Publishing type：Research paper (scientific journal)  

<p>The rhodium(III)-catalyzed annulative coupling of coumarin-3-carboxylic acids, prepared easily by condensation of salicylaldehydes with Meldrum’s acid, with alkynes proceeds smoothly through carboxy-directed C4–H bond cleavage. These procedures provide ready access to variously substituted pyrano[3,4-<i>c</i>]chromene-4,5-dione derivatives from readily available starting materials.</p>

DOI： 10.1246/cl.230082

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/ajoc.202300136

Publishing type：Research paper (scientific journal)  

DOI： 10.1039/d3ob00099k

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/asia.202201210

PubMed

Other URL： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/asia.202201210

Publishing type：Research paper (scientific journal)  

DOI： 10.1055/a-2015-4466

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

TAR DNA-binding protein 43 (TDP-43) is a predominant component of inclusions in the brains and spines of patients with amyotrophic lateral sclerosis (ALS). The progressive accumulation of inclusions leads to proteinopathy in neurons. We have previously shown that Met1(M1)-linked linear ubiquitin, which is specifically generated by the linear ubiquitin chain assembly complex (LUBAC), is colocalized with TDP-43 inclusions in neurons from optineurin-associated familial and sporadic ALS patients, and affects NF-κB activation and apoptosis. To examine the effects of LUBAC-mediated linear ubiquitination on TDP-43 proteinopathies, we performed cell biological analyses using full-length and truncated forms of the ALS-associated Ala315→Thr (A315T) mutant of TDP-43 in Neuro2a cells. The truncated A315T mutants of TDP-43, which lack a nuclear localization signal, efficiently generated cytoplasmic aggregates that were colocalized with multiple ubiquitin chains such as M1-, Lys(K)48-, and K63-chains. Genetic ablation of HOIP or treatment with a LUBAC inhibitor, HOIPIN-8, suppressed the cytoplasmic aggregation of A315T mutants of TDP-43. Moreover, the enhanced TNF-α-mediated NF-κB activity by truncated TDP-43 mutants was eliminated in the presence of HOIPIN-8. These results suggest that multiple ubiquitinations of TDP-43 including M1-ubiquitin affect protein aggregation and inflammatory responses in vitro, and therefore, LUBAC inhibition ameliorates TDP-43 proteinopathy.

DOI： 10.3390/cells11152398

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/ejoc.202200550

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

trans-Anethole (anethole) is a phenylpropanoid; with other drugs, it exhibits synergistic activity against several fungi and is expected to be used in new therapies that cause fewer patient side effects. However, the detailed substructure(s) of the molecule responsible for this synergy has not been fully elucidated. We investigated the structure-activity relationships of phenylpropanoids and related derivatives, with particular attention on the methoxy group and the double bond of the propenyl group in anethole, as well as the length of the p-alkyl chain in p-alkylanisoles. Antifungal potency was largely related to p-alkyl chain length and the methoxy group of anethole, but not to the double bond of its propenyl group. Production of reactive oxygen species also played a role in these fungicidal activities. Inhibition of drug efflux was associated with the length of the p-alkyl chain and the double bond of the propenyl group in anethole, but not with the methoxy group. Although a desirable synergy was observed between n-dodecanol and anethole or p-alkylanisoles with a length of C2-C6 in alkyl chains, it cannot be explained away as being solely due to the inhibition of drug efflux. Similar results were obtained when phenylpropanoid derivatives were combined with fluconazole against Candida albicans.

DOI： 10.1111/lam.13613

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/ajoc.202100774

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/lam.13613

Publishing type：Research paper (scientific journal)  

DOI： 10.1055/a-1416-6997

Publishing type：Research paper (scientific journal)  

DOI： 10.1055/a-1416-6997

Publishing type：Research paper (scientific journal)  

<p>The rhodium(III)-catalyzed annulative coupling of 9-benzoylcarbazoles with internal alkynes proceeds efficiently through <i>ortho</i> C–H and C–N bond cleavages. This reaction provides direct access to variously substituted indanone derivatives. The carbazolyl leaving group can be readily recovered and reused for preparing the starting materials.</p>

DOI： 10.1246/cl.200884

CiNii Article

Publishing type：Research paper (scientific journal)  

<p>The rhodium(III)-catalyzed annulative coupling of 9-benzoylcarbazoles with internal alkynes proceeds efficiently through <i>ortho</i> C–H and C–N bond cleavages. This reaction provides direct access to variously substituted indanone derivatives. The carbazolyl leaving group can be readily recovered and reused for preparing the starting materials.</p>

DOI： 10.1246/cl.200884

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/ajoc.202100071

Publishing type：Research paper (scientific journal)  

<p>The annulative coupling of secondary benzyl alcohols with internal alkynes efficiently proceeds in the presence of a silver catalyst. The reaction gives 1,2,3-substituted indene derivatives selectively as 1:1 coupling products. The procedure provides a straightforward synthetic route to indenes from readily available starting materials upon treatment with a simple reaction system under mild conditions.</p>

DOI： 10.1246/cl.200846

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/ajoc.202100071

Publishing type：Research paper (scientific journal)  

<p>The annulative coupling of secondary benzyl alcohols with internal alkynes efficiently proceeds in the presence of a silver catalyst. The reaction gives 1,2,3-substituted indene derivatives selectively as 1:1 coupling products. The procedure provides a straightforward synthetic route to indenes from readily available starting materials upon treatment with a simple reaction system under mild conditions.</p>

DOI： 10.1246/cl.200846

CiNii Article

Publishing type：Research paper (scientific journal)  

<p>The oxidative coupling of benzamides with methyl 2-trifluoromethylacrylate proceeds smoothly under rhodium(III) catalysis to produce trifluoromethyl-substituted isoindolinone derivatives. The catalyst system [Cp^ERhCl₂]₂/AgSbF₆ is effective for the oxidative coupling, while [Cp*RhCl₂]₂/AgSbF₆ leads to their redox-neutral coupling predominantly. The oxidative coupling reactions with related acrylates have also been examined.</p>

DOI： 10.1246/cl.200609

CiNii Article

Publishing type：Research paper (scientific journal)  

<p>The oxidative coupling of benzamides with methyl 2-trifluoromethylacrylate proceeds smoothly under rhodium(III) catalysis to produce trifluoromethyl-substituted isoindolinone derivatives. The catalyst system [Cp^ERhCl₂]₂/AgSbF₆ is effective for the oxidative coupling, while [Cp*RhCl₂]₂/AgSbF₆ leads to their redox-neutral coupling predominantly. The oxidative coupling reactions with related acrylates have also been examined.</p>

DOI： 10.1246/cl.200609

CiNii Article

Publishing type：Research paper (scientific journal)   Kind of work：Joint Work  

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/asia.201901776

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/asia.201901776

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.24496/tennenyuki.62.0_289-294

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/adsc.201900919

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/adsc.201900919

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

<p>The β-arylation and -alkenylation of trifluoromethylacrylic acid with arylboronic acids and alkenes proceed smoothly under rhodium(III) catalysis. The procedures provide useful synthetic routes from readily available building brocks to β-aryl-α-trifluoromethylpropanoic acid and 5,5,5-trifluoro-1,3-butadiene derivatives. Some of the obtained butadienes exhibit strong fluorescence in the solid state.</p>

DOI： 10.1246/cl.190024

CiNii Article

Publishing type：Research paper (scientific journal)  

<p>The β-arylation and -alkenylation of trifluoromethylacrylic acid with arylboronic acids and alkenes proceed smoothly under rhodium(III) catalysis. The procedures provide useful synthetic routes from readily available building brocks to β-aryl-α-trifluoromethylpropanoic acid and 5,5,5-trifluoro-1,3-butadiene derivatives. Some of the obtained butadienes exhibit strong fluorescence in the solid state.</p>

DOI： 10.1246/cl.190024

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acs.orglett.8b03944

Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acs.orglett.8b03944

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acs.jnatprod.8b00559

Other URL： http://orcid.org/0000-0003-2308-8693

Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acs.jnatprod.8b00559

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/chem.201801245

PubMed

Publishing type：Research paper (scientific journal)  

The iridium(III)/copper(II)-catalyzed dehydrogenative coupling of salicylaldehydes with internal alkynes proceeds efficiently under atmospheric oxygen through aldehyde C−H bond cleavage and decarbonylation. A variety of benzofuran derivatives can be synthesized by the environmentally benign procedure. DFT calculations suggest that this unique transformation involves the facile deinsertion of CO in the key metallacycle intermediate, which is in marked contrast to the corresponding rhodium(III) catalysis that leads to CO-retentive chromone derivatives.

DOI： 10.1002/chem.201801245

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.24496/tennenyuki.60.0_541-546

CiNii Article

Publishing type：Research paper (scientific journal)  

<p>The silver-catalyzed hydroacyloxylation of internal alkynes with tertiary alkanoic acids proceeds stereoselectively to produce (<i>Z</i>)-enol esters. α,β-Unsaturated carboxylic acids and benzoic acids also undergo silver-mediated addition toward alkynes effectively.</p>

DOI： 10.1246/cl.170986

CiNii Article

Publishing type：Research paper (scientific journal)  

<p>The silver-catalyzed hydroacyloxylation of internal alkynes with tertiary alkanoic acids proceeds stereoselectively to produce (<i>Z</i>)-enol esters. α,β-Unsaturated carboxylic acids and benzoic acids also undergo silver-mediated addition toward alkynes effectively.</p>

DOI： 10.1246/cl.170986

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.24496/tennenyuki.60.0_541-546

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1039/c7ob01732d

Publishing type：Research paper (scientific journal)  

First total syntheses of JBIR-04 and unantimycin A have been achieved. Comparison of our spectroscopic data with those reported for natural samples verified the structure of the natural products; (2S, 4S, 6S, 7R, 9S, 28S) configuration was thus assigned via total synthesis.

DOI： 10.1039/c7ob01732d

Publishing type：Research paper (scientific journal)  

First total syntheses of JBIR-04 and unantimycin A have been achieved. Comparison of our spectroscopic data with those reported for natural samples verified the structure of the natural products; (2S, 4S, 6S, 7R, 9S, 28S) configuration was thus assigned via total synthesis.

DOI： 10.1039/c7ob01732d

PubMed

Publishing type：Research paper (scientific journal)  

JBIR-04 (1) was isolated from <I>Streptomyces violaceoniger</I> 4541-SVS3 by Shinya andco-workers in 2007. It showed inhibitory activity against the GRP78 expression induced bythe stimulation of 2-deoxyglucose in HT1080 cells. Analyses of spectroscopic data revealedthat the planar structure of 1 is a 15-membered tetralactone of neoantimycin-classantibiotics. The recent discovery of prunustatin A as a selective GRP78 molecularchaperone down-regulator highlights the potential of this family as research probes. Thisdiscovery may lead to the development of new approaches for fighting cancer. Nevertheless,the absolute stereostructure of 1 has not been determined yet. In 2016, Hale reportedspectroscopic comparisons between JBIR-04 natural and its synthetic compound with a <I>2R</I>configuration, which is the same as that observed for prunustatin A and SW-163A, anothermember of the neoantimycin family. Significant differences were observed between thechemical shifts and coupling constants of H2 and H12, which confirms that the absolutestereochemistry of JBIR-04 is different than that of prunustatin A, <I>i.e.</I>, it has a <I>2S</I>configuration. Herein, we report our studies on the synthesis and stereochemical elucidationof JBIR-04 (1) and two neoantimycin-class antibiotics, namely unantimycin A (2) andJBIR-05 (3).Our synthetic strategy involves using intramolecular transesterification for theconstruction of a 15-membered tetralactone core, followed by the introduction of agem-dimethyl group. Cyclization precursor 4 was derived from L-phenylalanine,L-isoleucine, L-threonine, and L-lactic acid. The key 15-membered tetralactone 6 wassuccessfully obtained in moderate yield. Finally, amidation of 26 with benzoic acid and3-hydroxylbenzoic acid afforded JBIR-04 (1) and unantimucin A (2), respectively.Synthetic 1 and 2 and the natural samples of 1 and 2 were identical in all aspects. However,compound 29, which was derived from D-phenylalanine, was not identical to the naturalsample of 3. Further studies are now being pursued to elucidate the absolute stereostructureof JBIR-05 (3) and will be reported together.

