Tomohiro Asakawa

Catalytic Desymmetrization of Cyclohexadienes by Asymmetric Bromolactonization

Asymmetric bromolactonization of prochiral cyclohexadiene derivatives with N-bromosuccimide proceeded in the presence of (DHQD)(2)PHAL as a chiral catalyst to afford the corresponding bromolactones with up to 93% ee. This reaction was also applicable to the kinetic resolution of a racemic cyclic ene-carboxylic acid, where the starting material was recovered with high enantioselectivity.

Furan fatty acid as an anti-inflammatory component from the green-lipped mussel Perna canaliculus

A lipid extract of Perna canaliculus (New Zealand green-lipped mussel) has reportedly displayed anti-inflammatory effects in animal models and in human controlled studies. However, the anti-inflammatory lipid components have not been investigated in detail due to the instability of the lipid extract, which has made the identification of the distinct active components a formidable task. Considering the instability of the active component, we carefully fractionated a lipid extract of Perna canaliculus (Lyprinol) and detected furan fatty acids (F-acids). These naturally but rarely detected fatty acids show potent radical-scavenging ability and are essential constituents of plants and algae. Based on these data, it has been proposed that F-acids could be potential antioxidants, which may contribute to the protective properties of fish and fish oil diets against chronic inflammatory diseases. However, to date, in vivo data to support the hypothesis have not been obtained, presumably due to the limited availability of F-acids. To confirm the in vivo anti-inflammatory effect of F-acids in comparison with that of eicosapentaenoic acid (EPA), we developed a semisynthetic preparation and examined its anti-inflammatory activity in a rat model of adjuvant-induced arthritis. Indeed, the F-acid ethyl ester exhibited more potent anti-inflammatory activity than that of the EPA ethyl ester. We report on the in vivo activity of F-acids, confirming that the lipid extract of the green-lipped mussel includes an unstable fatty acid that is more effective than EPA.

Domino Heck–C–H activation reaction of unsymmetrically substituted [3]cumulene

The Heck reaction of an unsymmetrically substituted [3]cumulene has been investigated. Although a carbonyl conjugated alkene is present, the arylpalladium species selectively inserts into the C3-4 double bond, and a subsequent C-H activation reaction with a neighboring phenyl group gives the indene derivatives with a tetrasubstituted olefin moiety.

A Negative Feedback Loop Controlling bHLH Complexes Is Involved in Vascular Cell Division and Differentiation in the Root Apical Meristem.

Controlling cell division and differentiation in meristems is essential for proper plant growth. Two bHLH heterodimers consisting of LONESOME HIGHWAY (LHW) and TARGET OF MONOPTEROS 5 (TMO5)/TMO5-LIKE1 (T5L1) regulate periclinal cell division in vascular cells in the root apical meristem (RAM). In this study, we further investigated the functions of LHW-T5L1, finding that in addition to controlling cell division, this complex regulates xylem differentiation in the RAM via a novel negative regulatory system. LHW-T5L1 upregulated the thermospermine synthase gene ACAULIS5 (ACL5), as well as SUPPRESSOR OF ACAULIS5 LIKE3 (SACL3), which encodes a bHLH protein, in the RAM. The SACL3 promoter sequence contains a conserved upstream open reading frame (uORF), which blocked translation of the main SACL3 ORF in the absence of thermospermine. Thermospermine eliminated the negative effect of uORF and enhanced SACL3 production. Further genetic and molecular biological analyses indicated that ACL5 and SACL3 suppress the function of LHW-T5L1 through a protein-protein interaction between LHW and SACL3. Finally, we showed that a negative feedback loop consisting of LHW-T5L1, ACL5, SACL3, and LHW-SACL3 contributes to maintain RAM size and proper root growth. These findings suggest that a negative feedback loop regulates the LHW-T5L1 output level to coordinate cell division and differentiation in a cell-autonomous manner.

Neuroprotective effect of nobiletin on cerebral ischemia-reperfusion injury in transient middle cerebral artery-occluded rats.

Nobiletin, a citrus polymethoxylated flavone, is reported to possess various pharmacological activities such as anticancer, anti-inflammation, and antioxidant effects. Recently, nobiletin was shown to provide therapeutic benefit for the treatment of Alzheimer׳s disease by activating cAMP-response element-binding protein (CREB). In the present study, we investigated whether nobiletin could protect the brain against ischemia-reperfusion (I/R) injury and improve functional outcome in cerebral I/R model rats, since CREB activation is known to protect neuronal cells in cerebral ischemia. Nobiletin was injected twice at 0 and 1h after the start of reperfusion in transient middle cerebral artery occlusion (t-MCAO) rats. Cerebral I/R induced prominent brain damage in the ischemic hemisphere of t-MCAO rat brains; however, nobiletin treatment significantly reduced the infarct volume and suppressed the brain edema. Immunohistochemical and TUNEL staining indicated that nobiletin treatment significantly suppressed neutrophil invasion into the ischemic region and significantly decreased apoptotic brain cell death in ischemic hemisphere, suggesting that the anti-inflammatory effect and anti-apoptotic effect should be regarded as the neuroprotective mechanism of nobiletin. Moreover, nobiletin treatment ameliorated motor functional deficits in the ischemic rats compared with those deficits of the vehicle-treated group. These results indicate that nobiletin is a potential neuroprotectant for the treatment of cerebral I/R injury.

