Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.tet.2023.133623

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry (RSC)  

Polyamines are ubiquitously found in nature. In this paper, we disclose our iterative coupling strategy for the synthesis of structurally defined polymer of 1,3-propanediamine, the polymer can be used for...

DOI： 10.1039/d3ob00369h

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/ejoc.202200669

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ejoc.202200669

Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry (RSC)  

By interchanging the order of reactions, two types of skeletons were created and a neuroactive artificial glutamate analog was developed.

DOI： 10.1039/d2ra03744k

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Publishing type：Research paper (scientific journal)   Publisher：The Chemical Society of Japan  

DOI： 10.1246/cl.210241

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Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/acs.jnatprod.0c01280

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Beilstein Institut  

Herein, we report the enantiospecific synthesis of two artificial glutamate analogs designed based on IKM-159, an antagonist selective to the AMPA-type ionotropic glutamate receptor. The synthesis features the chiral resolution of the carboxylic acid intermediate by the esterification with ʟ-menthol, followed by a configurational analysis by NMR, conformational calculation, and X-ray crystallography. A mice in vivo assay showed that (2<italic>R</italic>)-MC-27, with a six-membered oxacycle, is neuroactive, whereas the (2<italic>S</italic>)-counterpart is inactive. It was also found that TKM-38, with an eight-membered azacycle, is neuronally inactive, showing that the activity is controlled by the ring C.

DOI： 10.3762/bjoc.17.48

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Other Link： https://www.beilstein-journals.org/bjoc/content/pdf/1860-5397-17-48.pdf

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

By establishing the procedures for sequential deprotections, reaction monitoring, purification, and handling, for the first time, we achieved the total synthesis of the proposed structure for protoaculeine B (2), which is a highly hydrophilic and polycationic amino acid. The NMR and mass spectra and chemical reactivity of the synthetic sample differed from those of natural protoaculeine B, which indicates the necessity for revision of the originally reported structure.

DOI： 10.1021/acs.jnatprod.0c00761

PubMed

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

By a hybrid design of naturally derived excitatory amino acids, dysiherbaines and kainic acid, we have successfully developed a series of artificial glutamate analogs with sp3-rich scaffold via domino Ugi/Diels–Alder reaction, and domino metathesis reaction of oxanorbornenes as key steps. All of the first-generation analogs were found to be neuronally active upon mice intracerebroventricular injection. As the second-generation analogs, we then synthetically modified the heterotricyclic structure, and found that analogs with a carbonyl group on the A-ring still keep the original activity of the first-generation analogs. Structural modification of the second-generation analogs by diversity-oriented reactions such as multicomponent Prins–Ritter reaction was furthermore studied to improve the activity profiles. Electrophysiological studies have identified IKM–159 of the second-generation analogs as an antagonist selective to AMPA-type ionotropic glutamate receptor. The molecular interactions were clarified from crystallographic studies of IKM–159 in complex with GluA2 ligand-binding domain (LBD). From the structure–activity relationships and the structural insights of the complex, a new structural design is proposed herein for neuronally active agents with improved potency and selectivity. We also propose here that generation of sp3-rich scaffold by hybrid strategy of known bioactive molecules would be of use for discovery of artificial bioactive agents with novel activity profiles.

DOI： 10.5059/yukigoseikyokaishi.78.292

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Language：Japanese   Publisher：公益社団法人 有機合成化学協会  

DOI： 10.5059/yukigoseikyokaishi.78.365

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Language：English   Publishing type：Research paper (scientific journal)  

Herein we report improved enantiospecific synthesis and some structure-activity relationships of our heterotricyclic artificial glutamate analogs bearing seven-membered ring for the C-ring. Starting from readily available oxanorbornene rac-3, optically pure (2R)-TKM-107, (2R)-IKM-154, and the antipodes were synthesized in total nine steps for each. Mice in vivo assay indicated that only the (2R)-enantiomer was active in both cases. Behaviors phenotypes observed in the mice assay suggested that these compounds are similar in mode of action to that of IKM-159 but with discrete potency.

DOI： 10.3987/COM-19-S(F)2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Efficient stereodivergent syntheses of (+)-lycoperdic acid (LPA) and 4-epi-LPA have been achieved based on asymmetric hydrogenation (H2, Rh/(R,S)-MeBoPhoz) of racemic enamide as a key step.

DOI： 10.1016/j.tetlet.2019.06.067

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Chemical Society of Japan  

Here, we report an empirical model for diastereoselective cyclopropanation of fumarate/maleate diesters with chloroacetate, sulfonium ylide, or ammonium ylide. With symmetrical fumarate/maleate diesters, cyclopropanation was found to proceed with a high level of diastereoselectivity in favor of the chiral isomer. In contrast, production of the meso isomer was observed in 38–48% diastereoselectivity when unsymmetrical fumarate/maleate was employed. An improved synthesis of (N-desmethy)dysibetaine CPa in both racemic and enantiomerically pure forms was furthermore achieved. Configurational analysis by experimental and calculated 13C NMR data is also reported.

DOI： 10.1246/bcsj.20190096

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Chemical Society of Japan  

Here, we report practical method for asymmetric synthesis of cyclopropane-fused GABA analogs. Starting from 2–furaldehyde, the cis–isomer (CAMP) was synthesized over 10 steps; (–)– and (+)–CAMP•HCl were synthesized by employing d– and l–menthol as the chiral auxiliary for total 2.5% and 1.3% yields, respectively. On the other hand, the trans–isomer (TAMP) was elaborated via double asymmetric induction, i.e. organocatalytic asymmetric cyclopropanation on chiral substrate. Thus, starting from l– and d–menthyl acrylate, in combination with quinidine-derived and quinine-derived organocatalysts, (–)– and (+)–TAMP•HCl were synthesized in total 6.6% and 3.7% yields, respectively, over 8 steps each. Configurational analysis of the synthetic intermediates based on 13C NMR is also reported. Preliminary oncological assays showed the weak but specific activities of CAMP and TAMP as the molecular basis of GABA analogs, which are still left unexplored.

