Persulfate promoted carbamoylation of N-arylacrylamides and N-arylcinnamamides with 4-carbamoyl-Hantzsch esters.

Carbamoyl-Hantzsch esters were used as carbamoyl radical precursors for oxidative carbamoylation of N-arylacrylamides and N-arylcinnamamides in the presence of inexpensive persulfates. This protocol can be applied to a broad range of substrates with various functional groups, providing a variety of 3,3-disubstituted oxindoles and 3,4-disubstituted dihydroquinolin-2(1H)-ones in moderate to good yields via an intermolecular addition/cyclization process.

Cross-dehydrogenative Coupling of N-Aryl Tetrahydroisoquinolines Catalyzed by an Anthraquinone-containing Polymeric Photosensitizer.

This work reports the photocatalytic application of an anthraquinone-containing polymeric photosensitizer (AQ-PHEMA) in the visible light-induced cross-dehydrogenative-coupling of N-aryl tetrahydroisoquinolines with several nucleophiles, including nitromethane, 1-methyl-2-alkyl ketone and dialkyl (aryl) phosphine oxide. The results revealed that the reaction could be catalyzed by AQ-PHEMA efficiently to afford a series of 1-substituted-2-aryl-1,2,3,4-tetrahydroisoquinolines in good to excellent yields with nice substrate tolerance under aerobic conditions at room temperature. The practical application potential was also showcased by a gram-scale synthesis. More importantly, the utilization of AQ-PHEMA as a heterogeneous photosensitizer also showed nice recyclability and reusability of the catalyst, whereas AQ-PHEMA can be easily separated and reused for at least 8 times without significant loss of photocatalytic activity.

Photoredox Generation of N-Centered Hydrazonyl Radicals Enables the Construction of Dihydropyrazole-Fused gem-Difluoroalkenes.

An efficient visible-light-promoted N-radical-mediated tandem radical cyclization/defluorinated alkylation of ß,γ-unsaturated hydrazones, and α-trifluoromethyl alkenes is described. This protocol provides a general and effective route to synthesize various dihydropyrazole-fused gem-difluoroalkenes at moderate to excellent yields under redox-neutral, metal-free, and mild conditions.

Mn(III)-Mediated Radical Cyclization of o-Alkenyl Aromatic Isocyanides with Boronic Acids: Access to N-Unprotected 2-Aryl-3-cyanoindoles.

The synthesis of N-unprotected 2-aryl-3-cyanoindoles was realized via the Mn(III)-mediated radical cascade cyclization of o-alkenyl aromatic isocyanides with boronic acids. A possible mechanism involving a sequential intermolecular radical addition, intramolecular cyclization, and cleavage of the C-C bond under mild reaction conditions is proposed. Mechanism studies show that H2O or O2 might provide the oxygen source for the elimination of benzaldehyde.

Ruthenium(II)-Catalyzed C-C/C-N Coupling of 2-Arylquinazolinones with Vinylene Carbonate: Access to Fused Quinazolinones.

In this work, ruthenium(II)-catalyzed C-C/C-N annulation of 2-arylquinazolinones with vinylene carbonate is reported to synthesize fused quinazolinones. This catalytic system tolerates a wide range of substrates with excellent functional-group compatibility. In this transformation, the vinylene carbonate acts as an ethynol surrogate without any external oxidant involved. Furthermore, preliminary mechanistic studies were conducted, and a plausible catalytic cycle was also proposed.

Synthesis of gem-Difluoroalkenes via Zn-Mediated Decarboxylative/Defluorinative Cross-Coupling.

An efficient and mild Zn-mediated decarboxylative/defluorinative alkylation of α-trifluoromethyl alkenes using N-hydroxyphthalimide esters as radical precursors was developed. Several α-trifluoromethyl alkenes were readily coupled to a wide range of primary, secondary, and tertiary radicals, affording the desired gem-difluoroethylenes in moderate to excellent yields. This reaction protocol was also successfully applied to the construction of complex molecules such as the bioactive natural dehydroabietic acid and glycosyl groups bearing the gem-difluoroethylene moiety.

Synthesis of pyrazolo[1,5-c]quinazoline derivatives through the copper-catalyzed domino reaction of o-alkenyl aromatic isocyanides with diazo compounds.