DOI： 10.24496/tennenyuki.59.0_447

CiNii Article

Publishing type：Research paper (scientific journal)  

JBIR-04 (1) was isolated from <I>Streptomyces violaceoniger</I> 4541-SVS3 by Shinya and
co-workers in 2007. It showed inhibitory activity against the GRP78 expression induced by
the stimulation of 2-deoxyglucose in HT1080 cells. Analyses of spectroscopic data revealed
that the planar structure of 1 is a 15-membered tetralactone of neoantimycin-class
antibiotics. The recent discovery of prunustatin A as a selective GRP78 molecular
chaperone down-regulator highlights the potential of this family as research probes. This
discovery may lead to the development of new approaches for fighting cancer. Nevertheless,
the absolute stereostructure of 1 has not been determined yet. In 2016, Hale reported
spectroscopic comparisons between JBIR-04 natural and its synthetic compound with a <I>2R</I>
configuration, which is the same as that observed for prunustatin A and SW-163A, another
member of the neoantimycin family. Significant differences were observed between the
chemical shifts and coupling constants of H2 and H12, which confirms that the absolute
stereochemistry of JBIR-04 is different than that of prunustatin A, <I>i.e.</I>, it has a <I>2S</I>
configuration. Herein, we report our studies on the synthesis and stereochemical elucidation
of JBIR-04 (1) and two neoantimycin-class antibiotics, namely unantimycin A (2) and
JBIR-05 (3).
Our synthetic strategy involves using intramolecular transesterification for the
construction of a 15-membered tetralactone core, followed by the introduction of a
gem-dimethyl group. Cyclization precursor 4 was derived from L-phenylalanine,
L-isoleucine, L-threonine, and L-lactic acid. The key 15-membered tetralactone 6 was
successfully obtained in moderate yield. Finally, amidation of 26 with benzoic acid and
3-hydroxylbenzoic acid afforded JBIR-04 (1) and unantimucin A (2), respectively.
Synthetic 1 and 2 and the natural samples of 1 and 2 were identical in all aspects. However,
compound 29, which was derived from D-phenylalanine, was not identical to the natural
sample of 3. Further studies are now being pursued to elucidate the absolute stereostructure
of JBIR-05 (3) and will be reported together.

DOI： 10.24496/tennenyuki.59.0_447

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acs.orglett.6b02919

Publishing type：Research paper (scientific journal)  

The Sonogashira-type coupling of 2,2-difluoroethenyl tosylate with a variety of aliphatic and aromatic terminal alkynes proceeds smoothly even at room temperature to produce the corresponding difluorinated enyne derivatives. 2,2-Difluoroethenyl tosylate is a useful difluoroethenyl source because of its ready availability from 2,2,2-trifluoroethanol. Some of the obtained enynes exhibit strong fluorescence in the solid state. Further derivatization of a difluorinated enyne through Rh(III)-catalyzed oxidative coupling has also been examined.

DOI： 10.1021/acs.orglett.6b02919

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.tet.2015.10.075

Publishing type：Research paper (scientific journal)  

The first total synthesis of splenocin B (1), a new potent anti-inflammatory antimycin-class antibiotic, has been described. The synthesis of 1 has been accomplished in 8 linear steps, starting from commercially available N-Boc-L-threonine benzyl ester 4 and 3,4-dihydroxypentanoic acid derivative 2. Kita-Trost lactonization via an ethoxyvinyl ester intermediate was utilized for the construction of the 9-membered dilactone core. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2015.10.075

Publishing type：Research paper (scientific journal)  

DOI： 10.24544/ocu.20171218-066

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1246/cl.150509

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/ajoc.201500142

Publishing type：Research paper (scientific journal)  

The defense toxins, spirostomins A and B, have been isolated as a diastereomeric mixture from the ciliate microorganism <i>Spirostomum teres</i>. The structure of spirostomin was elucidated through a number of NMR experiments which allowed assigning the unprecedented spiro[(2,5-dimethyl-5,6,7,8-tetrahydronaphthalene-1,4-dione)-8,6′-(pyrane-2′,5′-dione)] skeleton to this natural compound. The total syntheses of the racemic spirostomins confirmed their structure and relative configurations.

DOI： 10.1246/cl.150044

CiNii Article

Publishing type：Research paper (scientific journal)  

The first total synthesis of neoantimycin (<b>1</b>), an unusual ring-extended antibiotic of the antimycin class, has been achieved, using intramolecular transesterification for construction of the 15-membered tetralactone core.

DOI： 10.1246/cl.150509

CiNii Article

Publishing type：Research paper (scientific journal)  

The defense toxins, spirostomins A and B, have been isolated as a diastereomeric mixture from the ciliate microorganism <i>Spirostomum teres</i>. The structure of spirostomin was elucidated through a number of NMR experiments which allowed assigning the unprecedented spiro[(2,5-dimethyl-5,6,7,8-tetrahydronaphthalene-1,4-dione)-8,6′-(pyrane-2′,5′-dione)] skeleton to this natural compound. The total syntheses of the racemic spirostomins confirmed their structure and relative configurations.

DOI： 10.1246/cl.150044

CiNii Article

Publishing type：Research paper (scientific journal)  

A new concise and enantiocontrolled total synthesis of (+)-ipomeamarone (<b>1</b>), a well-known phytoalexin, is described. The key step involved a tetrahydrofuran ring construction from optically active furyl alcohol <b>5</b> via the π-allyl palladium complex with a chiral phosphine ligand. This procedure was also applicable to the synthesis of (−)-ngaione (<b>2</b>) and its stereoisomers.

DOI： 10.1246/cl.140811

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/ajoc.201402164

Publishing type：Research paper (scientific journal)  

DOI： 10.1140/epjc/s10052-014-3026-9

Publishing type：Research paper (scientific journal)  

A new concise and enantiocontrolled total synthesis of (+)-ipomeamarone (<b>1</b>), a well-known phytoalexin, is described. The key step involved a tetrahydrofuran ring construction from optically active furyl alcohol <b>5</b> via the π-allyl palladium complex with a chiral phosphine ligand. This procedure was also applicable to the synthesis of (−)-ngaione (<b>2</b>) and its stereoisomers.

DOI： 10.1246/cl.140811

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1099/mic.0.065714-0

Publishing type：Research paper (scientific journal)  

Here, we sought to investigate the vacuole-targeting fungicidal activity of amphotericin B (AmB) in the parent strain and AmB-resistant mutant of Saccharomyces cerevisiae and elucidate the mechanisms involved in this process. Our data demonstrated that the vacuole-targeting fungicidal activity of AmB was markedly enhanced by N-methyl-N ''-dodecylguanidine (MC12), a synthetic analogue of the alkyl side chain in niphimycin, as represented by the synergy in their antifungal activities against parent cells of S. cerevisiae. Indifference was observed only with Delta erg3 cells, indicating that the replacement of ergosterol with episterol facilitated their resistance to the combined lethal actions of AmB and MC12. Dansyl-labelled amphotericin B (AmB-Ds) was concentrated into normal rounded vacuoles when parent cells were treated with AmB-Ds alone, even at a non-lethal concentration. The additional supplementation of MC12 resulted in a marked loss of cell viability and vacuole disruption, as judged by the fluorescence from AmB-Ds scattered throughout the cytoplasm. In Delta erg3 cells, AmB-Ds was scarcely detected in the cytoplasm, even with the addition of MC12, reflecting its failure to normally incorporate across the plasma membrane into the vacuole. Thus, this study supported the hypothesis that ergosterol is involved in the mobilization of AmB into the vacuolar membrane so that AmB-dependent vacuole disruption can be fully enhanced by cotreatment with MC12.

DOI： 10.1099/mic.0.065714-0

PubMed

Publishing type：Research paper (scientific journal)  

Protozoan ciliates are eukaryotic unicellular organisms characterized by the presence of hair-like organelles called cilia. In this article the chemistries of biologically active natural products, especially focused on and also the toxic chemicals which function as defense substances against the predators the compounds leading to conjugation of the cells, are described. Isolation and the synthesis of the colorless defense toxins spirostomin from <i>Spirostomum teres</i> and climacostol from <i>Climacostomum virens</i>are also described.<br>Enantiomerically pure blepharismone (also named gamone 2), a mating inducing pheromone produced by type II cells of the ciliate <i>Blepharisma japonicum</i> were practically synthesized via Stille cross-coupling reaction.

DOI： 10.5059/yukigoseikyokaishi.71.207

CiNii Article

Publishing type：Research paper (scientific journal)  

Protozoan ciliates are eukaryotic unicellular organisms characterized by the presence of hair-like organelles called cilia. In this article the chemistries of biologically active natural products, especially focused on and also the toxic chemicals which function as defense substances against the predators the compounds leading to conjugation of the cells, are described. Isolation and the synthesis of the colorless defense toxins spirostomin from <i>Spirostomum teres</i> and climacostol from <i>Climacostomum virens</i>are also described.<br>Enantiomerically pure blepharismone (also named gamone 2), a mating inducing pheromone produced by type II cells of the ciliate <i>Blepharisma japonicum</i> were practically synthesized via Stille cross-coupling reaction.

DOI： 10.5059/yukigoseikyokaishi.71.207

CiNii Article

Publishing type：Research paper (scientific journal)  

Microbial species have a capability to produce a wide variety of bioactive compounds with novel structures and various biological activities. In our continuing studies on secondary metabolites from Streptomyces sp., we have been much interested in the bis/tri/tetra-lactone antibiotics with 3-formamidosalicylic or 3-hydroxy-4-methoxypicolinic moieties. A marine-derived Streptomyces sp. produced splenocin B (1), which has similarity to UK-2A and antimycin A_<3b> (AA) in structure and displays potent suppression of cytokine production in ranges from low micromolar to low nanomolar and exhibits minimal mammalian cell cytotoxity. Herein, we like to report our preliminary studies on the synthesis of splenocin B. Our synthetic strategy of 1 involves 1) Kita-Fujioka lactonization via ethylvinyl ester and 2) intramolecular Mitsunobu reaction for the construction of the 9-membered bislactone moiety. The cyclization precursors 4 and 5 were prepared from the corresponding β,γ-dihydroxycarboxylic acid, obtained by asymmetric Evans aldol reaction, and L-threonine / allo-L-threonine derivatives. The key cyclization reactions proceeded smoothly to construct the strained nine-membered ring framework of splenocin B in modest yields. Further approach to splenocin B is currently underway and will be reported.

DOI： 10.24496/tennenyuki.54.0_381

CiNii Article

Publishing type：Research paper (scientific journal)  

Microbial species have a capability to produce a wide variety of bioactive compounds with novel structures and various biological activities. In our continuing studies on secondary metabolites from Streptomyces sp., we have been much interested in the bis/tri/tetra-lactone antibiotics with 3-formamidosalicylic or 3-hydroxy-4-methoxypicolinic moieties. A marine-derived Streptomyces sp. produced splenocin B (1), which has similarity to UK-2A and antimycin A_<3b> (AA) in structure and displays potent suppression of cytokine production in ranges from low micromolar to low nanomolar and exhibits minimal mammalian cell cytotoxity. Herein, we like to report our preliminary studies on the synthesis of splenocin B. Our synthetic strategy of 1 involves 1) Kita-Fujioka lactonization via ethylvinyl ester and 2) intramolecular Mitsunobu reaction for the construction of the 9-membered bislactone moiety. The cyclization precursors 4 and 5 were prepared from the corresponding β,γ-dihydroxycarboxylic acid, obtained by asymmetric Evans aldol reaction, and L-threonine / allo-L-threonine derivatives. The key cyclization reactions proceeded smoothly to construct the strained nine-membered ring framework of splenocin B in modest yields. Further approach to splenocin B is currently underway and will be reported.

DOI： 10.24496/tennenyuki.54.0_381

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bmc.2011.08.010

Publishing type：Research paper (scientific journal)  

Conjugation in Blepharisma japonicum is induced by interaction between complementary mating-types I and II, which excrete blepharmone (gamone 1) and blepharismone (gamone 2), respectively. Gamone 1 transforms type II cells such that they can unite, and gamone 2 similarly transforms type I cells. Moreover, each gamone promotes the production of the other gamone. Gamone 2 has been identified as calcium-3-(2-formylamino-5-hydroxybenzoyl) lactate and has been synthesized chemically. Gamone 1 was first isolated and characterized as a glycoprotein of 20-30 kDa containing 175 amino acids and 6 sugars. The 305 amino acid sequence of gamone 1 was determined by Harumoto et al from gamone 1 cDNA, the N-terminus for the protein, however, could not found suggesting the modification of N-terminal amino acid of gamone 1. This time we identified by MALDI-TOFF MS analyses the N-terminus for gamone 1 as glutamine^<28> modified to be pyroglutamine. And also, we determined the structure and the position for the glycan moiety of the gamone 1, using the purified glyopeptides obtained by the chymotrypsin or pronase digestion. Six types of structural heterogeneity was observed for the glycan of gamone 1, and the glycans being attached to N^<141>, N^<149>, N^<165. and N^<213> glutamines which have the consensus sequence of NX[ST].