DOI： 10.1246/bcsj.20190168

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.tetlet.2018.10.045

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Language：English   Publishing type：Research paper (scientific journal)  

A synthetic strategy for accessing protoaculeine B (1), the N-terminal amino acid of the highly modified peptide toxin aculeine, was developed via the synthesis of the fully protected natural homologue of 1 with a 12-mer poly(propanediamine). The synthesis of mono(propanediamine) analog 2, as well as core amino acid 3, was demonstrated by this strategy. New amino acid 3 induced convulsions in mice; however, compound 2 showed no such activity.

DOI： 10.1021/acs.orglett.8b01331

PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Institute of Heterocyclic Chemistry  

The construction of cis-fused heterobicyclic system involved in neuroactive natural products such as dysiherbaine has been accomplished by employing Prins strategy using 1,3,5-trioxane as an equivalent for formaldehyde. The reactions allowed stereoselective construction of the trisubstituted cis-fused hexahydro-2H-furo[3,2-b]pyran with maximum yield of 60%.

DOI： 10.3987/COM-17-13776

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Monocyclic analog of neuroexcitatory neodysiherbaine has been designed and stereoselectively synthesized in 0.40% yield over total 24 steps starting from D-ribose, by employing domino aldol-Cannizzaro reaction and stereoselective aldol reaction for construction of two quaternary carbon stereogenic centers at C4 and C6 positions, respectively. The hyperactivity of neodysiherbaine in mice was found to deteriorate in the novel analog, upon intracerebroventricular injection. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2016.09.074

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Herein, we report an efficient construction of the lactone bridge of strongylophorine-2, which is a meroditerpenoid isolated from Strongylophora durissima and an inhibitor for HIF-1 transcriptional pathway. Starting from dehydroepiandrosterone acetate, the characteristic lactone has been constructed in 5.4% over 18 steps by employing, (1) modified oxy radical-mediated C-H functionalization at the C24 methyl group, and (2) four-step manipulation of C4 quaternary carbon stereogenic center. The lactone synthesized here is expected as a precursor for (8-desmethyl)strongylophorine-2 which is of particular interest in terms of structure-activity relationships in the inhibition of HIF-1 transcriptional pathway. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2016.07.067

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Here, we report an unprecedented, highly diastereoselective Prins-Ritter reaction of aldehydes, homoallylic alcohols, and nitriles in a three-component coupling reaction for the synthesis of tetra-cis-substituted 4-amidotetrahydropyrans. In this study, the reaction was not only applied for carbohydrate-based heterobicycles but also for more complex heterotricycles, showing acceptable levels of conversion yield (42-97% BRSM) and exclusive diastereoselectivity. Furthermore, the latter heterotricycles were converted to nine analogues of our neuronal receptor ligands IKM-159 and MC-27. An in vivo assay by intracerebroventricular injection in mice suggested that the substituent at C9 of the novel analogues interferes with the molecular interactions with the AMPA receptor, which was originally observed in the complex of IKM-159 and the GluA2 ligand binding domain. Our research has thus shown the power of a multicomponent coupling reaction for the preparation of a structurally diverse compound collection to study structure activity relationships of biologically active small molecules.

DOI： 10.1021/acscombsci.6b00046

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Taepeenin D is a meroterpenoid isolated from roots and stems of Caesalpinia crista, showing inhibitory activity of Hedgehog signaling pathway. Herein we report selective and short-step construction of two fragments of taepeenin D. First, we demonstrated alkoxy radical-mediated selective functionalization at C19 methyl group for construction of the C4 quaternary carbon stereogenic center. Second, the CD benzofuran rings were constructed in 6 short steps from decalone. The synthesis described herein is not only applicable to total synthesis, but also used for study of the structure-activity relationships of taepeenin D. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2016.05.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER INTERNATIONAL PUBLISHING AG  

(S)-(Hydroxymethyl) glutamic acid was successfully synthesized in total 12 % yield over eight steps from tris(hydroxymethyl) aminomethane hydrochloride (Tris center dot HCl), employing lipase TL-induced enantioselective acetylation of a prochiral 1,3-diol as the key step.

DOI： 10.1186/s40064-015-1503-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Ligands for neuronal receptors are important for understanding the biological functions as well as for treatment of neuronal diseases associated with. Here, we report diverted synthesis and biological evaluation of four C-ring analogs of IKM-159, a subtype-selective inhibitor for (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid (AMPA)-type ionotropic glutamate receptor. Starting from iodinated 7-oxanorbornene 7, those analogs 3-6 were successfully synthesized in 7.0-33% yields over 8-11 steps via a common intermediate 13. Intracerebroventricular injection of those analogs on mice showed that introduction of oxo group on the C-ring (analogs 4, 5) or cleavage of the C-ring (analog 6) caused significant loss of the activity, while the ether analog 3 still retain the suppressed motor activity, indicating the importance of the C-ring in the neuronal activity of IKM-159. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2015.03.037

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHEMICAL SOC JAPAN  

The synthetic efforts to dysibetaine CPb, isolated from Micronesian marine sponge, amenable to analog synthesis are reported. Cyclopropane was constructed by a sulfonium ylide-mediated reaction and enantioselective desymmetrization was performed by methanolysis mediated by a quinine derivative. (+)-N-(Desmethyl)dysibetaine CPb was finally synthesized in 0.37% yield in total 14 steps. This is the first synthesis of the dysibetaine CPb analog.