Stereocontrolled Synthesis of (+)-Methoxyphenylkainic Acid and (+)-Phenylkainic Acid

The efficient total syntheses of (+)-methoxyphenylkainic acid (3) and (+)-phenylkainic acid (4) were achieved using a rhodium carbenoid-mediated intermolecular C-H insertion reaction. Complete stereoselective construction of the kainoid skeleton was accomplished by utilizing the stereochemistry at the C-4 position as a pivotal stereogenic center.

Proof of the Existence of an Unstable Amino Acid: Pleurocybellaziridine in Pleurocybella porrigens

Angel s wing mushroom, Pleurocybella porrigens (Pers.) Singer, is distributed worldwide in temperate areas and has been eaten throughout the world, especially in Japan. Nonetheless, seventeen people who ate angel s wing mushroom died of acute encephalopathy in 2004 in Japan. Epidemiological investigation of the incident indicated that most patients were undergoing hemodialysis treatment for chronic renal failure and had digested the wild fruiting bodies before the onset of neurological symptoms. Although the mechanism of the acute encephalopathy has not yet been elucidated, several chemical investigations have reported that vitamin D analogues, fatty acids, and saccharides are potential causative agents of poisoning. Recently our group reported a lectin and cytotoxic amino acids, six of which were novel. The structural novelty and analogy of the amino acids is such that each acid has the b-hydroxyvaline unit attached to endogenous molecules (Scheme 1), which inspired us to conclude the occurrence of an aziridine amino acid (1) as the common precursor; one carbon atom of the aziridine ring is substituted with a carboxy group and the other with geminal methyl groups (Scheme 1). Thus the instability of this molecule could be demonstrated by nucleophilic attack by endogenous molecules and successive ring opening. Therefore, we hypothesized that the labile feature of the precursor should be the reason why it could not be isolated from the mushroom in the previous study. To confirm the existence of the aziridine as a component within the mushroom, we launched this unique project; synthesis of the proposed molecule and its esters, and isolation of the corresponding esters from the crude extract of the mushroom after esterification. Our synthesis plan is illustrated in Scheme 2. As a result of the labile nature of 1, utilizing appropriate protection of the nitrogen atom as well as the carboxylic group of 2 would play a crucial step in the total synthesis. Although racemic 1 has already been synthesized, employing a Mitsunobu reaction with 3 would be suitable for the preparation of an optically active compound. Recently we have developed a highly Scheme 1. Structure of the cytotoxic compounds (top) and their proposed precursor 1.

Physicochemical and biopharmaceutical characterization of amorphous solid dispersion of nobiletin, a citrus polymethoxylated flavone, with improved hepatoprotective effects

The present study aimed to develop an amorphous solid dispersion (SD) of nobiletin (NOB), a citrus polymethoxylated flavone, with the aim of improving its biopharmaceutical and hepatoprotective properties. SD formulation of NOB (NOB/SD) was prepared by wet-milling and subsequent freeze drying, and its stability and dissolution properties were characterized. The hepatoprotective effects and pharmacokinetic behavior of orally dosed NOB/SD were evaluated in rats. During the storage of NOB/SD for 4 weeks under accelerated conditions, there were no significant transitions in the appearance, particle size, and amorphousity of wet-milled NOB. In comparison with crystalline NOB, the NOB/SD exhibited significant improvement in the dissolution with a 10-fold higher dissolution rate. In a rat model of acute liver injury, repeated treatment with NOB/SD (2 mg NOB/kg) every 4 h led to marked attenuation of hepatic damage as evidenced by decreased ALT and AST, surrogate biomarkers for hepatic injury; however, crystalline NOB was found to be less effective. After oral administration of NOB/SD (2 mg NOB/kg) in rats, compared with crystalline NOB, improved pharmacokinetic behavior was observed with increases of bioavailability and hepatic delivery by ca. 7- and 6-fold, respectively, possibly leading to better hepatoprotection. Given the improved physicochemical and biopharmaceutical properties, the SD formulation strategy might be efficacious for enhancing the therapeutic potential of NOB.

Chemoselective hydrogenation reaction of unsaturated bonds in the presence of an o-nitrobenzenesulfonyl group.

Chemoselective hydrogenation of unsaturated compounds bearing an o-nitrobenzenesulfonyl (Ns)-amide moiety, affording the corresponding saturated compounds, was accomplished efficiently without loss of the nitro group by using the Pd/MS3A catalyst and a H2 balloon. Partial hydrogenation of alkynes bearing an Ns group to corresponding cis alkenes was achieved with the combination of the Pd/BN catalyst and an additive (diethylenetriamine or acetic acid).

Enantioselective Synthesis of SB-203207

Total synthesis of SB-203207 (1) was achieved, beginning with a desymmetrical C-H insertion reaction of a diazoester bearing our recently developed chiral auxiliary. Utilizing the optically active bicyclo[3.3.0]octane ring, four stereogenic centers were efficiently constructed in sequence. Finally, mild oxidation of 27 to carboxylic acid via a cyanohydrin intermediate and hydrolysis of cyanide to carboxyamide in the presence of the labile enamide group completed an efficient total synthesis of 1.