A novel copper-catalyzed domino reaction between o-alkenyl aromatic isocyanides and diazo compounds has been developed under mild reaction conditions. Various o-alkenyl aromatic isocyanides were prepared from readily available reactants. The reaction provides a general and efficient method for the synthesis of pyrazolo[1,5-c]quinazolines by the formation of two rings and three new bonds in a single step from readily available acyclic starting materials. A mechanism involving a tandem (3+2) cyclization/elimination/intramolecular aza-addition sequence was proposed.

Synthesis of Monofluoroalkenes through Visible-Light-Promoted Defluorinative Alkylation of gem-Difluoroalkenes with 4-Alkyl-1,4-dihydropyridines.

In this study, a facile and efficient method to synthesize monofluoroalkenes by photoredox catalytic defluorinative alkylation of gem-difluoroalkenes with 4-alkyl-1,4-dihydropyridines under mild conditions (room temperature) is described. This novel strategy is applicable for a broad range of gem-difluoroalkene substrates with good functional group tolerance and a variety of 4-alkyl-1,4-dihydropyridines (including primary, secondary, and even tertiary alkyl radicals). Moreover, it also allows the challenging radical coupling with glycosyl-based 4-alkyl-1,4-dihydropyridines (DHPs) to synthesize monofluoroalkenylated saccharides.

Anti-inflammatory effect of fucoxanthin on dextran sulfate sodium-induced colitis in mice.

The anti-inflammatory activities of fucoxanthin, a marine carotenoid derived from the macroalgae and microalgae, have been demonstrated in the previous studies. However, the effect of fucoxanthin on ulcerative colitis (UC), an inflammatory bowel disease, was still unclear. In this study, we evaluated the in vivo anti-inflammatory effect of fucoxanthin on dextran sulfate sodium(DSS)-induced colitis in mice. Fucoxanthin at the doses of 50 and 100 mg/kg/day significantly protected against DSS-induced gradual loss of body weight, exhibited inhibitory effects on the DSS-induced increase of disease activity index and colon shortening. Moreover, fucoxanthin treatment resulted in a marked amelioration of the histological damage in the colon, and reduced the colonic PGE2 levels in colitic mice. In addition, the DSS-induced overexpressions of inflammation-related molecules including COX-2 and NF-κB were significantly decreased in fucoxanthin-treated mice. These finding suggested that the use of fucoxanthin provides a new and attractive alternative to control UC.

Copper/B2pin2-Catalyzed Difluoroalkylation of Methylenecyclopropanes with Bromodifluorinated Acetates and Acetamides: One-Pot Synthesis of CF2-Containing Dihydronaphthalene Derivatives.

Novel copper/B2pin2-catalyzed difluoroalkylation of methylenecyclopropanes with bromodifluorinated acetates and acetamides via a tandem radical process involving ring-opening/intramolecular cyclization has been reported. This protocol is not only tolerated to a diverse range of substrates but also applicable to the synthesis of useful difluoromethylated compounds. Moreover, the reaction could be performed on a gram scale with a high yield, which opens up the possibility for practical applications.

Rhodium(III)-Catalyzed Meta-Selective C-H Alkenylation of Phenol Derivatives.

Rhodium(III)-catalyzed remote meta-selective-C-H alkenylation of phenol derivatives has been developed using a traceless organosilicon template as the directing group. This transformation proceeds smoothly with good yields and high meta-selectivities toward a series of phenol and alkene substrates. In addition, this protocol provides an effective strategy for late-stage transformations of various meta-alkenylated aromatic compounds.

A meta-selective-C-H alkenylation of phenol-derivatives employing a traceless organosilicon template.

A traceless organosilicon template-directed meta-selective-C-H alkenylation of phenols was realized with good yields and high selectivities. The template was readily removable through F--promoted O-Si cleavage under extremely mild conditions or recyclable through a p-TSA catalyzed process. The product was successfully applied in the preparation of a series of meta-alkenylated aromatic compounds.

Activation of hydrogen peroxide by ionic liquids: mechanistic studies and application in the epoxidation of olefins.