DOI： 10.1246/cl.141049

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The first total syntheses of (-)-dysibetaine CPa and the antipode have been achieved using enantioselective solvolysis of meso-cyclic anhydride mediated by quinine derivative as an organocatalyst. The synthesis features a demonstration of an enantiodivergent organic synthesis of both enantiomers of dysibetaine CPa whereby the absolute configurations of natural product were elucidated as (3R,4R). Application of the present methodology to an enantiomerically pure novel GABA analog is also reported. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2014.05.053

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

A new polyamine-modified indole derivative protoaculeine B (1) was isolated from Okinawan marine sponge Axinyssa aculeata. The structure of 1 was assigned on the basis of spectral data along with chemical transformations. Because the structure of 1 greatly inferred the N-terminal amino acid for highly modified peptide toxin aculeines, the probable structure for aculeine B was proposed on the basis of high-resolution mass spectral analysis.

DOI： 10.1021/ol5011888

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

An enantioselective synthesis of (-)-trans-2-aminomethylcyclopropanecarboxylic acid [(-)-TAMP], a partial agonist for GABAc receptor, has been achieved as the hydrochloride salt in 3.9% overall yield for total eight steps from l-menthol. The synthesis features double asymmetric cyclopropanation that employs cinchona alkaloid derived organocatalyst and l-menthyl chiral auxiliary.

DOI： 10.1055/s-0033-1340953

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CELL BIOLOGY  

LIM-kinases (LIMKs) play crucial roles in various cell activities, including migration, division, and morphogenesis, by phosphorylating and inactivating cofilin. Using a bimolecular fluorescence complementation assay to detect the actin-cofilin interaction, we screened LIMK1 inhibitors and identified two effective inhibitors, damnacanthal (Dam) and MO-26 (a pyrazolopyrimidine derivative). These compounds have already been shown to inhibit Lck, a Src family tyrosine kinase. However, in vitro kinase assays revealed that Dam inhibited LIMK1 more effectively than Lck. Dam suppressed LIMK1-induced cofilin phosphorylation and deceleration of actin retrograde flow in lamellipodia in N1E-115 cells. Dam impaired CXCL12-induced chemotactic migration of Jurkat T lymphocytes and Jurkat-derived, Lck-deficient JCaM1.6 cells and also inhibited serum-induced migration and invasion of MDA-MB-231 breast carcinoma cells. These results suggest that Dam has the potential to suppress cell migration and invasion primarily through the inhibition of LIMK kinase activity. Topical application of Dam also suppressed hapten-induced migration of epidermal Langerhans cells in mouse ears. Dam provides a useful tool for investigating cellular and physiological functions of LIMKs and holds promise for the development of agents against LIMK-related diseases. The bimolecular fluorescence complementation assay system used in this study will provide a useful method to screen for inhibitors of various protein kinases.

DOI： 10.1091/mbc.E13-09-0540

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

By natural product inspired diversity-oriented synthesis, we had developed a new class of selective antagonist, IKM-159, for the AMPA receptor. Here, we report syntheses of IKM-159 and skeletally diverse five analogues in racemic forms, two of which are heterotricycles and the other three compounds are truncated analogues, to study the structure-activity relationships. The key reactions are two domino reactions including Ugi/Diels-Alder reaction and domino metathesis reaction. An exceptionally high level of regiocontrol in the cross metathesis reaction is also reported.

DOI： 10.1055/s-0033-1338543

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Here we report total synthesis of enantiomerically pure dysibetaine CPa, isolated from Micronesian marine sponge and expected to serve as a neuroactive agent. Starting from meso-cyclopropane triester, the synthesis was achieved in 12.8% overall yield over 10 steps including organocatalytic enantioselective solvolysis of meso-succinic anhydride as a key step. This work established the absolute configurations of the natural product as (3R,4R). (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2013.08.113

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

The Ugi reaction is a useful four-component coupling reaction for alpha-(acylamino)amide. However, selective transformation of the two amides is generally difficult. Here, we report 1-hydroxy-2-methyl-2-propyl isocyanide (HMPI) as a new member of a 'convertible isocyanide' class used to solve the problem. HMPI is odorless and shows good reactivity in the Ugi reaction to give N-(1-hydroxy-2-methyl-2-propyl) amides, which are smoothly converted into esters upon Zn(OTf)(2)-mediated solvolysis. Overall, structurally diverse alpha-amino acid esters are readily accessible in two steps by using HMPI.

DOI： 10.1055/s-0033-1338967

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

An enantioselective synthesis of (-)-cis-2-aminomethylcyclopropanecarboxylic acid [(-)-CAMP] has been achieved in 2.5% total yield over ten steps starting from 2-furaldehyde. The synthesis features diastereoselective cyclopropane formation via diazene, followed by oxime formation and the reduction, for construction of the gamma-aminobutyric acid (GABA) motif.

DOI： 10.1055/s-0032-1317802

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2R)-IKM-159 at the glutamate binding site. (2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors.

DOI： 10.1021/jm301590z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

The syntheses of the marine sponge-derived ?-amino carboxylic acid dysibetaine CPa and five analogs in their racemic forms were successfully performed by taking advantage of an electron-withdrawing N-(4-nitrophenyl) group in the cyclopropanation reaction, the reductive ring opening of an imide, and the ethanolysis of an N-Boc-protected imide.

