Rapid access to 3-indolyl-1-trifluoromethyl-isobenzofurans by hybrid use of Lewis/Brønsted acid catalysts.

We report herein a rapid access to 3-indolyl-1-trifluoromethyl-isobenzofurans via a [1,4]-hydride shift/cyclizatin/intermolecular nucleophilic addition reaction sequence. In this process, a Lewis acid promoted internal redox reaction ([1,4]-hydride shift/cyclization) followed by a Brønsted acid promoted intermolecular reaction (generation of cyclic oxonium cation/intermolecular Friedel-Crafts reaction) occurred to give various 3-indolyl-1-trifluoromethyl-isobenzofurans in good chemical yields.

Chiral Magnesium Bisphosphate-Catalyzed Asymmetric Double C(sp3)-H Bond Functionalization Based on Sequential Hydride Shift/Cyclization Process.

Described herein is a chiral magnesium bisphosphate-catalyzed asymmetric double C(sp3)-H bond functionalization triggered by a sequential hydride shift/cyclization process. This reaction consists of stereoselective domino C(sp3)-H bond functionalization: (1) a highly enantio- and diastereoselective C(sp3)-H bond functionalization by chiral magnesium bisphosphate (first [1,5]-hydride shift), and (2) a highly diastereoselective C(sp3)-H bond functionalization by an achiral catalyst (Yb(OTf)3, second [1,5]-hydride shift).

Enantiodivergent Atroposelective Synthesis of Chiral Biaryls by Asymmetric Transfer Hydrogenation: Chiral Phosphoric Acid Catalyzed Dynamic Kinetic Resolution.

Reported herein is an enantiodivergent synthesis of chiral biaryls by a chiral phosphoric acid catalyzed asymmetric transfer hydrogenation reaction. Upon treatment of biaryl lactols with aromatic amines and a Hantzsch ester in the presence of chiral phosphoric acid, dynamic kinetic resolution (DKR) involving a reductive amination reaction proceeded smoothly to furnish both R and S isomers of chiral biaryls with excellent enantioselectivities by proper choice of hydroxyaniline derivative. This trend was observed in wide variety of substrates, and various chiral biphenyl and phenyl naphthyl adducts were synthesized with satisfactory enantioselectivities in enantiodivergent fashion. The enantiodivergent synthesis of synthetically challenging, chiral o-tetrasubstituted biaryls were also accomplished, and suggests high synthetic potential of the present method.

Lipopolysaccharide treatment arrests the cell cycle of BV-2 microglial cells in G1 phase and protects them from UV light-induced apoptosis.

We previously reported that an optimal dose of lipopolysaccharide (LPS) markedly extends the lifespan of murine primary-cultured microglia by suppressing cell death pathways. In this study, we investigated the effects of LPS pretreatment on UV light-induced apoptosis of cells from the microglial cell line BV-2. More than half of BV-2 cells were apoptotic, and procaspase-3 was cleaved into its active form at 3 h of UV irradiation. In contrast, in BV-2 cells treated with LPS for 24 h, UV irradiation caused neither apoptosis nor procaspase-3 cleavage. LPS treatment arrested the cell cycle in G1 phase and upregulated cyclin-dependent kinase inhibitor p21(Waf1/Cip1) and growth arrest and DNA damage-inducible (GADD) 45α in BV-2 cells. When p21(Waf1/Cip1) and GADD45α were knocked down by small interfering RNA, procaspase-3 was cleaved into its active form to induce apoptosis. Our findings suggest that LPS inhibits UV-induced apoptosis in BV-2 cells through arrest of the cell cycle in G1 phase by upregulation of p21(Waf1/Cip1) and GADD45α. Excessive activation of microglia may play a critical role in the exacerbation of neurodegeneration, therefore, normalizing the precise regulation of apoptosis may be a new strategy to prevent the deterioration caused by neurodegenerative disorders.

Aripiprazole increases NAD(P)H-quinone oxidoreductase-1 and heme oxygenase-1 in PC12 cells.