Imidazolium-based ionic liquids that contain perrhenate anions are very efficient reaction media for the epoxidation of olefins with H2O2 as an oxidant, thus affording cyclooctene in almost quantitative yields. The mechanism of this reaction does not follow the usual pathway through peroxo complexes, as is the case with long-known molecular transition-metal catalysts. By using in situ Raman, FTIR, and NMR spectroscopy and DFT calculations, we have shown that the formation of hydrogen bonds between the oxidant and perrhenate activates the oxidant, thereby leading to the transfer of an oxygen atom onto the olefin demonstrating the special features of an ionic liquid as a reaction environment. The influence of the imidazolium cation and the oxidant (aqueous H2O2, urea hydrogen peroxide, and tert-butyl hydrogen peroxide) on the efficiency of the epoxidation of cis-cyclooctene were examined. Other olefinic substrates were also used in this study and they exhibited good yields of the corresponding epoxides. This report shows the potential of using simple complexes or salts for the activation of hydrogen peroxide, owing to the interactions between the solvent medium and the active complex.

A recombinant human neuregulin-1 peptide improves preservation of the rodent heart after prolonged hypothermic storage.

BACKGROUND: Donor hearts are subjected to ischemia-reperfusion injury during transplantation. Recombinant human neuregulin (rhNRG)-1 peptide attenuates myocardial injury in various animal models of cardiomyopathy. Supplementing the organ-storage solution, Celsior (C), with glyceryl trinitrate (GTN) and cariporide improves cardiac preservation after hypothermic storage. We hypothesized that the addition of rhNRG-1 to C would improve cardiac preservation after hypothermic storage and provide incremental benefit in combination with GTN and cariporide. METHODS: An isolated working rat heart model was used. To assess the effect of rhNRG-1, hearts were stored for 6 hr at 4°C in C ± rhNRG-1 (14 nM). To assess the effect of using a combination of prosurvival kinase activators on cardiac preservation, the ischemic storage time was extended to 10 hr and hearts stored in C ± rhNRG-1 (14 nM) ± GTN (0.1 mg/mL) ± Cariporide (10 µM). Hearts were subsequently reperfused, cardiac function remeasured, and tissue collected for protein analysis and immunohistochemistry. Optimal timing of rhNRG-1 administration was also assessed. RESULTS: rhNRG-1 supplemented C improved functional recovery after 6 hr of storage (cardiac output recovery [mean ± SEM]: control 1.4% ± 0.6%; rhNRG-1+C 21.1% ± 7.9%; P<0.05). After 10-hr storage, no improvement in functional recovery was observed with rhNRG-1, GTN, or cariporide alone; however, GTN combined with cariporide did improve recovery (P<0.01), which was further enhanced by the addition of rhNRG-1 (P<0.01). Functional improvements were accompanied by increased phosphorylation of Akt, ERK1/2, STAT3, and GSK-3ß and reduced cleaved caspase-3 (P<0.01). CONCLUSIONS: rhNRG-1 given together with other activators of prosurvival pathways improves preservation of the rat heart and shows promise for increasing the cold-ischemic life of donor hearts in transplantation.

Parenteral administration of recombinant human neuregulin-1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses.

AIMS: Neuregulin-1 (NRG-1) plays a critical role in the adaptation of the heart to injury, inhibiting apoptosis and inducing cardiomyocyte proliferation. We have shown previously that rhNRG-1 improves cardiac function and survival in animal models of cardiomyopathy. Here we report the first human study aimed at exploring the acute and chronic haemodynamic responses to recombinant human NRG-1 (beta(2a) isoform; rhNRG-1) in patients with stable chronic heart failure (CHF). METHODS AND RESULTS: Fifteen patients (age, 60 ± 2; NYHA II:III, 9:6; left ventricular ejection fraction (LVEF) <40%) on optimal medical therapy for CHF, received a rhNRG-1 infusion daily for 11 days. Acute and chronic haemodynamic, structural and biochemical effects were determined by serial right heart catheterization, cardiac magnetic resonance (CMR), echocardiography and measurement of neurohumoral indices. Acutely, cardiac output increased by 30% during a 6 h rhNRG-1 infusion (P < 0.01). Pulmonary artery wedge pressure and systemic vascular resistance decreased 30 and 20%, respectively, at 2 h (P < 0.01). A 47% reduction in serum noradrenaline, a 55% reduction in serum aldosterone and a 3.6-fold increase in N-terminal prohormone brain natriuretic peptide levels were concurrently observed (P < 0.001). These acute haemodynamic effects were sustained, as demonstrated by the 12% increase in LVEF from 32.2 ± 2.0% (baseline) to 36.1 ± 2.3% (mean ± SE, P < 0.001) at 12 weeks. The therapy was well tolerated. CONCLUSION: rhNRG-1 appears to produce favourable acute and chronic haemodynamic effects in patients with stable CHF on optimal medical therapy. Randomized controlled trials of rhNRG-1 in cardiac disease are thus warranted. Clinical Trial Registration Information The trial was registered with the Australian New Zealand Clinical Trials Registry, anzctr.org.au Identifier: ACTRN12607000330448.