DOI： 10.1002/ejoc.201200730

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Naturally derived amino acids such as kainic acid (1), dysibetaine (2), and hydroxymethylglutamic acid (HMG, 3) are expected to serve as important leads for treatment of neuronal diseases. Here, we report our effort toward construction of their characteristic structure, a-monosubstituted and a,a-disubstituted α-amino acids, efficiently by short synthesis. We anticipated that, by using optically active amine for amine component as a chiral auxiliary, Ugi four-component coupling (U4CC) reaction would allow us to construct the amino acid framework in a stereoselective manner. As the optically active amine, (R)-2-amino-2-(4-methoxyphenyl)ethanol (4) was employed in the present study as shown in Scheme 1. The U4CC reaction of 4 with benzyl isocyanide, 2,2-dimethylpropionaldehyde, and octanoic acid provided 12 as a diastereomeric mixture, which was then converted into diastereomerically pure morpholinone 13 over three steps including acetylation, N-Boc formation, and alkaline methanolysis. Since methoxyphenyl and tert-butyl groups occupy pseudoequatorial orientation on the morpholinone ring, the methanolysis was apparently controlled thermodynamically. Finally, CAN-mediated ring opening followed by removal of the resultant 4-methoxyphenacyl group furnished (2S)-N-octanoyl-tert-leucine (15) in 14% overall yield for 6 steps. Furthermore, the efficiency was improved by shortening the number of steps to four, by employing convertible isocyanide 16 instead of benzyl isocyanide. Toward the synthesis of a,a-disubstituted a-amino acid, we first investigated efficient conditions for diastereoselective alkylation of morpholinone 18. After several experiments, we eventually found that potassium tert-butoxide and methyl iodide induce stereoselective methylation of 18 to give rise to 19 in 44% yield. Finally, we report asymmetric synthesis of IKM-159, a subtype-selective antagonist for AMPA receptor, by applying the U4CC reaction using optically active amine 4 as a chiral auxiliary. As shown in Scheme 5, the U4CC reaction using 2-furaldehyde and 3-iodoacrylic acid for aldehyde and carboxylic acid components, respectively, provided two diastereomeric oxanorbornenes 20 and 21. After acetylation, the diastereomers were separated, and the minor isomer was determined to be (2R)-isomer unambiguously by X-ray crystallography. By domino metathesis as a key reaction, the major isomer ((2S)-22) was led to heterotricycle 26. A series of functional group transformations then gave dimethyl ester 28. Through subsequent four steps for protecting group manipulations, we have successfully accomplished asymmetric synthesis of (2S)-IKM-159 (10). Total yield was 1.5% for 18 steps. (2R)-IKM-159 (11) was also synthesized by way of acetate (2R)-23 in 6.3% overall yield for 18 steps.

DOI： 10.24496/tennenyuki.54.0_429

CiNii Books

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Cofilin, a key regulator of actin filament dynamics, binds to G- and F-actin and promotes actin filament turnover by stimulating depolymerization and severance of actin filaments. In this study, cytochalasin D (CytoD), a widely used inhibitor of actin dynamics, was found to act as an inhibitor of the G-actin-cofilin interaction by binding to G-actin. CytoD also inhibited the binding of cofilin to F-actin and decreased the rate of both actin polymerization and depolymerization in living cells. CytoD altered cellular F-actin organization but did not induce net actin polymerization or depolymerization. These results suggest that CytoD inhibits actin filament dynamics in cells via multiple mechanisms, including the well-known barbed-end capping mechanism and as shown in this study, the inhibition of G- and F-actin binding to cofilin. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2012.06.063

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The cyclopropane-containing amino acid, dysibetaine CPa, isolated from Micronesian marine sponge, has been synthesized in 4.53% total yield over 12 steps starting from maleic anhydride to study the biological function in detail, by taking advantage of electron-withdrawing 4-nitrophenyl group. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2011.06.034

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

We report herein the approach to the key advanced intermediate in the synthesis of the bioactive marine natural product dragmacidin D. By employing a modular synthesis strategy of three fragments (5, 7, and 8), the advanced intermediate 3 has been successfully synthesized in 2.5 % yield over 15 steps by starting from nitrotoluene 20. The synthesis also involves sequential cross-coupling reactions, namely Sonogashira and Suzuki-Miyaura reactions, so that various analogues can be efficiently synthesized, which will allow the study of structure-activity relationships of dragmacidin D.

DOI： 10.1002/ejoc.201100242

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Synthesis of the DEF-ring terpenoid fragment of terpendole E, an Eg5 inhibitor, is described. The DE-ring was constructed by a modification of Barrero&apos;s radical cyclization. The F-ring tetrahydropyran was then constructed by acid-induced cyclization of an epoxy alcohol, which was prepared by cross-metathesis followed by Shi&apos;s epoxidation. Cell-based assays indicated that the DEF-ring fragment is not capable of inhibiting cell growth and cell cycle progression of human cancer cell lines, indicating that the DEF-ring fragment alone is not sufficient for the biological activity.

DOI： 10.1002/ejoc.201001104

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Other Link： http://orcid.org/0000-0002-3919-811X

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Background and purpose:
A new class of heterotricyclic glutamate analogues recently was generated by incorporating structural elements of two excitotoxic marine compounds, kainic acid and neodysiherbaine A. Rather than acting as convulsants, several of these 'IKM' compounds markedly depressed CNS activity in mice. Here, we characterize the pharmacological profile of the series with a focus on the most potent of these molecules, IKM-159.
Experimental approach:
The pharmacological activity and specificity of IKM compounds were characterized using whole-cell patch clamp recording from neurons and heterologous receptor expression systems, in combination with radioligand binding techniques.
Key results:
The majority of the IKM compounds tested reduced excitatory synaptic transmission in neuronal cultures, and IKM-159 inhibited synaptic currents from CA1 pyramidal neurons in hippocampal slices. IKM-159 inhibited glutamate-evoked whole-cell currents from recombinant GluA2- and GluA4-containing alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors most potently, whereas kainate and NMDA receptor currents were not reduced by IKM-159. Antagonism of steady-state currents was agonist concentration dependent, suggesting that its mechanism of action was competitive, although it paradoxically did not displace [3H]-AMPA from receptor binding sites. IKM-159 reduced spontaneous action potential firing in both cultured hippocampal neurons in control conditions and during hyperactive states in an in vitro model of status epilepticus.
Conclusions and implications:
IKM-159 is an AMPA receptor-selective antagonist. IKM-159 and related nitrogen heterocycles represent structurally novel AMPA receptor antagonists with accessible synthetic pathways and potentially unique pharmacology, which could be of use in exploring the role of specific populations of receptors in neurophysiological and neuropathological processes.