DOI： 10.24496/tennenyuki.53.0_37

CiNii Article

Publishing type：Research paper (scientific journal)  

Cyclothiazomycin B1 (CTB1) is an antifungal cyclic thiopeptide isolated from the culture broth of Streptomyces sp. HA 125-40. CTB1 inhibited the growth of several filamentous fungi including plant pathogens along with swelling of hyphae and spores. The antifungal activity of CTB1 was weakened by hyperosmotic conditions, and hyphae treated with CTB1 burst under hypoosmotic conditions, indicating increased cell wall fragility. CTB1-sensitive fungal species contain high levels of cell wall chitin and/or chitosan. Unlike nikkomycin Z, a competitive inhibitor of chitin synthase (CHS), CTB1 did not inhibit CHS activity. Although CTB1 inhibited CHS biosynthesis, the same result was also obtained with a nonspecific proteins inhibitor, cycloheximide, which did not reduce cell wall rigidity. These results indicate that the primary target of CTB1 is not CHS, and we concluded that CTB1 antifungal activity was independent of this sole inhibition. We found that CTB1 bound to chitin but did not bind to beta-glucan and chitosan. The results of the present study suggest that CTB1 induces cell wall fragility by binding to chitin, which forms the fungal cell wall. The antifungal activity of CTB1 could be explained by this chitin-binding ability. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2011.08.010

PubMed

Publishing type：Research paper (scientific journal)  

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/ja.2011.31

Publishing type：Research paper (scientific journal)  

アンホテリシンB(AmB)の液胞標的抗真菌活性に及ぼすN-メチル-N''-ドデシルグアニジンの促進効果を、C.albicansを用いて検討した。このグアニジン誘導体はC.albicans細胞に致死的であるだけでなく、AmBによるその液胞破壊活性を増加させた。また、単独添加では用量依存性に活性酸素種の生成を増加させたが、AmB殺菌率への促進効果は酸化ストレス誘導の増幅に付随しなかった。一方、C.albicans細胞はH2O2単独処置、またはH2O2とAmBとの併用処置を受けても真菌液胞は破壊的損傷から保護された。この細胞をエルゴステロールで前処理すると、このグアニジン誘導体によるAmB殺菌率やAmB誘導性液胞破壊の促進は起きなかった。以上より、C.albicans細胞中でAmBが液胞標的抗真菌活性を促進する際のグアニジン誘導体の標的は、エルゴステロール依存性機序と考えられた。

Publishing type：Research paper (scientific journal)  

The alkylguanidium chain attached to the polyol lactone ring of niphimycin (NM) is considered a requisite for the fungicidal activity of NM characterized by vacuole membrane fragmentation and oxidative stress induction. The addition of N-methylN &apos;&apos;-dodecylguanidine to the medium can enhance the vacuole-targeting fungicidal activity of amphotericin B (AmB), in which the lactone ring has no such alkylguanidium chain, on Saccharomyces cerevisiae cells. In this study, the enhancement effect of N-methyl-N &apos;&apos;-dodecylguanidine on the vacuole-targeting fungicidal activity of AmB was examined against Candida albicans in RPMI 1640 medium at 37 degrees C. N-methyl-N &apos;&apos;-dodecylguanidine was lethal to C. albicans cells and additionally enhanced the vacuole disruptive activity of AmB against this pathogenic fungus. N-methyl-N &apos;&apos;-dodecylguanidine elevated the generation of cellular reactive oxygen species when added alone in a dose-dependent manner, but its enhancement effect on AmB lethality did not accompany amplification of oxidative stress induction. The fungal vacuoles were protected against the disruptive damage even if cells were treated with H(2)O(2) alone at a lethal concentration or treated with H(2)O(2) at a sublethal concentration in combination with AmB. N-methyl-N &apos;&apos;-dodecylguanidine was ineffective in enhancing AmB lethality or AmB-induced vacuole disruption when cells had been pretreated with ergosterol. Ergosterol-dependent mechanism is thus considered to be a possible target of N-methyl-N &apos;&apos;-dodecylguanidine in enhancing the vacuole-targeting fungicidal activity of AmB in C. albicans cells. The Journal of Antibiotics (2011) 64, 469-474; doi: 10.1038/ja.2011.31; published online 27 April 2011

DOI： 10.1038/ja.2011.31

PubMed

Publishing type：Research paper (scientific journal)  

アンホテリシンB(AmB)の液胞標的抗真菌活性に及ぼすN-メチル-N''-ドデシルグアニジンの促進効果を、C.albicansを用いて検討した。このグアニジン誘導体はC.albicans細胞に致死的であるだけでなく、AmBによるその液胞破壊活性を増加させた。また、単独添加では用量依存性に活性酸素種の生成を増加させたが、AmB殺菌率への促進効果は酸化ストレス誘導の増幅に付随しなかった。一方、C.albicans細胞はH2O2単独処置、またはH2O2とAmBとの併用処置を受けても真菌液胞は破壊的損傷から保護された。この細胞をエルゴステロールで前処理すると、このグアニジン誘導体によるAmB殺菌率やAmB誘導性液胞破壊の促進は起きなかった。以上より、C.albicans細胞中でAmBが液胞標的抗真菌活性を促進する際のグアニジン誘導体の標的は、エルゴステロール依存性機序と考えられた。

Publishing type：Research paper (scientific journal)  

DOI： 10.4149/gpb_2011_01_106

Publishing type：Research paper (scientific journal)  

Sporulation of the yeast Saccharomyces cerevisiae is negatively regulated by cyclic AMP (cAMP). This microbial cell differentiation process was applied for the screening of a substance that can elevate the intracellular cAMP level. Among nucleoside 5&apos;-alkylphosphates, uridine 5&apos;-eicosylphosphate (UMPC20) selectively and predominantly inhibited ascospore formation of the yeast cells. We suppose the inhibitory effect of UMPC20 could indeed reflect the elevation of the cellular cAMP level.

DOI： 10.4149/gpb_2011_01_106

PubMed

Publishing type：Research paper (scientific journal)  

Conjugation in Blepharisma japonicum is induced by interaction between complementary mating-types I and II, which excrete blepharmone (gamone 1) and blepharismone (gamone 2), respectively. Gamone 1 transforms type II cells such that they can unite, and gamone 2 similarly transforms type I cells. Moreover, each gamone promotes the production of the other gamone. Gamone 2 has been identified as calcium-3-(2-formylamino-5-hydroxybenzoyl) lactate and has been synthesized chemically. Gamone 1 was first isolated and characterized as a glycoprotein of 20-30 kDa containing 175 amino acids and 6 sugars. The 305 amino acid sequence of gamone 1 was determined by Harumoto et al from gamone 1 cDNA, the N-terminus for the protein, however, could not found suggesting the modification of N-terminal amino acid of gamone 1. This time we identified by MALDI-TOFF MS analyses the N-terminus for gamone 1 as glutamine^<28> modified to be pyroglutamine. And also, we determined the structure and the position for the glycan moiety of the gamone 1, using the purified glyopeptides obtained by the chymotrypsin or pronase digestion. Six types of structural heterogeneity was observed for the glycan of gamone 1, and the glycans being attached to N^<141>, N^<149>, N^<165. and N^<213> glutamines which have the consensus sequence of NX[ST].

DOI： 10.24496/tennenyuki.53.0_37

CiNii Article

Publishing type：Research paper (international conference proceedings)  

イソプレノイド誘導体、1-ゲラニルゲラニルピリジニウム（GGPy）は、熱ストレスや浸透圧ストレスなど、さまざまなストレス条件下細胞成長または細胞の生存により重要に関与する細胞機能を阻害することが知られている。本研究では、GGPyの作用機序を明らかにするために、ヒトのモデル細胞としてS. cerevisiae細胞から、GGPyをリガンドとしたアフィニティークロマトグラフィーにより、GGPy結合タンパク質を単離しGGPyの分子標的の特定を試みた。その結果、脂肪酸合成酵素（Fas1）およびグリセルアルデヒド-3-リン酸デヒドロゲナーゼ（GAPDH）アイソザイム3のタンパク質を確認した。

Publishing type：Research paper (scientific journal)  

DOI： 10.1055/s-0030-1259013

Publishing type：Research paper (scientific journal)  

Prunustatin A (1), was isolated from a strain of Streptomyces violaceoniger 4521-SVS3 by Shin-ya and co-workers in 2005, and showed inhibitory activity against GRP78 expression induced by 2-deoxyglucose stimulation in HT1080 cells. We have been interested in establishing the structure-activity relationship of 1, and engaged in studies toward the total synthesis of 1. We have planed to construct the tetralactone ring of 1 via intramolecular Mitsunobu reaction of 2a, which would be prepared by esterification of carboxylic acid 3 with alcohol 4. We first attempted to prepare 3 by esterification between alcohol 9 and carboxylic acid 10, which was syn-selectively synthesized via Mukaiyama aldol reaction of aldehyde 6, derived from L-phenylalanine, with silyl enolether 17. However, the desired esterification would not proceed at all, which were presumably due to the steric hindrance of the quaternary carbon adjacent to the carbonyl group of 10. We next forced on the C-C bond formation reaction between C1 and C11 via Reformatsky reaction. Under optimized condition, the reaction of aldehyde 6 with α-bromoester 5 proceeded successfully to afford 3 in 82% yield. The following esterification of 4 and hydrogenolysis provided the ring-closing precursor 2a in 65% yield.

DOI： 10.24496/tennenyuki.52.0_457

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jfluchem.2010.03.005

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ijantimicag.2009.08.014

Publishing type：Research paper (scientific journal)  

In this study, the polyene macrolide antibiotics amphotericin B (AmB), nystatin and. lipin III were evaluated for their fungicidal activity and their ability to produce vacuole disruption as well as enhancement of these activities by allicin using Saccharomyces cerevisiae. Nystatin has a macrocyclic lactone ring analogous to AmB and their fungicidal activities were both increased by allicin, an allyl-sulfur compound, whereas. lipin III, a pentaene macrolide, did not show an increase in fungicidal activity in the presence of allicin. Vacuole staining with the fluorescent probe FM4-64 showed that both AmB and nystatin induced vacuole membrane disintegration at their lethal concentrations; in addition, the vacuole disruptive effect was also enhanced by allicin. In contrast, filipin III did not affect vacuole morphology and addition of allicin had no effect despite. lipin III localising to the cell cytoplasm. Isolated S. cerevisiae vacuoles were disrupted following treatment both with nystatin and AmB, though this activity was not potentiated in the presence of allicin. In contrast, filipin III had little effect on the vacuole architecture. This study reveals differential effects of polyene antibiotics on vacuoles in S. cerevisiae, which may be due to differences in the structure of the macrocyclic ring. (C) 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

DOI： 10.1016/j.ijantimicag.2009.08.014

PubMed

Publishing type：Research paper (scientific journal)  

Prunustatin A (1), was isolated from a strain of Streptomyces violaceoniger 4521-SVS3 by Shin-ya and co-workers in 2005, and showed inhibitory activity against GRP78 expression induced by 2-deoxyglucose stimulation in HT1080 cells. We have been interested in establishing the structure-activity relationship of 1, and engaged in studies toward the total synthesis of 1. We have planed to construct the tetralactone ring of 1 via intramolecular Mitsunobu reaction of 2a, which would be prepared by esterification of carboxylic acid 3 with alcohol 4. We first attempted to prepare 3 by esterification between alcohol 9 and carboxylic acid 10, which was syn-selectively synthesized via Mukaiyama aldol reaction of aldehyde 6, derived from L-phenylalanine, with silyl enolether 17. However, the desired esterification would not proceed at all, which were presumably due to the steric hindrance of the quaternary carbon adjacent to the carbonyl group of 10. We next forced on the C-C bond formation reaction between C1 and C11 via Reformatsky reaction. Under optimized condition, the reaction of aldehyde 6 with α-bromoester 5 proceeded successfully to afford 3 in 82% yield. The following esterification of 4 and hydrogenolysis provided the ring-closing precursor 2a in 65% yield.

DOI： 10.24496/tennenyuki.52.0_457

CiNii Article

Publishing type：Research paper (international conference proceedings)  

細胞の形態形成機構はあらゆる細胞機能に関与している。本研究では、イソアミルアルコール（IAA）によって誘発される酵母の偽菌糸形成について分析を行った。 ヒト細胞のモデルとして使用される出芽酵母S. cerevisiae BY4741株をモデルとして分析した結果、α-チューブリンレベルの低下は転写によって制御され、β-チューブリンの減少はRNAプロセシング、翻訳、タンパク質分解によって制御されていることが判った。

Publishing type：Research paper (scientific journal)  

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.physletb.2009.01.058

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/ja.2009.2

Publishing type：Research paper (scientific journal)  

ヒト白血病HL-60細胞におけるアンチマイシンA(AA)誘導性アポトーシス様細胞死の生化学的過程を明らかにするため、ポリ(ADP-リボース)ポリメラーゼ(PARP)インヒビター介在カスケードに焦点を当て、更にAAによるアポトーシス進展に伴って生成される反応性酸素/窒素種を含むフリーラジカルの関連性について検討した。AA処理細胞内ではチトクロームC放出、カスパーゼ-3活性化は観察されなかった。AA誘発性細胞死は呼吸阻害及びそれに続くカスケードによるものではなく、AAは、細胞NO生成、PARP過活性化、及びミトコンドリアから核へのアポトーシス誘導因子転位によるDNA断片化を誘導し、その結果、HL-60細胞はアポトーシス様細胞死に至ることが示唆された。

Publishing type：Research paper (scientific journal)  

A respiratory inhibitor, antimycin A (AA), induced an apoptotic-like cell death characterized by nuclear and DNA fragmentation in human leukemia HL-60 cells. This cell death was significantly restricted by a nitric oxide synthase (NOS) inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), and a poly(ADP-ribose) polymerase (PARP) inhibitor, 5-aminoisoquinoline (AIQ). Indeed, NO production and PARP overactivation were detected in the cells treated with AA. On the one hand, L-NMMA partly eliminated NO production and on the other, AIQ and L-NMMA also restricted PARP activation. Excessive signals related to PARP overactivation induce the translocation of an apoptosis-inducing factor (AIF) from the mitochondria to the nuclei, resulting in DNA fragmentation. In AA-treated cells, the nuclear translocation of AIF occurred. This translocation was restricted by pretreatment with AIQ and L-NMMA. Although pretreatment with ascorbic acid eliminated the reactive oxygen species (ROS) generation induced by the blockade of complex III by AA, the pretreatment did not protect the cells from AA-induced cell death. Furthermore, cytochrome c release or caspase-3 activation was not observed in the cells treated with AA. These results suggest that AA-induced cell death does not depend on respiratory inhibition and the succeeding cascades, but on NO production, PARP overactivation and AIF translocation.