[Establishment of an ErbB3- and ErbB4-specific ligand screening system, and a screen of neuregulin-1 mutants].

Neuregulin-1 (NRG1), now in a phase II clinical trial, has beneficial effects on heart failure patients through the activation of ErbB2/ErbB4 receptor pair. To decrease the side effect of NRG1 on activating ErbB3, a mutation screen was carried out to get NRG1 mutants, which have more specific binding to ErbB2/ErbB4 receptor pair. Two CHO stable cell lines were constructed, which express ErbB2/ErbB3 or ErbB2/ErbB4 receptor pair, respectively. The ErbB2/ErbB4 cell line showed similar characteristics in ligand-binding activity and the activation of downstream signaling molecules, such as the AKT and PI3K to the primary neonatal rat ventricular myocytes (NRVM), which endogenously expresses ErbB2/ErbB4. Both cell lines have good dose-response. Thirty-one NRG1 mutants were successfully expressed in Escherichia coli and purified. Their ability to stimulate the downstream signaling was measured by detecting AKT phosphorylation. Some mutants showed more specific activation activity in ErbB2/ErbB4 cells. Further study on five of these mutants demonstrated that the change of the activation activity is associated with that of their binding activities to ErbB2/ErbB4 and ErbB2/ErbB3. Four of the candidates are more specific ligands for ErbB2/ErbB4 activation, and thus may serve as more potent drug candidates for heart failure.

Studies on bis(halogeno) dioxomolybdenum(VI)-bipyridine complexes: synthesis and catalytic activity.

Dioxomolybdenum(VI) complexes with the general formula [MoO2Cl2L2] (L2=3,3'-dimethyl-2,2'-bipyridine, 5,5'-dimethyl-2,2'-bipyridine, 6,6'-dimethyl-2,2'-bipyridine, 4,4'-dibromo-2,2'-bipyridine, 5,5'-dibromo-2,2'-bipyridine, 5,5'-diamino-2,2'-bipyridine; 5,5'-dinitro-2,2'-bipyridine; 5,5'-di-ethoxycarbonyl-2,2'-bipyridine; 6-phenyl-2,2'-bipyridine; 2,2':6',2''-terpyridine) have been prepared and characterised. [MoO2Cl2(5,5'-di-ethoxycarbonyl-2,2'-bipyridine)] has been examined by single crystal X-ray analysis. The complexes were applied as homogenous catalysts for the epoxidation of cyclooctene with tert-butyl hydroperoxide (TBHP) as oxidising agent. The new compounds show an overall high activity and are highly selective catalysts in the epoxidation of cyclooctene. The stability of the complexes and differences in the catalytic activity can be clearly attributed to electronic contributions of the functional groups on bipyridine ligands and to steric restrictions. DFT calculations have assisted in a better understanding of the stability of the complexes and are in agreement with experiment. The influence of the terminal oxo ligands and the Lewis base ligands on the Mo center keep the compounds on quite a stable level of electron density.

Mono- and bis- methyltrioxorhenium(VII) complexes with salen ligands: synthesis, properties, applications.

Methyltrioxorhenium(VII) (MTO) forms 1:1 (mono-) or/and 2:1 (bis-) complexes with salen ligands, undergoing a hydrogen transfer from a ligand-bound OH-group to a ligand nitrogen atom. Some complexes show good stability both in the solid state and in solution, while others must be kept at low temperatures under an argon atmosphere. X-ray crystallography shows distorted trigonal bipyramidal structures of all examined complexes in the solid state, this structure being due to the steric demands of the ligands, with the methyl group of MTO residing in the apical sites in the cis position. Temperature-dependent proton NMR data indicate that the coordination between salen ligands and MTO at low temperatures is considerably stronger than at room temperature. Density functional theory calculations have been performed to find approximate structures for all described complexes and to try to find a rationale for the preferred formation of mono- versus bis-MTO complexes. The formation of mono- or bis-MTO adducts is dependent on both the steric and the electronic influence of the respective salen ligands. The catalytic performance is strongly influenced by the ring substitution. Two MTO molecules coordinated to one salen ligand lead to an additional boost of catalytic activity because there is not only double the amount of catalytic centers present but also a "ligand enhanced" activity increase.