DOI： 10.1111/j.1476-5381.2010.00784.x

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Other Link： http://orcid.org/0000-0002-3919-811X

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Here, we report our second-generation synthesis of 12 artificial glutamate analogs, starting from heterotricycle intermediates 3a-3d, readily prepared in three steps including tandem Ugi/Diels-Alder reactions. The new synthesis employs imidate intermediates for the deoxygenation of pyrrolidones (10a-10d to 6a-6d), and each advanced intermediate 6a-6d was diversified into three glutamate analogs (1a-1d, 5a-5d, 7a-7d) in 1-2 steps.
In vitro electrophysiological assays revealed that the new piperidine-type analog 7c alters neuronal function with lower potency than 1a. Conversely, intracranial injection of 7c into mice produced a greater degree of hypoactivity than 1a. Our recent investigation has revealed that this series of compounds antagonizes AMPA-type glutamate receptor-mediated currents in a subtype selective manner. The more efficient syntheses of this novel set of neuroactive molecules will facilitate their pharmacological characterization. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2010.04.044

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

By developing an improved procedure for arylboronates, twenty 1H-pyrazolo[3,4-d]pyrimidine analogs were efficiently synthesized as a source of a potent kinase inhibitor.

DOI： 10.3987/COM-09-11857

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

In this article a regioselective domino metathesis reaction of unsymmetrical 7-oxanorbornenes, readily available by a tandem Ugi/Diels-Alder reaction as a key step, promoted by the Hoveyda-Grubbs second-generation catalyst in the presence of electron-rich vinyl acetate as a cross metathesis (CM) substrate is reported. The mechanism for the unusually high regioselectivity observed in the CM reaction was investigated, and a reaction course where a Fischer-type carbene ["Ru"= CH(OAc)] generates a steric interaction is proposed. The metathesis products were further converted to four artificial glutamate analogues whose structures were inspired by naturally derived excitatory glutamate analogues, dysiherbaine and neodysiherbaine. Interestingly, one of the synthetic analogues (28a) induced a cataleptic state in mice. Further electrophysiological studies suggest that 28a might inhibit excitatory synaptic transmission by a yet unknown indirect pathway. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

DOI： 10.1002/ejoc.200900580

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Here, we report a synthesis of a differentially protected, open-chain C21-C40 fragment of azaspiracid-1, corresponding to the lower half EFGHI-ring domain. The synthesis features modular coupling of three advanced intermediates, aiming for diverted analogue synthesis. A new method for construction of E-ring moiety amenable to the diverted synthesis is also reported.

DOI： 10.3987/COM-08-11555

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

We report a synthetic strategy for skeletally diverse heterocycles featuring appendage diversity based on a tandem Ugi/Diels-Alder reaction followed by domino metathesis. An associating effect of the amide carbonyl functionality to the ruthenium metal center is proposed in order to account for the difference in the metathesis yields. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

DOI： 10.1002/ejoc.200800781

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OPTICAL SOC AMER  

We demonstrate a highly sensitive imaging method combined a terahertz time-domain spectroscopy and an interference effect for label-free protein detection on a polyvinylidene difluoride membrane. The method is based on terahertz time-domain spectroscopy and uses an interference effect. Biotin is linked to the membrane using poly ethylene glycol or poly ethylene glycol methyl ether to prevent it from being washed off. Binding of the biotin with streptavidin is then observed by measuring the terahertz signal change due to the variation of the membrane refractive index. We demonstrate the detection of the binding streptavidin protein in gradually decreasing concentrations, down to 27 ng mm(-2), using the image recorded at 1.5 THz. (C) 2008 Optical Society of America

DOI： 10.1364/OE.16.022083

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We report a synthesis of a left-hand fragment of bis(indole)-class marine alkaloid, dragmacidin D. The synthesis features Suzuki-Miyaura reaction for the coupling of imidazolyl boronic acid and (4-indolyl)vinyl bromide. (C) 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2008.10.020

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Other Link： http://orcid.org/0000-0002-3919-811X

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

A highly regioselective domino metathesis reaction of 7-oxanorbornene was developed that employed an intramolecular association of an amide carbonyl group to a ruthenium metal centre. By using this reaction, twelve glutamate analogues inspired by dysiherbaine were efficiently synthesized over 12-14 steps; one of the analogues exhibited bioactivity consistent with central nervous system depression. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

DOI： 10.1002/ejoc.200800704

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Other Link： http://orcid.org/0000-0002-3919-811X

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

The complete absolute configuration of goniodomin A, an actin-targeting polyether macrolide isolated from the marine dinoflagellate Alexandrium, hiranoi, was established from analysis of ROESY experiments and coupling constants, synthesis of suitable model compounds for NMR spectroscopic comparisons, degradation experiments, and correlation with synthetic reference compounds.

DOI： 10.1021/ol8000377

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Here, we report our strategy to synthesize structurally diverse cis-fused heterocycles via 7-oxanorbornene analogs. By the intramolecular Diels-Alder reaction of 3-iodoacrylamide, followed by the domino metathesis reaction, the cis-fused heterobicyclic skeleton was efficiently constructed in 5-8 steps. (C) 2008 Elsevier Ltd. All fights reserved.