DOI： 10.1038/ja.2009.2

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.physletb.2009.01.047

Publishing type：Research paper (scientific journal)  

DOI： 10.1080/14786410802055535

Publishing type：Research paper (scientific journal)  

Nucleoside analogs have been evaluated as useful tools for the investigation of the mechanism of cell differentiation. We thus examined the effects of nucleoside 5&apos;-alkylphosphates (1-10) on the morphogenetic development of starfish embryos. These nucleotide derivatives were all permissive for their development up to the blastula stage, but the derivatives with lauryl side chain selectively inhibited one of the following stages into bipinnaria larvae. Among them, uridine 5&apos;-laurylphosphate (2) inhibited gastrulation of the blastula, as is the case with the antibiotic tunicamycin, suggesting its inhibitory activity on sulfated and non-sulfated glycoprotein syntheses. Unexpectedly, adenosine 5&apos;-laurylphosphate (8) was evaluated as a novel class of inhibitor that can arrest the embryos exactly at the late gastrula stage, absolutely inhibiting cell differentiation involved in the development of gastrointestinal tract. This is the first report on the appearance of biological activity due to the structural modification of a naturally-occurring molecule, which is critical to the morphogenetic development of multicellular organisms.

DOI： 10.1080/14786410802055535

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.tet.2008.02.004

Publishing type：Research paper (scientific journal)  

A copper(I) complex with thiacalix[3]pyridine, [Cu(Py<SUB>3</SUB>S<SUB>3</SUB>)]<SUB>2</SUB>(PF<SUB>6</SUB>)<SUB>2</SUB>, is a competent catalyst for aziridination of olefins. The reaction of styrene (1 equiv) with PhI=NTs (1 equiv) at 20 °C produced <I>N</I>-(<I>p</I>-toluenesulfonyl)-2-phenylaziridine (71%, turnover number = 55) in the presence of 1.2 mol % catalyst under aerobic conditions. The turnover number increased up to 350 with a 0.12 mol % catalyst and a 5:1 styrene/PhI=NTs ratio in 41% yield.

DOI： 10.1246/cl.2008.452

CiNii Article

Publishing type：Research paper (scientific journal)  

A microorganism capable of liquefying cross-linked poly(γ-glutamic acid) (C-L PGA) was isolated and identified to be an <i>Acremonium</i> sp. The fungus produced an enzyme that can disrupt the cross-linkages of C-L PGA generated by γ-ray irradiation. The enzyme can also liquefy C-L PGA prepared by chemical cross-linkage, suggesting the involvement of ester bonds in the γ-ray irradiation-mediated cross-linking of PGA.<br>

DOI： 10.1263/jbb.105.422

CiNii Article

Publishing type：Research paper (scientific journal)  

A microorganism capable of liquefying cross-linked poly(gamma-glutamic acid) (C-L PGA) was isolated and identified to be an Acremonium sp. The fungus produced an enzyme that can disrupt the cross-linkages of C-L PGA generated by gamma-ray irradiation. The enzyme can also liquefy C-L PGA prepared by chemical cross-linkage, suggesting the involvement of ester bonds in the gamma-ray irradiation-mediated cross-linking of PGA.

DOI： 10.1263/jbb.105.422

Publishing type：Research paper (scientific journal)  

The heterotrich ciliate Blepharisma japonicum produces red pigment blepharismins, which function as self-defense toxin against predators and as a photoreceptor for step-up photonegativity. The dibenzoperylenequinone moiety of blepharismins was shown to be biosynthesized via the polyketide pathway. In this paper, the starter units of the biosynthetic pathway of blepharismins were determined to be isovaleryl-CoA and butyryl-CoA by HPLC, LC/ESI-MS, and H-1 and H-2 NMR analyses of the pigments obtained from feeding experiment Of L-leucine or sodium butyrate in excess and deuterium-labeled L-leucine. (c) 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2008.02.004

Publishing type：Research paper (scientific journal)  

A copper(I) complex with thiacalix[3]pyridine, [Cu(Py<SUB>3</SUB>S<SUB>3</SUB>)]<SUB>2</SUB>(PF<SUB>6</SUB>)<SUB>2</SUB>, is a competent catalyst for aziridination of olefins. The reaction of styrene (1 equiv) with PhI=NTs (1 equiv) at 20 °C produced <I>N</I>-(<I>p</I>-toluenesulfonyl)-2-phenylaziridine (71%, turnover number = 55) in the presence of 1.2 mol % catalyst under aerobic conditions. The turnover number increased up to 350 with a 0.12 mol % catalyst and a 5:1 styrene/PhI=NTs ratio in 41% yield.

DOI： 10.1246/cl.2008.452

CiNii Article

Publishing type：Research paper (scientific journal)  

CiNii Article

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/ja.2007.101

PubMed

Publishing type：Research paper (scientific journal)  

In our survey for antifungal compounds, a fermentation broth of Streptomyces sp. HA81-2 was found to inhibit the in vitro growth of Aspergillus fumigatus IFO 5840 accompanied by hyphal morphological abnormalities. One of the isolated antibiotics was identified as phoslactomycin E based on LC-MS and NMR spectral data. In a preliminary assay using the membrane fractions of A. fumigatus, phoslactomycin E was found to inhibit the activity of 1,3-beta glucan synthase.

DOI： 10.1038/ja.2007.101

Publishing type：Research paper (scientific journal)  

著者等の抗真菌化合物の探索過程において、Streptomyces sp.HA81-2の発酵液がA.fumigatus IFO 5840のin vitro成長を、菌糸形態学的異常を伴って阻害することを明らかにした。LC-MS及びNMRスペクトルのデータを基にして、単離した抗生物質の一つがphoslactomycin Eであることを確認した。また、A.fumigatusの膜成分を用いた予備的分析の結果から、phoslactomycin Eは1,3-βグルカンシンターゼの活性を阻害することが分かった。

Publishing type：Research paper (scientific journal)  

Blepharismins (BPs) are toxic pigments of a negatively phototactic ciliate Blepharisma japonicum. This pigment was first reported in 1905, and was extensively studied by Giese. The chemical structure of BP(s) was elucidated in 1997 independently by Song, and Naoki. with analyzing HMQC and HMBC NMR spectra of BP-C or tetramethoxy derivatives of BPs. BPs (1), which consist as a mixture of five congeners, are structurally related to naturally occurring polycyclic phenanthroperylene quinones such as hypericin, a photodynamic toxin of Hypericum, and stentorin isolated from another negatively phototactic ciliate Stentor coeruleus. BPs are shown to be converted to stentorin via oxyblepharismines (OxyBPs) by UV-irradiation, whose structures were determined by Spitzner. Lensi studied OxyBP-choromoprotein association, and helical properties of OxyBP with or without the chromoprotein. The function of BPs has not been fully elucidated, but three functions have been clarified: light perception, defense against predators or UV irradiation. BPs are highly ring-condensed compound with a lot of substituted sp^2 carbons, therefore assignment of the ^<13>C NMR signals has not been completely achieved in the previous reports. Herein we like to report full assignment of the ^<13>C NMR signals of BP-C (1c) using samples obtained by feeding of ^<13>C-labeled sodium acetates to the cells of B. japonicum in the culture media.

DOI： 10.24496/tennenyuki.49.0_281

CiNii Article

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

ヒトの細胞に対する様々なストレス条件下における生理活性について、本研究では呼吸阻害剤として知られている antimycin A (AA) のヒト培養細胞に対する致死作用について分析を行った。AAの作用はチトクロームCの漏出、カスパーゼ３の活性を示さなかった。本研究の結果は、AAの作用が呼吸阻害ではなく、アポトーシスに起因していることを示している。

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.tet.2007.04.015

Publishing type：Research paper (scientific journal)  

Blepharismins, toxic pigments of the ciliate Blepharisma japonicum, are polycyclic ring-condensed compounds. Assignment of C-13 NMR signals for blepharismin C, a major constituent of blepharismins, was achieved by analyses of the HMQC, HMBC, and INADEQUATE spectra of C-13-enriched samples obtained by feeding experiments using sodium [1-C-13], [2-C-13], and [1,2-C-13(2)]acetates. (c) 2007 Published by Elsevier Ltd.

DOI： 10.1016/j.tet.2007.04.015

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bmc.2006.12.021

Publishing type：Research paper (scientific journal)  

Blepharismone (gamone 2) is a mating-inducing pheromone of the ciliate Blepharisma japonicum. N-Pyrenylbutyryl-blepharismone and N-biphenylacetyl-blepharismone, which are fluorescent derivatives of blepharismone, were synthesized as molecular probes for the gamone 2 receptor. Further, we proved that they have inhibitory activities against the blepharismone-induced monotypic pairing of B. japonicum. Published by Elsevier Ltd.

DOI： 10.1016/j.bmc.2006.12.021

Publishing type：Research paper (scientific journal)  

CiNii Article

Publishing type：Research paper (scientific journal)  

ニフィマイシン(NM)のアルキルグアニジニウム鎖と、アルキル側鎖を欠くポリエンマクロライド系抗生物質アンホテリシンB(AmB)との相乗作用を、合成した類似体N-メチル-N''-アルキルグアニジン類を対象として調べた。その中で、N-メチル-N''-ドデシルグアニジン(MC12)がSaccharomyces cerevisiaeほかの真菌類の生育をAmBと相乗的に最も強く阻害した。MC12自体に致死作用はないが、非致死濃度のAmBの存在下で速やかな酵母細胞死が起きた。両化合物の作用が一体化して、原形質膜障害や細胞反応性酸素種の産生によりNM様の抗真菌活性が生じる。NM処理した細胞同様に、MC12とAmBで同時処理した細胞には液胞の形態異常と、付随して液胞膜の欠陥を認めた。これらはNMのアルキルグアニジウム鎖がポリオールラクトン環部をエンハンサーとして共働することで、抗真菌活性に主要な役割を発揮すると言う考えを支持する。

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/ja.2007.4

PubMed

Publishing type：Research paper (scientific journal)  

The synergy between the alkylguanidinium chain of niphimycin (NM), a polyol macrolicle antibiotic, and polyene macrolide amphotericin B (AmB) without such an alkyl side chain was examined using N-methyl-N''alkylguanidines as its synthetic analogs. Among the analogs, N-methyl-N"-dodecylguanidine (MC12) most strongly inhibited the growth of Saccharomyces cerevisiae cells and those of other fungal strains in synergy with AmB. MC12 itself was not lethal but the analog could be a cause of a rapid cell death progression of yeast cells in the presence of AmB at a nonlethal concentration. Their combined actions resulted in the generation of NM-like fungicidal activity that depended on plasma membrane disability and cellular reactive oxygen species production. We also found an aberrant vacuolar morphogenesis and an associated vacuolar membrane disability in cells treated simultaneously with MC12 and AmB, as in the case of NM-treated cells. These findings support the idea that the alkylguanidinium chain plays a major role in the fungicidal activity of NM in cooperation with the polyol lactone ring as its enhancer.

DOI： 10.1038/ja.2007.4

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Publishing type：Research paper (scientific journal)  

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Blepharismins (BPs) are toxic pigments of a negatively phototactic ciliate Blepharisma japonicum. This pigment was first reported in 1905, and was extensively studied by Giese. The chemical structure of BP(s) was elucidated in 1997 independently by Song, and Naoki. with analyzing HMQC and HMBC NMR spectra of BP-C or tetramethoxy derivatives of BPs. BPs (1), which consist as a mixture of five congeners, are structurally related to naturally occurring polycyclic phenanthroperylene quinones such as hypericin, a photodynamic toxin of Hypericum, and stentorin isolated from another negatively phototactic ciliate Stentor coeruleus. BPs are shown to be converted to stentorin via oxyblepharismines (OxyBPs) by UV-irradiation, whose structures were determined by Spitzner. Lensi studied OxyBP-choromoprotein association, and helical properties of OxyBP with or without the chromoprotein. The function of BPs has not been fully elucidated, but three functions have been clarified: light perception, defense against predators or UV irradiation. BPs are highly ring-condensed compound with a lot of substituted sp^2 carbons, therefore assignment of the ^<13>C NMR signals has not been completely achieved in the previous reports. Herein we like to report full assignment of the ^<13>C NMR signals of BP-C (1c) using samples obtained by feeding of ^<13>C-labeled sodium acetates to the cells of B. japonicum in the culture media.