We previously showed that aripiprazole increases intracellular NADPH and glucose-6-phosphate dehydrogenase mRNA in PC12 cells. Aripiprazole presumably activates a system that concurrently detoxifies reactive oxygen species and replenishes NADPH. Nrf2, a master transcriptional regulator of redox homeostasis genes, also activates the pentose phosphate pathway, including NADPH production. Therefore, our aim was to determine whether aripiprazole activates Nrf2 in PC12 cells. Aripiprazole increased mRNA expression of Nrf2-dependent genes (NAD(P)H-quinone oxidoreductase-1, Nqo1; heme oxygenase-1, HO1; and glutamate-cysteine ligase catalytic subunit) and protein expression of Nqo1 and HO1 in these cells (p < 0.05). To maintain increased Nrf2 activity, it is necessary to inhibit Nrf2 degradation; this is done by causing Nrf2 to dissociate from Keap1 or ß-TrCP. However, in aripiprazole-treated cells, the relative amount of Nrf2 anchored to Keap1 or ß-TrCP was unaffected and Nrf2 in the nuclear fraction decreased (p < 0.05). Aripiprazole did not affect phosphorylation of Nrf2 at Ser40 and decreased the relative amount of acetylated Nrf2 (p < 0.05). The increase in Nqo1 and HO1 in aripiprazole-treated cells cannot be explained by the canonical Nrf2-degrading pathways. Further experiments are needed to determine the biochemical mechanisms underlying the aripiprazole-induced increase in these enzymes.

Double C(sp3)-H bond functionalization mediated by sequential hydride shift/cyclization process: diastereoselective construction of polyheterocycles.

Described herein are two novel types of double C(sp(3))-H bond functionalizations triggered by a sequential hydride shift/cyclization process: (1) construction of a bicyclo[3.2.2]nonane skeleton by a [1,6]- and [1,5]-hydride shift sequence and (2) sequential [1,4]- and [1,5]-hydride shift mediated construction of a linear tricyclic skeleton.

Silyl-Group Boosted Internal Redox Reaction: Hydride Shift from an Aliphatic Secondary Position for the Formation of Six- and Seven-Membered Carbocycles.

We report a hydride shift/cyclization reaction at the aliphatic secondary position (methylene group). The key to accomplishing this reaction was the employment of benzylidene malonate having a silyl group ß to the hydride donor carbon. When the corresponding malonates were treated with a catalytic amount of Al(OTf)3, the [1,5]-hydride shift from the simple aliphatic secondary position proceeded smoothly to afford silyl-group substituted tetralin derivatives in excellent chemical yields (up to 98%). This reaction system was applied to the formation of seven-membered carbocycles via the [1,6]-hydride shift mediated process.

Stereoselective synthesis of 6/7/6-fused heterocycles with multiple stereocenters via an internal redox reaction/inverse electron-demand hetero-Diels-Alder reaction sequence.

A highly stereoselective synthesis of fused heterocycles with multiple stereocenters via an internal redox reaction/inverse electron-demand hetero-Diels-Alder (IEDHDA) reaction sequence is described. The present reaction sequence has three interesting features: (1) complete control of two potentially competitive processes, i.e., hetero-Diels-Alder reaction and [1,5]-hydride shift; (2) one-shot construction of the complicated 6/7/6-fused heterocyclic structure having multiple stereocenters; and (3) high control of its stereoselectivity. When alkenylidene barbiturates with an allyl benzyl ether moiety were treated with a catalytic amount of Sc(OTf)3 and 2,2'-bipyridine, the internal redox reaction/IEDHDA reaction proceeded successively to afford 6/7/6-fused heterocycles in good chemical yields with good to excellent diastereoselectivities.

Synthesis of Polysubstituted Naphthalenes by a Hydride Shift Mediated C-H Bond Functionalization/Aromatization Sequence.

A synthetic strategy for forming multisubstituted naphthalenes based on hydride shift mediated C(sp3)-H bond functionalization was developed. This strategy consists of three successive transformations: (1) an intramolecular hydride shift mediated C(sp3)-H bond functionalization; (2) a decarboxylative fragmentation; and (3) an oxidation reaction. When benzylidene malonates having a 2-alkoxyethyl group at the ortho position were treated with a catalytic amount of Al(OTf)3, the hydride shift/cyclization reaction proceeded smoothly to afford tetralin derivatives in good chemical yields. The resulting tetralins were easily converted into naphthalenes by exposing them to modified Krapcho decarboxylation reaction conditions (LiCl, DMSO, and heating under an O2 atmosphere). The one-pot operation of these two reactions was also realized.

Divergent synthesis of multi-substituted phenanthrenes via an internal redox reaction/ring expansion sequence.

We report an effective synthetic route to multi-substituted phenanthrenes via an internal redox reaction/ring expansion sequence. The interesting feature of the present system is that it allows for the divergent synthesis of the target skeleton depending on the selected Lewis acid catalyst. When benzylidene malonates with a cyclic structure at the ortho-position were treated with BF3·OEt2, three sequential processes (internal redox reaction/elimination of the alkoxy group/ring expansion) proceeded to give phenanthrene derivatives in which the alkoxycarbonyl (CO2R) group and the alkyl (R) group were in close proximity to each other, in good chemical yields. In sharp contrast, treatment with Bi(OTf)3 exclusively led to the formation of another type of phenanthrene, whose R group was positioned distal to the CO2R group.