DOI： 10.1016/j.tet.2008.01.067

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

[GRAPHICS]
A rapid and efficient total synthesis of dysiherbaine (1), a potent and subtype-selective agonist for ionotropic glutamate receptors, has been accomplished. A key intermediate 15 was synthesized by two approaches. The first synthetic route utilized compound 9, an advanced intermediate in our previous total synthesis of neodysiherbaine A, as the starting point, and the cis-oriented amino alcohol functionality on the tetrahydropyran ring was installed by using an intramolecular S(N)2 cyclization of N-Boc-protected amino alcohol 20. An alternative and even more efficient synthetic approach to 15 featured stereoselective introduction of an amino group at C8 by iodoaminocyclization prior to constructing the bicyclic ether skeleton. The amino acid appendage was efficiently constructed by a catalytic asymmetric hydrogenation of enamide ester 36. The synthetic route developed here provided access to several dysiherbaine analogues, including 9-epi-dysiherbaine (38), 9-deoxydysiherbaine (39), 9-methoxydysiherbaine (40), and N-ethyldysiherbaine (41). The preliminary structure-activity relationship studies revealed that the presence and stereochemistry of the C9 hydroxy group in dysiherbaine is important for high-affinity and selective binding to glutamate subtype receptors.

DOI： 10.1021/jo702116c

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Here we report a strategy to alter the skeletal complexity of Ugi four-component coupling reaction products by using allylations followed by ring-closing metathesis. Principal component analysis is also performed for these compounds.

DOI： 10.3987/COM-07-S(U)8

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

The latest study on our NMR analysis of various saccharides shows that the ^2J_<C4,H5> value on the pyranosyl ring of N-acetyl-α-galactosamine (GalNAc) is not agree with either value of α-galactose (Gal) and α-galactosamine (GalN). To elucidate the origin of the large differences among them, we have perfomed conformational analyses of these amino saccharides and the derivatives by using CONFLEX conformation searches and theoretical NMR predictions of the Density Functional Theory (DFT) calculations. A lot of stable conformers of GalN and GalNAc found by CONFLEX conformation search were subjected to optimizations with various theoretical levels including solvent eflects. Finally, we found that thermodynamically averaged ^2J_<C,H> values based on the Boltzmann law using their theoretical conformation energies at B3PW91/6-311+G(2d,p) level were in good agreement with the observed ones within 1.3 Hz RMS difference.

DOI： 10.24496/tennenyuki.49.0_739

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

An efficient total synthesis of dysiherbaine, a potent and subtype-selective agonist for ionotropic glutamate receptors, has been achieved. An advanced key intermediate in the previous synthesis of neodysiherbaine A and its analogues was selected as the starting point, and cis-oriented amino alcohol functionality on the tetrahydropyran ring was installed by using an intramolecular S(N)2 cyclization of N-Boc-protected amino alcohol. The amino acid appendage was constructed by catalytic asymmetric hydrogenation of enamide ester. (c) 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2007.05.180

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Here, we report a three-component coupling reaction approach between an aldehyde, an allyloxyamine, and a maleimide toward isocluinoline derivatives. At first, an oxime O-allylic ether, prepared by dehydrative condensation of the aldehyde and the allyloxyamine, was reacted with the maleimide in the presence of a Pd2+ species. The cycloadduct obtained was then subjected to the Heck cyclization employing a Pd-0 species to give thermodynamically stable diastereomer of isoquinoline derivatives selectively in 25-78% yields. (c) 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2007.04.082

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

To enable studies to elucidate the detailed biological function of dysiherbaine and neodysiherbaine A, potent and subunit-selective agonists for ionotropic glutamate receptors, the derivative with a hydroxymethyl substituent at the C10 position has been developed. Preliminary biological evaluation of the analogue showed that a C10 hydroxymethyl substituent produced significant alterations in binding affinities for the ionotropic glutamate receptor subtypes. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2006.08.082

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Azaspiracid-1 (1) is a causative toxin for a new type of shellfish poisoning syndrome named azaspiracid poisoning (AZP), prevailed since November 1995 at a coastal region in Europe. After isolation and structural elucidation by a group led by Yasumoto and Satake at Tohoku University in 1998, the first total synthesis and the structural revision of 1 were made by the Nicolaou group in 2004. We have been working toward total synthesis of 1 to clarify the molecular mechanism of AZP. Here we report our efforts toward this goal and the synthesis of the C_<21>-C_<40> EFGHI-ring fragment 2. Our retrosynthetic analysis of 1 generated the C_<21>-C_<40> fragment 2, which would be assembled with the C_1-C_<20> fragment by the coupling between a benzotriazole amide and a sulfonylpyran. The synthesis of 2 started with a coupling between the C_<36>-C_<40> dithiane 6 and the C_<28>-C_<35> epoxide 7, prepared from the known meso-diol 8 and D-glutamic acid, respectively. Manipulations of the protecting groups and subsequent spiroaminal formation using a catalytic amount of Yb(OTf)_3 delivered the desired spiroaminal 22 stereoselectively. After leading to the corresponding aldehyde 4, the key coupling reaction with the allylic stannane 3 was carried out by using InCl_3 to afford homoallylic alcohol 33 in good yield. Finally, the FG-ring was constructed by the action of HF-pyridine to accomplish the synthesis of the suitably protected C_<21>-C_<40> fragment 2. The total yield was 0.025% for the longest linear pathway from D-glutamic acid (37 steps).

DOI： 10.24496/tennenyuki.48.0_583

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Here, we report a synthesis of the lower half C-21-C-40 fragment of the shellfish toxin, azaspiracid-1. The C-28-C-40 fragment was synthesized by a coupling between the C-28-C-35 epoxide and the C-36-C-40 dithioacetal anion, followed by the HI-ring spiroaminal formation. An aldehyde corresponding to the C-28-C-40 fragment was then coupled with the C-21-C-27 allylic stannane by using InCl3. Finally, the FG-ring was constructed by HF, pyridine to accomplish the synthesis of the suitably protected C-21-C-40 fragment.