DOI： 10.24496/tennenyuki.49.0_281

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DOI： 10.1093/jb/mvj218

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The modes of actions of 1-farnesylpyridinium (FPy) on yeast cell growth were investigated on the basis of its effects on cell cycle progression, morphogenesis and the related events for construction of cell wall architecture in Schizosacchromyces pombe. FPy predominantly inhibited the growth of the yeast cells after various cycles of cell division so that cells were arrested at the phase of separation into daughter cells accompanying morphological changes to swollen spherical cells at 24 h of incubation. FPy-treated cells were osmotically stable but were susceptible to the lytic action of (1, 3) beta-D-glucanases, and characterized by serious damages to the cell wall architecture as represented by a rough and irregular surface outlook. The isolated cell wall fraction gave a similar hexose composition with or without FPy treatment, suggesting that FPy did not inhibit the synthesis of each cell wall polysaccharide. FPy was permissive for the extracellular accumulation of amorphous cell wall materials and septum development in protoplasts, but absolutely interfered with the following morphogenetic process for construction of the rod-shaped cell wall architecture. Our results suggest the inhibitory activity of FPy on the spatial control over the assembly of cell wall polysaccharides.

DOI： 10.1093/jb/mvj218

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DOI： 10.1016/j.tetasy.2006.09.005

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Both enantiomers of blepharismone, a mating inducing pheromone produced by type II cells of Blepharisma japonicum, were synthesized via the Stille cross-coupling. reaction of [4-(tert-butyl-dimethyl-silanyloxy)-2-trimethylstannanyl-phenyl]-carbamic acid tert-butyl ester with an acid chloride derived from (S)- and (R)-malic acid as a key reaction. The mating inducing activity of synthetic (S)-blepharismone was as effective as that of the natural one. The enantiomer (R)-blepharismone showed no mating inducing activity. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetasy.2006.09.005

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DOI： 10.1016/j.carres.2006.04.015

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We describe the efficient synthesis of the tetrasaccharide, 2-O-acetyl-3,4,6-tri-O-benzyl-alpha-D-mannopyranosyl-(1 -&gt; 6)-2,4-di-O-acetyl-3-O-allyl-p-D-mannopyranosyl-(1 -&gt; 4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-O-D-glucopyranosyl-(1 -&gt; 4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl azide, which is the protected form of the sugar unit of TIME-EA4 that is isolated from the diapausing eggs of the silkworm, Bombyx mori. The P-linked D-mannoside of the tetrasaccharide was obtained using the conventional oxidation-reduction method for inversion of the configuration at the C-2 hydroxyl group Of P-D-glucoside. The reduction was effected with NaBH4 in a methanolic solution in a ratio of 98:2 in favor of the P-D-mannoside that was obtained in 87% yield. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.carres.2006.04.015

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DOI： 10.24496/intnaturalprod.2006.0__P-368_

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DOI： 10.24496/intnaturalprod.2006.0__P-503_

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DOI： 10.24496/intnaturalprod.2006.0__P-502_

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DOI： 10.1016/j.bmcl.2006.03.023

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DOI： 10.1016/j.jfluchem.2006.02.016

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DOI： 10.1016/j.bmcl.2005.12.024

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Uridine 5′-hexadecylphosphate (UMPC16) inhibited the growth of <i>Saccharomyces cerevisiae</i> under a hypersaline stress condition with Na⁺ more strongly than the calcineurin inhibitor cyclosporine A (CsA). Additional Ca²⁺ supplementation similarly suppressed the inhibitory activities of UMPC16 and CsA on yeast cell growth in a medium with Na⁺. UMPC16, but not CsA, accelerated mitochondrial reactive oxygen species (ROS) generation in combination with Na⁺, suggesting its inhibition of a Ca²⁺-dependent but calcineurin-independent mechanism for protection against Na⁺ toxicity.<br>

DOI： 10.1263/jbb.101.77

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Treatment of an oxaziridine with low-valent iron or copper salts generates a carbon-centered radical able to cyclize onto an appended olefin.

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Treatment of an oxaziridine with low-valent iron or copper salts generates a carbon-centered radical able to cyclize onto an appended olefin.

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DOI： 10.24496/intnaturalprod.2006.0__p-503_

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DOI： 10.24496/intnaturalprod.2006.0__p-502_

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DOI： 10.24496/intnaturalprod.2006.0__p-368_

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Cross-linked poly-γ-glutamic acid (C-L γ-PGA) at 5 μg/ml flocculated bentonite suspension pretreated with polyaluminum chloride (PAC) at 2 μg/ml Al³⁺-PAC to a transparency of approximately 30% after 30 min and more than 90% after 4 h, while Al³⁺ concentration in the upper phase of the suspension decreased with incubation time. When pretreated with FeCl₃ at 16 μg/ml Fe³⁺-FeCl₃, similar results were obtained. In the case of <i>Escherichia coli</i> suspension, the combination of C-L γ-PGA and FeCl₃ demonstrated a more marked flocculating activity with a satisfactory transparency occurring after 30 min of treatment, accompanied by a decrease in residual Fe³⁺ concentration. In the above two suspensions pretreated with FeCl₃, small visible floats appeared in the early stage of incubation. These floats were found to be due to the direct interaction between FeCl₃ and C-L γ-PGA, indicating the formation of a water-insoluble complex. After allowing the suspension to stand for a long time, elemental analysis and inductively coupled plasma spectroscopy of the precipitates produced suggested that not only the complex was formed due to the interaction between Fe³⁺ in FeCl₃ and COO^– in the C-L γ-PGA molecule, but also Fe₂O₃ and Fe(OH)₃ might be entrapped in this complex. This could be applied to scavenge metal ions including Fe³⁺ from polluted water.<br>

DOI： 10.1263/jbb.100.207

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DOI： 10.1016/j.bmcl.2005.02.065

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DOI： 10.1016/j.bmcl.2004.12.059

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DOI： 10.7164/antibiotics.57.687

PubMed

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UK-2A is a potent antifungal antibiotic and its structure is highly similar to that of antimycin A₃ (AA). UK-2A and AA inhibit mitochondrial electron transport at complex III. C9-UK-2A, which has been prepared to improve the duration of the antifungal activity of UK-2A, shows durable fungicidal activities against various species of fungi and induces both membrane injury and the generation of cellular reactive oxygen species (ROS) against <i>Rhodotorula mucilaginosa</i> IFO 0001 cells. We found that C9-UK-2A inhibited the vegetative growth of <i>Saccharomyces cerevisiae</i> IFO 0203 cells accompanying cellular ROS generation in Sabouraud dextrose (SD) medium, which contained a fermentable carbon source. The ROS generation was completely restricted by pretreatment with a lipophilic antioxidant α-tocopherol. In addition, the pretreatment with the antioxidant protected against the growth inhibition induced by C9-UK-2A. C9-UK-2A also induced ROS generation in isolated mitochondria of the <i>S. cerevisiae</i> cells. The addition of both a complex I inhibitor rotenone and a complex II inhibitor thenoyltrifluoroacetone reduced ROS generation induced by C9-UK-2A in the whole cells and the isolated mitochondria. The addition of the inhibitors of complex III, AA or myxothiazol, or of complex IV, KCN, did not reduce ROS generation. These results suggest that C9-UK-2A induces ROS generation due to the blockade of electron flow at complex III, thereby inhibiting the growth of <i>S. cerevisiae</i> in SD medium.

DOI： 10.7164/antibiotics.57.511

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In the continuing study on predator-prey interaction between ciliates, we reported the isolation and structural determination of a defense toxin climacostol from a heterotrich ciliate Climacostomum virens. On the preliminary study of the predator-prey interaction between ciliates Dileptus margaritifer as a predator and Spirostomum teres an another heterotrich ciliate as a prey, we observed elusive behavior of S. teres from the predator and the presence of the cortical vesicle in S. teres just beneath the cell membrane, which suggested that S. teres had some toxic substance against the predator. We report the isolation and structural determination of a toxic substance spirortomin from S. teres. The whole cells of S. teres were dipped in aqueous 70% EtOH. After removal of the cells by filtration and concentration of the solvent, the residue was partitioned between ethyl acetate and water. From the organic layer, an active fraction based on lethal toxicity against a ciliate Paramecium caudatum was obtained by chromatography on silica gel eluted with 1.5% Me0H/CH2Cl2 (Rf value=0.44). The fraction contained a new compound spirostomin (1),4 whose molecular formula was estimated to be C16H14O5 by HREIMS and 1H and 13C NMR. Based on 1H, 13C NMR and UV spectrum, the structure of spirostomin was established as spiro[(2,5-dimethyl-5,6,7,8-tetrahydronaphtalene-1,4-dione)-8,6'-(pyrane-2',5'-dione)], a spiro compound having a carbon framework hitherto unknown.

DOI： 10.24496/tennenyuki.46.0_617

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DOI： 10.7164/antibiotics.56.314

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ポリオールマクロライド系抗生物質ニフィマイシン(NM)を10μM以上のカリウムイオン存在下にSaccharomyces cerevisiae細胞に添加したところ,ヌクレオチド様物質を含む細胞質成分の漏出を伴う抗真菌活性を示した.過酸化水素にて同細胞を処置したところ同様の形質膜変化が認められたが,ポリエンマクロライド系抗生物質であるアンホテリシンB(AmB)の添加では認められなかった.NM誘発性細胞死はホスファチジルコリン添加により抑制されたが,この細胞保護作用はAmBの分子標的であるエルゴステロールでは弱かった.NM処置細胞ではグルタチオンの著明な減少も認められ,抗酸化分子のNM誘発性代謝転換を呈していた.NM処置により濃度依存性に活性酸素種の細胞産生が促進された.以上より,S.cerevisiaeに対するNMの抗真菌活性は,形質膜に対する直接作用と酸化ストレスの相乗作用であることが示唆された

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UK-2A is a potent antifungal antibiotic and its structure is highly similar to that of antimycin A₃ (AA). UK-2A and AA inhibit mitochondrial electron transport at complex III. However, the antifungal activities of UK-2A and AA disappear after 48-hour treatment. In an attempt to improve the duration of the antifungal activity of UK-2A, several UK-2A derivatives were prepared by substituting its nine-membered dilactone ring with an <i>n</i>-alkyl or an isoprenyl moiety. Among all the derivatives tested, C9- and C10-UK-2A showed the most potent and durable antifungal activities against a strict aerobic yeast, <i>Rhodotorula mucilaginosa</i> IFO 0001. C9-UK-2A, in particular, continued to demonstrate its broad-spectrum antifungal activity after 120-hour treatment. Therefore, we focused on C9-UK-2A to further examine its mode of action against the yeast. Interestingly, C9-UK-2A did not inhibit cellular respiration of the cells even at concentrations greater than 100μg/ml. C9-UK-2A gradually induced the efflux of potassium ions from the cells. Moreover, C9-UK-2A gradually induced the release of glucose from glucose-encapsulating liposomes. The patterns of efflux and release induced by C9-UK-2A were not as rapid as those seen with amphotericin B. These results suggest a membrane injury caused by C9-UK-2A in <i>R. mucilaginosa</i> IFO 0001.

DOI： 10.7164/antibiotics.55.315

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DOI： 10.7164/antibiotics.55.607

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The heterotrich ciliates Stentor coeruleus and Blepharisma japonicum have pigment granules which contain the blue pigment stentorin and the red pigment blepharismin, respectively. We found that the pigment granules are extrusomes, extrusive organellas in protists, and that the pigments function for defense against the predatory ciliate Dileptus margaritifer. Climacostomum virens, another heterotrich ciliate, is colorless, and has cortical vesicles which are morphologically similar to the pigment granules in the red species of Blepharisma. The retreating behavior of D. margaritifer observed when it attacks C. virens suggested that C. virens also has a toxin against the predator. We already reported isolation, characterization and synthesis of climacostol (1) which was a potent toxin of C. virens. When S. coeruleus and B. japonicum are mixed with SMB (Synthetic Medium for Blepharisma) at 0℃ (cold shock), they discharge pigment granules as extrusomes in a similar way as a response to the attack by the predator. The cells of C. virens were treated by cold shock to discharge the extrusomes to the medium, which showed a lethal toxicity to the predatory ciliates. Climacostol was found to be truly present in the medium by the analysis of the content using HPLC and LC/MS analysis. We concluded climacostol function as a self-defense against the predatory ciliates. We also found that the contents consisted of congeners of climacostol, 2 and 3. Their structures were assumed by the ^1H NMR spectra and ESI-LC/MS/MS analyses to be 5-undeca-2,5-dienyl-benzene-1,3-diol and (Z,Z,Z)-5-undeca-2,5,8-trienyl-benzene-1,3-diol, respectively.

