.02 microM, respectively. J78 also produced a shift to the right of the concentration-response curve of U46619, indicating an antagonistic effect on the TXA(2) receptor. J78 concentration-dependently inhibited collagen-induced arachidonic acid liberation. In addition, J78 potently suppressed TXA(2) formation by platelets that were exposed to arachidonic acid in a concentration-dependent manner but had no effect on the production of PGD(2), indicating an inhibitory effect on TXA(2) synthase. This was supported by a TXA(2) synthase activity assay that J78 concentration-dependently inhibited TXB(2) formation converted from PGH(2). Furthermore, J78 was also able to inhibit the [Ca(2+)](i) mobilization induced by collagen or thrombin at such a concentration that completely inhibited platelet aggregation. Taken together, these results suggest that the antiplatelet activity of J78 may be mediated by TXA(2) receptor blockade with TXA(2) synthase inhibition and suppression of cytosolic Ca(2+) mobilization.