DOI： 10.1021/ol0613766

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Other Link： http://orcid.org/0000-0002-3919-811X

Language：English   Publisher：Symposium on the chemistry of natural products  

DOI： 10.24496/intnaturalprod.2006.0__P-557_

CiNii Books

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Language：English   Publisher：Symposium on the chemistry of natural products  

DOI： 10.24496/intnaturalprod.2006.0__P-512_

CiNii Books

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Here, we report a diversity-oriented synthetic approach toward skeletally diverse, cyclized peptidomimetics with diverse appendages. Starting from alpha-(N-acylamino)amides with various appendages, 12 to 16-membered lactams with defined olefin geometry were synthesized by a common synthetic sequence. We also synthesized the macrocycle in a liquid phase directed toward a construction of the peptidomimetics library. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2006.04.098

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

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Dysiherbaine (1) and its congener neodysiherbaine A (2) are naturally occurring excitatory amino acids with selective and potent agonistic activity for ionotropic glutamate receptors. We describe herein the total synthesis of 2 and its structural analogues 3-8. Advanced key intermediate 16 was employed as a branching point to assemble a series of these analogues 3-8 with respect to the C-8 and C-9 functionalities, which would not have been accessible through manipulations of the natural product itself. The synthesis of key intermediate 16 features (i) stereocontrolled C-glycosylation to set the C-6 stereocenter, (ii) concise synthesis of the bicyclic ether skeleton through chemo- and stereoselective dihydroxylation of the exo-olefin and stereoselective epoxidation of the endo-olefin, followed by epoxide ring opening/5-exo ring closure, and (iii) catalytic asymmetric hydrogenation of enamide ester to construct the amino acid appendage. A preliminary biological evaluation of analogues for their in vivo toxicity against mice and binding affinity for glutamate receptors showed that both the type and stereochemistry of the C8 and C9 functional groups affected the subtype selectivity of dysiherbaine analogues for members of the kainic acid receptor family.

DOI： 10.1021/jo0605593

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Synthesis of dysiherbaine analogue 4, which corresponds to 8,9-epi-neodysiherbaine A, is described. The synthesis features a concise route to the bicyclic ether skeleton through stereoselective C-glycosylation to set the C-6 stereocenter and 5-exo ring-closure to form the tetrahydrofuran ring. The results of preliminary biological studies of 4 are also provided. (c) 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2005.06.093

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Diversity-oriented organic synthesis (DOS) is a key concept for construction of skeletally diverse small molecule libraries to discover drug-like small molecules. Here, we describe a DOS class to transform a complex 7-oxanorbornene skeleton, which is readily accessible by a tandem Ugi/Diels-Alder reaction, into two heterotricycle skeletons selectively by using tandem ROM/CM/RCM reaction. In the present study, the mode of cyclization is pre-encoded by building blocks used in the complexity-generating tandem Ugi/Diels-Alder reaction. Since variable alkenes can be used in the CM reaction, our approach can be extended to construct both skeleton- and appendage-diverse small molecule libraries. (c) 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2005.06.147

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

2-Oxo-1,2-ethylenedioxy (2-OED) functionality has been prepared on a soluble MPEG polymer and solid (HM resin and Lanterns) supports as platforms for discovery of drug-like small molecules. The functionality is cleaved either by Yb(OTf)(3) or TMSCHN2 in MeOH, or by various amines to release small molecules synthesized on the platform in good yield. Application of these platforms aiming for discovery of potent agonists for growth hormone secretagogue is reported by using the Ugi four-component coupling reaction. (c) 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2005.04.138

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

A new (2)J(C,H) index method is described for identification of aldohexopyranose. This method is based on a fact that (2)J(C,H) values reflect the stereochernistry for glycol connectivity. Based on the observed (2)J(C,H) values for galactose, glucose, and mannose, (2)J(C,H) profiles for other aldohexopyranoses are proposed. A combination of (2)J(C,H) values was found to be useful for identification of aldohexopyranosyl residues in glycans.

DOI： 10.1021/ol047358a

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

A series of parallel reactions were carried out for the tandem Ugi/Diels-Alder reaction on our MPEG-O-CH2 platform. Ninety-six out of a 100 entries were successful to give complex heterotricycles. The stereoselectivity was found not to be influenced by the building blocks used for amine and carboxylic acid components. An unexpected side pathway was found but was suppressed by employing appropriate reaction conditions. The reaction was also performed on solid phase, by which a larger library is potentially realized by employing the split-pool method. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2004.11.115

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

By the combined use of solid -supported reactivity-opposing reagents, that is, basic PTBD and acidic Nafion(R)-SAC resins., sequential reactions consisting of glycosyl trichloroacetimidate formation and glycosylation can be effected in a one-pot operation startitiv front 1-O-unprotected sugars. The solid-supported reagents can be introduced into the reaction vessel either sequentially or, more conveniently. in a 'one-shot' manner in comparable yields. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2004.03.170

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

An alkoxyacetyl group (AAc) group was found to be an efficient linker for high-throughput synthesis of small molecules on a soluble polymer support. The linker allows high-yield loading of alcohols and pbenols either by conventional carbodiimidemediated esterification or transesterification using Yb(OTf)(3). Chemoselective cleavage to release small molecules is attained also by Yb(OTf)3 of TMSCHN2. The preparation, protocols for loading and releasing of small molecules, and an application to the Ugi four-component coupling reaction are reported. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2004.01.103

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Described herein is a new formylacetal (CH2) linker for immobilization of small molecules onto a soluble-polymer support, poly(ethylene glycol) omega-monomethyl ether (MPEG), and its application to saccharide synthesis. This small linker allows immobilization of a hindered hydroxy group such as the 4-hydroxy group of glucose onto MPEG. The linker is stable under several reaction conditions including glycosylation. Removal of this support was found to be achieved through cleavage of the CH, linker either by a Lewis acid (TMSI or Ce(OTf)(x)) or a Bronsted acid (trifluoroacetic acid) in moderate to good yields. In combination with solid acid catalyst, simpler operations became possible during the working-up and purification processes. (C) 2003 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2003.11.036

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

The detailed conformational analysis of a single molecule of the tetraacyl biosynthetic precursor-type lipid A and its characteristic supramolecular assembly in aqueous SDS-micelles are described. Regular molecular arrangements were observed by detailed analysis of the NMR spectra of synthetically pure specimens, including regiospecically C-13-labeled ones. NMR analysis of a biologically inactive precursor-type analogue with four shorter acyl chains demonstrated its conformational flexibility, indicating the importance of hydrophobic interactions for maintaining the conformation of such molecules.