DOI： 10.24496/tennenyuki.44.0_343

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L-2,5-Dihydrophenylalanine(DHPA)によるヒト前骨髄細胞白血病のアポトーシスは核の断片化やクロマチン濃縮化のような細胞の形態学的変化やDNA階段やcaspase 3の活性化のような生化学的分析でみられる証拠によって示された.このアポトーシスにはpan-caspase抑制剤や,Z-VAD-fmkや,systein protease抑制剤のE-64dで抑制される.Calpain抑制剤のZ-LL-Hはこのアポトーシスに影響せず,カテプシンB特異的抑制剤のCA074-Meはクロマチン濃縮のみを抑制した.しかし,E-64dやカテプシンL特異的抑制剤のZ-FY(t-Bu)-dmkはクロマチン濃縮とoligonucleosomal DNA断片化の両方を抑制した.アポトーシスに先立ってカテプシンBおよびLの活性化が次第に高まった.以上,DHPAはHL-60細胞のカテプシン依存アポトーシスの誘導物質であることを示唆した

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UK-2A,AA,及びそれ等の誘導体はグラム陰性及びグラム陽性細菌に対して100μg/ml迄発育抑制活性を示さなかった.しかし,C8-UK-2A,C8-2HNA,C4-AA及びC8-AAは抗真菌活性を示した.C8-UK-2Aの活性はUK-2Aの約100分の1であるのに対し,C8-AAの活性はAAの約1/3であった.C8-UK-2Aの作用様式はUK-2Aのそれと異なることが示唆された

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DOI： 10.7164/antibiotics.54.600

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J-GLOBAL

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L-2, 5-Dihydrophenylalanine (DHPA), a phenylalanine analogue, induced apoptosis in human promyelocytic leukemia cells (HL-60). This apoptosis was demonstrated by morphological changes of the cells, such as fragmentation of nuclei and chromatin condensation, and by some evidence found in biochemical analysis, such as DNA ladder and activation of caspase 3. The DHPA-induced apoptosis was prevented by a pan-caspase inhibitor, Z-VAD-fmk, and a cysteine protease inhibitor, E-64d, which inhibits calpains and camepsin B and L. A calpain inhibitor, Z-LL-H, did not affect this apoptosis. A cathepsin B specific inhibitor, CA074-Me, prevented only chromatin condensation. However, E-64d and a cathepsin L specific inhibitor, Z-FY(<i>t</i>-Bu)-dmk, protected the cells from both chromatin condensation and oligonucleosomal DNA fragmentation. As proceeding to the apoptotic process, the activities of both cathepsin B and L increased gradually. These results indicated that DHPA was an inducer of cathepsin-dependent apoptosis in HL-60 cells.

DOI： 10.7164/antibiotics.54.810

PubMed

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J-GLOBAL

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Haliclorensin 1, a novel diamino alkaloid possessing an aza-cyclodecane ring, has been isolated from the sponge, Haliclona tulearensis by Kashman et al. in 1998. The structure of the alkaloid was proposed from spectroscopic data. Furthermore haliclorensin forms part of the structure of halitulin 2, a more complex bisquinolylpyrrole alkaloid from the same organism that exhibits strong cytotoxic activity against mouse leukemia cell. The unique structure as well as the significant biological activities led us to undertake the enantioselective synthesis of haliclorensin. Our synthetic strategy of haliclorensin involves regio-selective photochemical rearrangement of spirocyclic oxaziridines into lactams. Oxaziridine 8 derived from cyclononanone and (R)-phenylethylamine was irradiated with a low-pressure lamp (254nm) in benzene at rt to afford the corresponding lactam 9 in 54% yield. Methylation of 9 with LDA/MeI afforded 10 in 70% yield as a 4: 1 mixture of two diastereomers. Other chiral amines were screened with intend to optimize the diastereoselectivity. Lactam 14 derived from cyclononanone and the methyl ether of (R)-phenylglycinol was methylated with sec-BuLi/MeI to give the desired product 16 in 62% yield as a 9: 1 mixture of two diastereomers. Further synthetic studies directing toward the proposed structure of 1 is now in progress. Recently the total synthesis of the structure proposed for haliclorensin has been reported. The ^<13>C NMR data and optical rotation of the synthetic compound differ from the values given for haliclorensin. We also have been reexamining the spectroscopic data reported by Kashman to revise the structure of haliclorensin.

DOI： 10.24496/tennenyuki.43.0_587

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The heterotrich ciliates, Stentor coeruleus and Blepharisma japonicum, have pigment granules which contain blue pigment stentorin and red pigment blepharismin, respectively. We recently reported that the pigment granules and the pigments act as defense against the predatory ciliate, Dileptus margaritifer. Although Climacostomum virens, another heterotrich ciliate, is colorless, it has cortical vesicles, which are morphologically similar to the pigment granules in the red species of Blepharisma. The retreating behavior of D. margaritifer observed when it attacks C. virens suggests that C. virens also has the defense toxin against the predator. Indeed, we found a potent toxin against D. margaritifer in 70% ethanol extract of C. virens. The active fraction obtained by repeated chromatography on silica gel contained a new compound climacostol (1) (LD_<50> 1.8μg/ml), whose molecular formula was estimated to be C_<15>H_<22>O_2 by HRMS and ^1H and ^<13>C NMR. The presence of two phenolic OH protons and the close resemblance of the chemical shifts of the aromatic protons and the carbons of 1 to that of olivetol (1,3-dihydoxy-5-pentylbenzene) suggested that 1 is a derivative of 5-alkenyl resorcinol. The ^1H-^1H COSY, HMBC, and HMQC spectra of 1 indicated the presence of Ar-CH_2-CH=CH-CH_2, from which is deduced the presence of the 2-nonenyl group as the side chain attached to resorcinol at the 5-position. The Z-configuration of △2,3-olefin was determined by the observation of NOE between the 1'- and 4'-methylene protons. Thus, the structure of 1 was established to be 1,3-dihydoxy-5-[(Z)-2-nonenyl]benzene. The structure and biological activity of climacostol were confirmed by the total synthesis of 1.

DOI： 10.24496/tennenyuki.42.0_523

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DOI： 10.7164/antibiotics.52.345

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J-GLOBAL

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A new synthesis in enantiomerically pure form of blepharismone (1), a gamone of ciliate Blepharisma japonicum was developed. The Stille reaction in the presence of Pd_2Cl_2(CH_3CN)_2 between trimethyltin derivative 2 and acid chloride 3 derived from (S)-malic acid gave 4 which had carbon skeleton of 1. While N-Boc group of 4 was converted to N-formyl group by HCO_2H/Ac_2O, deprotection of methoxy and clorolalide groups was unsuccssful. Then, the Stille reaction was carried out between 7 and 8, affording 9, the protection groups of which could be removed easily. (S)-blepharismone (1) was synthesized from 9 in two steps (1. HF/pyr. 2. HCO_2H/Ac_2O). (R)-Blepharismone was also synthsized using (R)-malic acid in the same way. The optical purity of synthetic compounds were determined with dimethyl compound 11 derived from 10 by ^1H NMR, using chiral shift reagent (+)-Eu(hfc)_3. It was found that racemization of OH group at 2 position did not occured during the reaction. Synthetic (S)-1 was active as the natural blepharismone in the test of mating induction of Blepharisma, while (R)-1 was inactive at up to 500μg/ml. The photoaffinity label compound of 1 was also designed.

DOI： 10.24496/tennenyuki.39.0_343

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CiNii Article

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A total synthesis of prunustatin A, a GRP78 molecular chaperone down-regulator, has been achieved. The key step in the synthesis is an intramolecular transesterification of the beta-keto ester alcohol intermediate to construct the 15-membered tetralactone core of the natural product.

DOI： 10.1002/ajoc.201500142

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© 2015 The Chemical Society of Japan. The defense toxins, spirostomins A and B, have been isolated as a diastereomeric mixture from the ciliate microorganism Spirostomum teres. The structure of spirostomin was elucidated through a number of NMR experiments which allowed assigning the unprecedented spiro[(2,5-dimethyl- 5,6,7,8-tetrahydronaphthalene-1,4-dione)-8,6′-(pyrane-2′,5′-dione)] skeleton to this natural compound. The total syntheses of the racemic spirostomins confirmed their structure and relative configurations.

DOI： 10.1246/cl.150044

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© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. A total synthesis of prunustatinA, a GRP78 molecular chaperone down-regulator, has been achieved. The key step in the synthesis is an intramolecular transesterification of the β-keto ester alcohol intermediate to construct the 15-membered tetralactone core of the natural product.

DOI： 10.1002/ajoc.201500142

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© 2015 The Chemical Society of Japan. The first total synthesis of neoantimycin (1), an unusual ring-extended antibiotic of the antimycin class, has been achieved, using intramolecular transesterification for construction of the 15-membered tetralactone core.

DOI： 10.1246/cl.150509

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&lt;p&gt;Neoantimycin (1) is a rare and unusual ring-extended member of the antimycin class. First isolated in 1967 from a South American soil isolate of Streptomyces orinoci, the partial configuration of 1 was assigned in 1969 by preparative-scale degradation. A subsequent study using nOe experiments was reported by Takeda in 1998. Literature references to 1 were thus limited, but the recent discovery of prunustatin A (2) as a selective GRP78 molecular chaperone down-regulator, which could lead to the development of new approaches toward combatting cancer, highlights the potential of this class as research probes. Herein, we report the first total synthesis of neoantimycin (1) and SW-163A (27), another neoantimycin-class antibiotic. &lt;/p&gt;&lt;p&gt;Our synthetic strategy involves intramolecular transesterification for the construction of 15-membered tetralactone core, followed by introduction of gem-dimethyl group. The cyclization precursor 7was derived from D-phenylalanine, L-isoleucine, L-threonine and L-valine. The key 15-membered tetralactone 5 was successfully obtained in good yield. Reduction of 5 with NaBH&lt;sub&gt;4&lt;/sub&gt; proceeded smoothly to provide the corresponding alcohol as a single diastereomer with the desired configuration. Finally, amidation and the following deprotection furnished neoantimycin (1). This strategy is applicable to the synthesis of SW-163A (27). Synthetic 1 and 27 were identical in all respects to the natural samples, respectively. &lt;/p&gt;

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A synthesis of fluorine-containing asparagine and glutamine analogues via palladium-catalyzed formate reduction of fluorinated carbonate esters is described. Primary amide moieties at the side-chain of asparagine and glutamine were successfully replaced with fluoroolefins, which are proposed to be aprotic mimics for amides due to their electronic properties.

DOI： 10.1002/ajoc.201402164

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© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. A synthesis of fluorine-containing asparagine and glutamine analogues via palladium-catalyzed formate reduction of fluorinated carbonate esters is described. Primary amide moieties at the side-chain of asparagine and glutamine were successfully replaced with fluoroolefins, which are proposed to be aprotic mimics for amides due to their electronic properties. Fluoro can you go: Fluorine imparts unique properties to organic molecules. Fluoroolefins are proposed to be aprotic mimic for amides due to their electronic properties.

DOI： 10.1002/ajoc.201402164

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© 2014 The Chemical Society of Japan. A new concise and enantiocontrolled total synthesis of (+)-ipomeamarone (1), a well-known phytoalexin, is described. The key step involved a tetrahydrofuran ring construction from optically active furyl alcohol 5 via the π-allyl palladium complex with a chiral phosphine ligand. This procedure was also applicable to the synthesis of (1)-ngaione (2) and its stereoisomers.

DOI： 10.1246/cl.140811

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Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Kind of work：Single Work  

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&lt;p&gt;Microbial species have a capability to produce a wide variety of bioactive compounds with novel structures and various biological activities. In our continuing studies on secondary metabolites from Streptomycessp., we have been much interested in the bis/tri/tetra-lactone antibiotics with 3-formamidosalicylic or 3-hydroxy-4-methoxypicolinic moieties. Prunustatin A (1) was isolated from a strain of Streptomyces violaceoniger 4521-SVS3 by Shinya and co-workers in 2005 and showed inhibitory activity against GRP78 expression induced by 2-deoxyglucose stimulation in HT1080 cells&lt;sup&gt;1)&lt;/sup&gt;. We have been interested in the structure and biological activities of 1 and have pursued toward the total synthesis. Herein, we like to report on a new total synthesis of prunustatin A. &lt;/p&gt;&lt;p&gt;We first attempted to synthesize 15-membered tetralactone moiety by intramolecular Mitsunobu reaction and Shiina macrolactonization at C2-C3 and by intramolecular Reformasky reaction at C11-C1. However, our trials of cyclization resulted in the formation of undesired products, which is presumably due to the presence of gem-dimethyl group at C11. &lt;/p&gt;&lt;p&gt;We revised synthetic strategy of 1, which involves intramolecular transesterification for the construction of 15-membered tetralactone moiety, followed by introduction of gem-dimethyl group. The cyclization precursor 4 was derived from D-phenylalanine, L-isoleucine, L-threonine and L-lactic acid. The key 15-membered tetralactone moiety 2a was successfully obtained in moderate yield. Finally, amidation of 2a with 2b and the following deprotection furnished prunustatin A (1). Synthetic prunustatin A (1) was identical in all respects to the natural sample.&lt;/p&gt;

CiNii Article

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Protozoan ciliates are eukaryotic unicellular organisms characterized by the presence of hair-like organelles called cilia. In this article the chemistries of biologically active natural products, especially focused on and also the toxic chemicals which function as defense substances against the predators the compounds leading to conjugation of the cells, are described. Isolation and the synthesis of the colorless defense toxins spirostomin from Spirostomum teres and climacostol from Climacostomum virensare also described. Enantiomerically pure blepharismone(also named gamone 2), a mating inducing pheromone produced by type II cells of the ciliate Blepharisma japonicum were practically synthesized via Stille cross-coupling reaction.