Enantioselective synthesis of multisubstituted biaryl skeleton by chiral phosphoric acid catalyzed desymmetrization/kinetic resolution sequence.

Described herein is the enantioselective synthesis of multisubstituted biaryl derivatives by chiral phosphoric acid catalyzed asymmetric bromination. Two asymmetric reactions (desymmetrization and kinetic resolution) proceeded successively to afford chiral biaryls in excellent enantioselectivities (up to 99% ee). Both experimental and computational studies suggested that this excellent selectivity could be achieved via a highly organized hydrogen bond network among a substrate, a catalyst (chiral phosphoric acid), and a brominating reagent (N-bromophthalimide).

A possible pathophysiological role of tyrosine hydroxylase in Parkinson's disease suggested by postmortem brain biochemistry: a contribution for the special 70th birthday symposium in honor of Prof. Peter Riederer.

Postmortem brain biochemistry has revealed that the main symptom of movement disorder in Parkinson's disease (PD) is caused by a deficiency in dopamine (DA) at the nerve terminals of degenerating nigro-striatal DA neurons in the striatum. Since tyrosine hydroxylase (TH) is the rate-limiting enzyme for the biosynthesis of DA, TH may play an important role in the disease process of PD. DA regulated by TH activity is thought to interact with α-synuclein protein, which results in intracellular aggregates called Lewy bodies and causes apoptotic cell death during the aging process. Human TH has several isoforms produced by alternative mRNA splicing, which may affect activation by phosphorylation of serine residues in the N-terminus of TH. The activity and protein level of TH are decreased to cause DA deficiency in the striatum in PD. However, the homo-specific activity (activity/enzyme protein) of TH is increased. This increase in TH homo-specific activity suggests activation by increased phosphorylation at the N-terminus of the TH protein for a compensatory increase in DA synthesis. We recently found that phosphorylation of the N-terminal portion of TH triggers proteasomal degradation of the enzyme to increase TH turnover. We propose a hypothesis that this compensatory activation of TH by phosphorylation in the remaining DA neurons may contribute to a further decrease in TH protein and activity in DA neurons in PD, causing a vicious circle of decreasing TH activity, protein level and DA contents. Furthermore, increased TH homo-specific activity leading to an increase in DA may cause toxic reactive oxygen species in the neurons to promote neurodegeneration.

Lewis acid-catalyzed formal 1,3-aminomethyl migration.

Here we report a Lewis acid-catalyzed 1,3-aminomethyl migration rection. When δ-amino acid derivatives were treated with a catalytic amount of Sc(OTf)3, 1,3-migration of the aminomethyl group proceeded smoothly to afford ß-amino acid derivatives in moderate to good chemical yields. Detailed investigation suggested that this migration reaction proceeded through the fragmentation/recombination pathway.

Subventricular zone under the neuroinflammatory stress and Parkinson's disease.

This review summarizes the effects of neuroinflammatory stress on the subventricular zone (SVZ), where new neurons are constitutively produced in the adult brain, especially focusing on the relation with Parkinson's disease (PD), because the SVZ is under the control of dopaminergic afferents from the substantia nigra (SN). In Lewy bodies-positive-PD, microglia is known to phagocytoze aggregated α-synuclein, resulting in the release of inflammatory cytokines. The neurogenesis in the SVZ should be affected in PD brain by the neuroinflammatory process. The administration of lipopolysaccaharide is available as an alternative model for microglia-induced loss of dopaminergic neurons and also the impairment of stem cell maintenance. Therefore, the research on the neuroinflammatory process in the SVZ gives us a hint to prevent the outbreak of PD or at least slow the disease process.

Effects of aripiprazole and clozapine on the treatment of glycolytic carbon in PC12 cells.