DOI： 10.5059/yukigoseikyokaishi.71.207

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Protozoan ciliates are eukaryotic unicellular organisms characterized by the presence of hairlike organelles called cilia. In this article the chemistries of biologically active natural products, especially focused on and also the toxic chemicals which function as defense substances against the predators the compounds leading to conjugation of the cells, are described. Isolation and the synthesis of the colorless defense toxins spirostomin from Spirostomum teres and climacostol from Climacostomum virensare also described.
Enantiomerically pure blepharismone (also named gamone 2), a mating inducing pheromone produced by type II cells of the ciliate Blepharisma japonicum were practically synthesized via Stille cross-coupling reaction.

DOI： 10.5059/yukigoseikyokaishi.71.207

CiNii Article

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Protozoan ciliates are eukaryotic unicellular organisms characterized by the presence of hair-like organelles called cilia. In this article the chemistries of biologically active natural products, especially focused on and also the toxic chemicals which function as defense substances against the predators the compounds leading to conjugation of the cells, are described. Isolation and the synthesis of the colorless defense toxins spirostomin from Spirostomum teres and climacostol from Climacostomum virensare also described. Enantiomerically pure blepharismone(also named gamone 2), a mating inducing pheromone produced by type II cells of the ciliate Blepharisma japonicum were practically synthesized via Stille cross-coupling reaction.

DOI： 10.5059/yukigoseikyokaishi.71.207

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Microbial species have a capability to produce a wide variety of bioactive compounds with novel structures and various biological activities. In our continuing studies on secondary metabolites from Streptomyces sp., we have been much interested in the bis/tri/tetra-lactone antibiotics with 3-formamidosalicylic or 3-hydroxy-4-methoxypicolinic moieties. A marine-derived Streptomyces sp. produced splenocin B (1), which has similarity to UK-2A and antimycin A_<3b> (AA) in structure and displays potent suppression of cytokine production in ranges from low micromolar to low nanomolar and exhibits minimal mammalian cell cytotoxity. Herein, we like to report our preliminary studies on the synthesis of splenocin B. Our synthetic strategy of 1 involves 1) Kita-Fujioka lactonization via ethylvinyl ester and 2) intramolecular Mitsunobu reaction for the construction of the 9-membered bislactone moiety. The cyclization precursors 4 and 5 were prepared from the corresponding β,γ-dihydroxycarboxylic acid, obtained by asymmetric Evans aldol reaction, and L-threonine / allo-L-threonine derivatives. The key cyclization reactions proceeded smoothly to construct the strained nine-membered ring framework of splenocin B in modest yields. Further approach to splenocin B is currently underway and will be reported.

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DOI： 10.1038/ja.2011.77

DOI： 10.1038/ja.2011.77

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Conjugation in Blepharisma japonicum is induced by interaction between complementary mating-types I and II, which excrete blepharmone (gamone 1) and blepharismone (gamone 2), respectively. Gamone 1 transforms type II cells such that they can unite, and gamone 2 similarly transforms type I cells. Moreover, each gamone promotes the production of the other gamone. Gamone 2 has been identified as calcium-3-(2-formylamino-5-hydroxybenzoyl) lactate and has been synthesized chemically. Gamone 1 was first isolated and characterized as a glycoprotein of 20-30 kDa containing 175 amino acids and 6 sugars. The 305 amino acid sequence of gamone 1 was determined by Harumoto et al from gamone 1 cDNA, the N-terminus for the protein, however, could not found suggesting the modification of N-terminal amino acid of gamone 1. This time we identified by MALDI-TOFF MS analyses the N-terminus for gamone 1 as glutamine^<28> modified to be pyroglutamine. And also, we determined the structure and the position for the glycan moiety of the gamone 1, using the purified glyopeptides obtained by the chymotrypsin or pronase digestion. Six types of structural heterogeneity was observed for the glycan of gamone 1, and the glycans being attached to N^<141>, N^<149>, N^<165. and N^<213> glutamines which have the consensus sequence of NX[ST].

CiNii Article

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A new approach has been developed for the synthesis of the fluorinated Kitahara-Danishefsky&apos;s diene analogue, (E)-1-benzyloxy- 3-fluoro-1,3-butadiene, via a Pd-catalyzed process. This novel fluorine-containing diene reacts with various dienophiles to provide useful 1-fluorocyclohexene derivatives in good yields.

DOI： 10.1055/s-0030-1259013

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A new approach has been developed for the synthesis of the fluorinated Kitahara-Danishefskys diene analogue, (E)-1-benzyloxy-3-fluoro-1,3-butadiene, via a Pd-catalyzed process. This novel fluorine-containing diene reacts with various dienophiles to provide useful 1-fluorocyclohexene derivatives in good yields. © Georg Thieme Verlag Stuttgart - New York.

DOI： 10.1055/s-0030-1259013

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2-Fluoro-3-phenyl-allyltrimethylsilane, prepared from β-fluorinated allylic acetate via a π-allylpalladium intermediate, reacted with various aldehydes and acetals in the presence of TiCl4to afford the corresponding homoallyl alcohols and homoallyl ethers, respectively, in good to moderate yields. © 2010 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jfluchem.2010.03.005

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2-Fluoro-3-phenyl-allyltrimethylsilane, prepared from beta-fluorinated allylic acetate via a pi-allylpalladium intermediate, reacted with various aldehydes and acetals in the presence of TiCl(4) to afford the corresponding homoallyl alcohols and homoallyl ethers, respectively, in good to moderate yields. (C) 2010 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jfluchem.2010.03.005

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Prunustatin A (1), was isolated from a strain of Streptomyces violaceoniger 4521-SVS3 by Shin-ya and co-workers in 2005, and showed inhibitory activity against GRP78 expression induced by 2-deoxyglucose stimulation in HT1080 cells. We have been interested in establishing the structure-activity relationship of 1, and engaged in studies toward the total synthesis of 1. We have planed to construct the tetralactone ring of 1 via intramolecular Mitsunobu reaction of 2a, which would be prepared by esterification of carboxylic acid 3 with alcohol 4. We first attempted to prepare 3 by esterification between alcohol 9 and carboxylic acid 10, which was syn-selectively synthesized via Mukaiyama aldol reaction of aldehyde 6, derived from L-phenylalanine, with silyl enolether 17. However, the desired esterification would not proceed at all, which were presumably due to the steric hindrance of the quaternary carbon adjacent to the carbonyl group of 10. We next forced on the C-C bond formation reaction between C1 and C11 via Reformatsky reaction. Under optimized condition, the reaction of aldehyde 6 with α-bromoester 5 proceeded successfully to afford 3 in 82% yield. The following esterification of 4 and hydrogenolysis provided the ring-closing precursor 2a in 65% yield.

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Blepharismins (BPs) are toxic pigments of a negatively phototactic ciliate Blepharisma japonicum. This pigment was first reported in 1905, and was extensively studied by Giese. The chemical structure of BP(s) was elucidated in 1997 independently by Song, and Naoki. with analyzing HMQC and HMBC NMR spectra of BP-C or tetramethoxy derivatives of BPs. BPs (1), which consist as a mixture of five congeners, are structurally related to naturally occurring polycyclic phenanthroperylene quinones such as hypericin, a photodynamic toxin of Hypericum, and stentorin isolated from another negatively phototactic ciliate Stentor coeruleus. BPs are shown to be converted to stentorin via oxyblepharismines (OxyBPs) by UV-irradiation, whose structures were determined by Spitzner. Lensi studied OxyBP-choromoprotein association, and helical properties of OxyBP with or without the chromoprotein. The function of BPs has not been fully elucidated, but three functions have been clarified: light perception, defense against predators or UV irradiation. BPs are highly ring-condensed compound with a lot of substituted sp^2 carbons, therefore assignment of the ^<13>C NMR signals has not been completely achieved in the previous reports. Herein we like to report full assignment of the ^<13>C NMR signals of BP-C (1c) using samples obtained by feeding of ^<13>C-labeled sodium acetates to the cells of B. japonicum in the culture media.

CiNii Article

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Several open-chained analogues of UK-2A, a novel antifungal antibiotic isolated from Streptomyces sp. 517-02, were prepared for structure-activity studies. The in vitro antifungal activities of these compounds against Rhodotorula mucilaginosa IFO 0001 and the inhibition of uncoupler-stimulated respiration in bovine heart submitochondrial particles (SMP) were evaluated. Oxidative potentials were measured by cyclic voltammetry. An analogue prepared from dihexyl l-glutamate showed comparable inhibitory activity as UK-2A. © 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2006.03.023

PubMed

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Several γ-fluoro-β,γ-unsaturated acids, fluorine-containing analogues of N-acyl glycines, were synthesized via Julia-Lythgoe olefination. The antimicrobial activities of these compounds and synthetic intermediates were evaluated. Analogues with an octyl group showed in vitro antifungal activity agaist Penicillium chrysogenum IFO4626. © 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jfluchem.2006.02.016

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Several open-chained analogues of UK-2A, a novel antifungal antibiotic isolated from Streptomyces sp. 517-02, were prepared for structure-activity studies. The in vitro antifungal activities of these compounds against Rhodotorula mucilaginosa IFO 0001 and the inhibition of uncoupler-stimulated respiration in bovine heart submitochondrial particles (SMP) were evaluated. Oxidative potentials were measured by cyclic voltammetry. An analogue prepared from dihexyl L-glutamate showed comparable inhibitory activity as UK-2A. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2006.03.023

PubMed

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Several gamma-fluoro-beta, gamma-unsaturated acids, fluorine-containing analogues of N-acyl glycines, were synthesized via Julia-Lythgoe olefination. The antimicrobial activities of these compounds and synthetic intermediates were evaluated. Analogues with an octyl group showed in vitro antifungal activity agaist Penicillium chrysogenum IFO4626. (c) 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jfluchem.2006.02.016

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Several N-methyl-N″-alkylguanidinium derivatives were synthesized and used as simplified analogues of niphimycin (NM), a guanidylpolyol macrolide, in structure-activity relationship studies. The C16-alkylated derivative exerted fungicidal activity by directly damaging the fungal plasma membrane and inducing oxidative stress in a manner similar to niphimycin. These results indicate that the N-methyl-N″-alkylguanidinium moiety is required for antifungal activity by NM. © 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2005.12.024

PubMed

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Several N-methyl-N ''-alkylguanidinium derivatives were synthesized and used as simplified analogues of niphimycin (NM), a guanidylpolyol macrolide, in structure-activity relationship studies. The C16-alkylated derivative exerted fungicidal activity by directly damaging the fungal plasma membrane and inducing oxidative stress in a manner similar to niphimycin. These results indicate that the N-methyl-N ''-alkylguanidinium moiety is required for antifungal activity by NM. (C) 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2005.12.024

PubMed

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Uridine 5′-hexadecylphosphate (UMPC16) inhibited the growth of Saccharomyces cerevisiae under a hypersaline stress condition with Na+more strongly than the calcineurin inhibitor cyclosporine A (CsA). Additional Ca2+supplementation similarly suppressed the inhibitory activities of UMPC16 and CsA on yeast cell growth in a medium with Na+. UMPC16, but not CsA, accelerated mitochondrial reactive oxygen species (ROS) generation in combination with Na+, suggesting its inhibition of a Ca2+-dependent but calcineurin-independent mechanism for protection against Na+toxicity. © 2006 The Society for Biotechnology, Japan.

DOI： 10.1263/jbb.101.77

PubMed

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Uridine 5'-hexadecylphosphate (UMPC16) inhibited the growth of Saceharomyces cerevisiae under a hypersaline stress condition with Na+ more strongly than the calcineurin inhibitor cyclosporine A (CsA). Additional Ca2+ supplementation similarly suppressed the inhibitory activities of UMPC16 and CsA on yeast cell growth in a medium with Na+. UMPC16, but not CsA, accelerated mitochondrial reactive oxygen species (ROS) generation in combination with Na', suggesting its inhibition of a Ca2+-dependent but calcineurin-independent mechanism for protection against Na+ toxicity.

DOI： 10.1263/jbb.101.77

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Cross-linked poly-gamma-glutamic acid (C-L gamma-PGA) at 5 mu g/ml flocculated bentonite suspension pretreated with polyaluminum chloride (PAC) at 2 mu g/ml AI(3+)-PAC to a transparency of approximately 30% after 30 min and more than 90% after 4 h, while Al3+ concentration in the upper phase of the suspension decreased with incubation time. When pretreated with FeCl3 at 16 mu g/ml Fe3+-FeCl3, similar results were obtained. In the case of Escherichia coli suspension, the combination of C-L gamma-PGA and FeCI3 demonstrated a more marked flocculating activity with a satisfactory transparency occurring after 30 min of treatment, accompanied by a decrease in residual Fe3+ concentration. In the above two suspensions pretreated with FeCI3, small visible floats appeared in the early stage of incubation. These floats were found to be due to the direct interaction between FeCl3 and C-L gamma-PGA, indicating the formation of a water-insoluble complex. After allowing the suspension to stand for a long time, elemental analysis and inductively coupled plasma spectroscopy of the precipitates produced suggested that not only the complex was formed due to the interaction between Fe3+ in FeCl3 and COO- in the C-L gamma-PGA molecule, but also Fe2O3 and Fe(OH)(3) might be entrapped in this complex. This could be applied to scavenge metal ions including Fe3+ from polluted water.

DOI： 10.1263/jbb.100.207

PubMed

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Several analogues of UK-2A, a novel antifungal antibiotic isolated from Streptomyces sp. 517-02, were semi-synthesized for structure-activity studies. In vitro antifungal activities of these compounds against Saccharomyces cerevisiae IFO 0203 were evaluated by the conventional paper disk method. Several derivatives exhibited growth inhibitory activity similar to UK-2A. © 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2005.02.065

PubMed

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Several analogues of UK-2A, a novel antifungal antibiotic isolated from Streptomyces sp. 517-02, were semi-synthesized for structure-activity studies. In vitro antifungal activities of these compounds against Saccharomyces cerevisiae IFO 0203 were evaluated by the conventional paper disk method. Several derivatives exhibited growth inhibitory activity similar to UK-2A. (c) 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2005.02.065

PubMed

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Antimicrobial activities of two azafluorenones, four 1-azaanthraquinones, five 2-azaanthraquinones, and one 2-azaquinone were tested. Several azaanthraquinones possessed broad, potent activity, while the azafluorenones demonstrated weak activity. The following structure-activity relationship was postulated: (1) activity decreased in the order 2-azaanthraquinones > 1-azaanthraquinones > azafluorenones; and (2) a hydroxyl group at the peri-carbonyl group enhanced activity. In addition, correlations among reduction potential, hydrophobic parameter, and antimicrobial activity were discussed. © 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2004.12.059

PubMed

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Antimicrobial activities of two azafluorenones, four 1-azaanthraquinones, five 2-azaanthraquinones, and one 2-azaquinone were tested. Several azaanthraquinones possessed broad, potent activity, while the azafluorenones demonstrated weak activity. The following structure-activity relationship was postulated: (1) activity decreased in the order 2-azaanthraquinones &gt;1-azaanthraquinones &gt; azafluorenones; and (2) a hydroxyl group at the peri-carbonyl group enhanced activity. In addition, correlations among reduction potential, hydrophobic parameter, and antimicrobial activity were discussed. (C) 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2004.12.059

PubMed

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Cross-linked poly-γ-glutamic acid (C-L γ-PGA) at 5 μg/ml flocculated bentonite suspension pretreated with polyaluminum chloride (PAC) at 2 μg/ml Al3+-PAC to a transparency of approximately 30% after 30 min and more than 90% after 4 h, while Al3+concentration in the upper phase of the suspension decreased with incubation time. When pretreated with FeCl3at 16 μg/ml Fe3+-FeCl3, similar results were obtained. In the case of Escherichia coli suspension, the combination of C-L γ-PGA and FeCl3demonstrated a more marked flocculating activity with a satisfactory transparency occurring after 30 min of treatment, accompanied by a decrease in residual Fe3+concentration. In the above two suspensions pretreated with FeCl3, small visible floats appeared in the early stage of incubation. These floats were found to be due to the direct interaction between FeCl3and C-L γ-PGA, indicating the formation of a water-insoluble complex. After allowing the suspension to stand for a long time, elemental analysis and inductively coupled plasma spectroscopy of the precipitates produced suggested that not only the complex was formed due to the interaction between Fe3+in FeCl3and COO-in the C-L γ-PGA molecule, but also Fe2O3and Fe(OH)3might be entrapped in this complex. This could be applied to scavenge metal ions including Fe3+from polluted water. ©2005, The Society for Biotechnology.

DOI： 10.1263/jbb.100.207

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Climacostol (1), a defense toxin of the heterotrich ciliate Climacostomum virens was established as 5-(Z)-non-2-enyl-benzene-1,3-diol. The structure was rigorously confirmed by the total synthesis. The two congeners of climacostol contained in this ciliate were determined as 5-(Z,Z)-undeca-2,5-dienyl-benzene-1,3-diol (2) and 5-(Z,Z,Z)-undeca-2,5,8-trienyl-benzene-1,3-diol (3). (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2003.09.105

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Among various analogs of the isoprenoid farnesol (FOH), farnesylamine (FNH2) inhibited the growth of the budding yeast Saccharomyces cerevisiae by accelerating cellular reactive oxygen species (ROS) generation. Unlike the case with FOH, however, FNH2 did not cause mitochondrial transmembrane potential (mtΔψ) hyperpolarization so that FNH 2-treated cells were not protected against ROS production by inhibiting the proton pumping function of mitochondrial F0F 1-ATPaSe. FNH2 promoted ROS generation even in cells of a respiration-deficient mutant, indicating a yeast metabolic pathway other than mitochondrial electron transport as the origin of ROS. FNH2 oxidase activity was detected in the yeast mitochondrial fraction, which produces hydrogen peroxide (H2O2) in the reaction with either FNH2 or geranylgeranylamine (GGNH2), in addition to polyamine oxidase activity specific for spermine. GGNH2 also exhibited the growth inhibitory effect with the accompanying induction of ROS generation, while such an activity was not detected with any of the polyamines tested or geranylarnine. FNH2 oxidase, which was sensitive to a typical copper-chelating agent, diethyidithiocarbainic acid (DDC), could be solubilized with Triton X-100, and detected as a single band upon activity staining with FNH2 bat not with spermine in polyacrylamide gel electrophoresis. FNH2-treated cells were partly protected against ROS production by the additional supplementation of DDC in the medium. Our results suggest the involvement of H2O2 production due to direct oxidation of FNH2 by copper amine oxidase in oxidative stress-dependent inhibition of yeast cell growth.

DOI： 10.1016/S1389-1723(05)00314-2

PubMed

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alpha-Fluoro-alpha-silyl-substituted sulfones 1 are readily prepared from fluoromethyl phenyl sulfone and the appropriate silyl chloride. The use of TBSCl improves both the stability and yield of 1. Lithium derivatives 4 undergo a smooth Peterson olefination reaction with less-enolizable carbonyl compounds to give moderate to good yields of the expected alpha-fluorovinylsulfones 6, in some cases with high E-stereoselectivity. One-pot reaction with 4 generated in situ from fluoromethyl phenyl sulfone in tetrahydrofuran (THF) also proceeds smoothly, particularly with aldehydes. (C) 2003 Elsevier B.V. All rights reserved.

DOI： 10.1016/S0022-1139(03)00194-5

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A UMP-derivative, uridine 5′-hexadecylphosphate (UMPC16), exhibited a fungicidal action against various yeast strains including the fission yeast Schizosaccharomyces pombe in combination with Ba2+ ion. UMPC16 accelerated reactive oxygen species (ROS) generation in medium with Ba 2+ ion in a dose- and time-dependent manner. Additional supplementation of Ca2+ ion into medium could suppress such a combined fungicidal action due to oxidative stress induction.

DOI： 10.1016/S1389-1723(03)70139-X

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CiNii Article

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1-Farnesylpyridinium (FPy), an analog of isoprenoid farnesol, initially induced morphological changes similar to those of typical apoptosis in human leukemia HL-60 cells but FPy-treated cells were characterized by the absolute absence of final apoptotic events such as fragmentation into apoptotic bodies. FPy-induced cell death was considered to be apoptotic on the basis of the induction of DNA fragmentation and the protection against these events by the coaddition of a pan-caspase inhibitor. The increase in the cytoplasmic cytochrome e level supported the possibility that FPy-treated cells should have the ability to complete the entire apoptotic process ending in cell fragmentation and apoptotic body formation. At concentrations too low to induce apoptosis, FPy could suppress the induction of apoptotic body formation in HL-60 cells by typical inducers of apoptosis such as actinomycin D or anisomycin. FPy exhibited a cytochalasin-like effect on spatial arrangement of actin filament independent of its apoptosis-inducing activity. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0014-5793(02)02373-6

PubMed

J-GLOBAL

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

The polyol macrolide niphimycin (NM) exhibited fungicidal activity against Saccharomyces cerevisiae cells accompanying the leakage of cytoplasmic components including nucleotide-like materials in addition to K+ at 10 μM or above. Such a dynamic change in the plasma membrane was observed upon treatment of cells with H2O2 but not with the polyene macrolide antibiotic amphotericin B (AmB). The NM-induced cell death could be prevented by the exogenous addition of phosphatidylcholine (PC) whereas such a protective effect was only weakly observed with ergosterol, the molecular target of AmB. NM-treated cells were further characterized with a dramatic loss of glutathione even at a dose of 5 μM or less, representing NM-triggered metabolic conversion of the antioxidant molecule. NM-treatment indeed accelerated the cellular production of reactive oxygen species (ROS) such as H2O2 detectable with a specific fluorescent probe in a dose-dependent manner. These results suggested a synergistic combination of direct plasma membrane damage and oxidative stress as a cause of antifungal activity of NM against S. cerevisiae.

DOI： 10.1263/jbb.94.207

PubMed

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

CiNii Article

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

A new enantioselective total synthesis of N-(3'-aminopropyl)-3-methylazacyclodecane, a partial structure of halitulin, has been achieved in eight steps with 14% overall yield. The key steps are the photochemical ring-expansion reaction of spirooxaziridine to lactam for constructing the azacyclodecane moiety and 1,4-stereoinductive methylation of the resulting lactam. (C) 2002 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0957-4166(02)00007-1

CiNii Article

J-GLOBAL

Publishing type：Article, review, commentary, editorial, etc. (other)   Kind of work：Single Work  

Publishing type：Article, review, commentary, editorial, etc. (other)  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

CiNii Article

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

CiNii Article

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

A toxic substance (climacostol) of the protozoan ciliate Climacostomum virens against the predatory ciliate Dileptus margaritifer was established as 1,3-dihydoxy-5-[(Z)-2'-nonenyl]benzene. The structure was rigorously confirmed by the total synthesis. (C) 1999 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4039(99)01722-0

CiNii Article

J-GLOBAL

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

CiNii Article

Publishing type：Article, review, commentary, editorial, etc. (other)   Kind of work：Single Work  

Publishing type：Article, review, commentary, editorial, etc. (other)  

CiNii Article

Publishing type：Article, review, commentary, editorial, etc. (other)  

Publishing type：Article, review, commentary, editorial, etc. (other)  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

The H-1 NMR spectra of spirocyclic oxaziridines derived from substituted cyclohexanones and benzylamines were studied. Depending on substitution and on stereochemistry, these compounds often exhibit a substantial upfield shift of the cyclohexyl methylene or methine protons with a 1,3-diaxial relationship to the oxaziridine N-substituent. This effect is ascribed to a conformation that places an aromatic group over the plane of the cyclohexane ring. This conformation has also been found in the solid state by X-ray crystallography and is supported by molecular mechanics calculations. The use of the effect in assigning stereochemistry to this series of compounds is discussed.

DOI： 10.1021/jo00129a050

CiNii Article

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

The carbanion derived from the title beta-silylsulfone reacts with aldehydes and ketones readily to afford fluoro olefins, which was produced via desulfination of initially formed adducts with concomitant 1,4-migration of the diphenylmethylsilyl group from the carbon to the oxygen atom.

DOI： 10.1055/s-1994-22986

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Benzeneselenenyl fluoride equivalent was generated in situ by the reaction of silver(I) fluoride with benzeneselenenyl bromide in dichloromethane under ultrasound irradiation. Treatment of internal alkynes with this reagent afforded 2-fluoro-1-alkenyl phenyl selenides in moderate yields.

DOI： 10.1246/cl.1992.1507

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Fluoroselenenylation of alpha-diazoketones and alpha-diazoesters using a phenylselenenyl fluoride equivalent, generated in situ from phenylselenenyl bromide and AgF, followed by oxidation with hydrogen peroxide, provided alpha-fluoro-alpha,beta-unsaturated ketones and ester, respectively, in moderate yields.

DOI： 10.1039/c39920001148

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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