Aripiprazole is the only atypical antipsychotic drug known to cause the phosphorylation of AMP-activated protein kinase (AMPK) in PC12 cells. However, the molecular mechanisms underlying this phosphorylation in aripiprazole-treated PC12 cells have not yet been clarified. Here, using PC12 cells, we show that these cells incubated for 24 h with aripiprazole at 50 µM and 25 mM glucose underwent a decrease in their NAD⁺/NADH ratio. Aripiprazole suppressed cytochrome c oxidase (COX) activity but enhanced the activities of pyruvate dehydrogenase (PDH), citrate synthase and Complex I. The changes in enzyme activities coincided well with those in NADH, NAD⁺, and NAD⁺/NADH ratio. However, the bioenergetic peril judged by the lowered COX activity might not be accompanied by excessive occurrence of apoptotic cell death in aripiprazole-treated cells, because the mitochondrial membrane potential was not decreased, but rather increased. On the other hand, when PC12 cells were incubated for 24 h with clozapine at 50 µM and 25 mM glucose, the NAD⁺/NADH ratio did not change. Also, the COX activity was decreased; and the PDH activity was enhanced. These results suggest that aripiprazole-treated PC12 cells responded to the bioenergetic peril more effectively than the clozapine-treated ones to return the ATP biosynthesis back toward its ordinary level. This finding might be related to the fact that aripiprazole alone causes phosphorylation of AMPK in PC12 cells.

Regulation of oxidative stress in long-lived lipopolysaccharide-activated microglia.

1. Previously, we reported that an optimal dose of lipopolysaccharide (LPS) markedly extends the life span of mouse primary-cultured microglia by suppressing apoptotic and autophagic cell death pathways. The aim of the present study was to assess how these cells protect themselves against reactive oxygen species (ROS) generated by LPS treatment. 2. The study was conducted in microglia obtained from murine neonate brain, which are destined to die within a few days under ordinary culture conditions. 3. The generation of ROS was maximal after 15 h LPS treatment (1 ng/mL LPS and 100 ng/mL LPS). The expression of inducible nitric oxide (NO) synthase protein was significantly increased by Day 1 of LPS treatment and was followed by the production of NO. The expression of either Cu/Zn- or Mn-superoxide dismutase protein (SOD) was also increased by 16 h and Day 1 of LPS treatment. LPS did not affect the expression of Cu/Zn- and Mn-SOD proteins, nor did it extend the life span of microglia that had mutated Toll-like receptor (TLR) 4. 4. The findings of the present study suggest that SODs function as a potent barrier to overcome ROS generated in primary-cultured microglia following LPS treatment and that TLR4 may be significantly involved in inducing these proteins. The microglia may be able to protect themselves against oxidative stress, allowing them to live for more than 1 month. Because long-lived microglia may play a critical role in the exacerbation of neurodegeneration, bringing activated microglia back to their resting stage could be a new and promising strategy to inhibit the deterioration underlying neurodegenerative disorders.

Microglial activation in neuroinflammation: implications for the etiology of neurodegeneration.

BACKGROUND: Activated microglia secrete inflammatory cytokines and may play roles in the progression of neurodegenerative diseases. However, the mechanism underlying microglial activation remains unclear. OBJECTIVE: Our aim was to examine the regulation of activated microglia through their cell death and survival pathways. METHODS: We used mouse primary-cultured microglia, which are destined to die within a few days under ordinary culture conditions. The microglia live for longer than 1 month, without any measurable increase in apoptotic or necrotic cell death, when kept activated by sublethal concentrations of lipopolysaccharide (LPS). RESULTS: LPS-treated microglia showed changes in shape. LPS treatment had no effect on the level of the proapoptotic Bcl-2-associated X protein but increased the level of the antiapoptotic protein Bcl-xL at day 1. Furthermore, the level of microtubule-associated light chain 3-II, a marker protein for autophagy, was decreased 3 h after exposure to LPS. CONCLUSION: An increase in Bcl-xL seems to inhibit both apoptosis and autophagy. Our results suggest that long-lived microglia resulting from exposure to the optimal dose of LPS may play critical roles in the progression of neurodegeneration.

Access to ortho-Hydroxyphenyl Ketimines via Imine Anion-Mediated Smiles Rearrangement.

We have achieved a facile access to N-(2-halophenyl)-2-hydroxyphenylimine derivatives via imine anion-mediated Smiles rearrangement. When 2-(2-halophenoxy)benzonitriles were treated with 1.2-1.4 equiv of organolithium reagents, nucleophilic addition to the nitrile group followed by Smiles rearrangement occurred to give various N-(2-halophenyl)-2-hydroxyphenylimine derivatives, which are sometimes difficult to synthesize by the conventional acid-promoted condensation reaction between carbonyl compounds and aniline derivatives, in good to excellent chemical yields (up to 91%).

Expeditious construction of a carbobicyclic skeleton via sp3-C-H functionalization: hydride shift from an aliphatic tertiary position in an internal redox process.

Described herein is the first example of an aliphatic, nonbenzylic hydride shift/cyclization sequence that contains two types of novel sp(3)-C-H functionalization: (1) construction of a tetraline skeleton via [1,5]-hydride shift/cyclization and (2) [1,6]-hydride shift/cyclization to form a five-membered ring (indane derivatives).