DOI： 10.1039/b410544c

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Synthesis of the FGHI ring domain of azaspiracids, the causative agents for a new type of shellfish poisoning, azaspiracid poisoning (AZP), has been achieved. The synthesis features dithiane anion-epoxide coupling for convergent fragment assembly. (C) 2003 Elsevier Ltd. All rights reserved.

DOI： 10.1016/S0040-4039(03)01553-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

A synthetic lipid A of Helicobacter pylori strain 206-1 (compound HP206-1), which is similar to its natural lipid A, exhibited no or very low endotoxic activities as compared to Escherichia coli-type synthetic lipid A (compound 506), Furthermore, compound HP206-1 as well as its natural lipid A demonstrated no or very low mitogenic responses in murine spleen cell. On the other hand, compound HP206-1 showed a weaker but significant production of interleukin-8 in a gastric cancer cell line, MKN-1, in comparison with compound 506. Furthermore, compound HP206-1 exhibited induction of tumor necrosis factor-a production in human peripheral blood mononuclear cells and the cytokine production was clearly inhibited by mouse anti-human Toll-like receptor (TLR) 4 monoclonal antibody HTA125. Our findings indicate that the chemically synthesized lipid A, mimicking the natural lipid A portion of lipopolysaccharide from H. pylori strain 206-1, has a low endotoxic potency and immunobiological activities, and is recognized by TLR4. (C) 2003 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0928-8244(03)00093-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHEMICAL SOC JAPAN  

New lipid A analogs having acidic groups beta-glycosidically linked at the 1-position were synthesized in order to investigate the structural requirement for immunostimulating and endotoxic activity of lipid A. The beta-(phosphonoxy)ethyl (PE) and carboxymethyl (CM) analogs of Escherichia coli type having six acyl groups and those of the biosynthetic prepursor type having four acyl groups were synthesized via a divergent synthetic route. The E. coli type beta-(phosphonoxy)ethyl analog, which was previously reported to be not endotoxic, showed strong immunostimulating activity comparable to the natural-type alpha-analog. The acidic functional groups are concluded to be essential but their strict spatial arrangement is not required for expression of the biological activity.

DOI： 10.1246/bcsj.76.485

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MANEY PUBLISHING  

Our early work using homogeneous synthetic preparations demonstrated the presence of a lipid A analog which antagonizes endotoxic activities of LPS and lipid A. The first example was a tetraacylated biosynthetic precursor, now known as precursor Ia or lipid IVa, that contains four 3-hydroxytetradecanoyl moieties linked to the bisphosphorylated disaccharide backbone common to the endotoxic hexa-acyl Escherichia coli lipid A. Various compounds with both endotoxic and antagonistic activities have subsequently been reported from either natural or synthetic sources, but little is known about the factors determining the type of the activities of the respective compounds. To approach this issue, we have synthesized a series of lipid A analogs with various numbers and chain lengths of acyl groups on the backbone. Some were prepared by the aid of a novel affinity separation procedure. The phosphate moieties were also synthetically replaced. Biological tests showed that at least three acyl groups are required for antagonistic activity but one or even both of the phosphates can be replaced with other acidic moieties without losing the activity. The effect of Kdo residues linked to lipid A is also briefly discussed. Molecular dynamics calculations reasonably explain possible conformations required for the biological activity.

DOI： 10.1179/096805103225002737

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Lipid A is an immunostimulating glycoconjugate characteristic to gram-negative bacteria. In order to understand the role of the acyl moieties for the biological activity, the effect of distribution of acyl groups was systematically investigated. A new efficient route for the synthesis of lipid A and its analogs was hence established by using our new strategy, i.e., synthesis based on affinity separation (SAS), where compounds possessing a barbituric acid tag (BA) were selectively and rapidly purified by the aid of its interaction with an artificial receptor. After successful synthesis of E. coli lipid A by the SAS-strategy, a small library of lipid A analogs having a carboxymethyl (CM) group at the 1 position in place of the phosphate was synthesized. CM analogs had proved to exhibit biological activity indistinguishable with that of lipid A, but are chemically stable and are easier to synthesize than the latter. All the target structures possess hexaacyl groups with different acylation pattern: each has two (R)-3-hydroxydecanoyl groups and two (R)-3-(dodecanoyloxy)decanoyl groups. A suitably protected glucosamine α-carboxymethyl glycoside possessing the BA-tag was glycosylated with a 4'-phosphorylated glycosyl trichloroacetimidate to give a disaccharide, which was purified by the affinity separation. Successive removal of protective groups and introduction of acyl groups were then effected and the synthetic intermediate at each step was purified rapidly by the affinity separation. The final deprotection and cleavage of the tag by catalytic hydrogenolysis afforded the desired CM-analogues. Biological tests of them clearly demonstrated that the acylation patterns of the individual compounds determine the biological activity.

DOI： 10.24496/tennenyuki.44.0_103

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Publishing type：Research paper (international conference proceedings)  

Typical bacterial glycoconjugates are known to stimulate immunological systems of higher animals and thereby play important roles in the primary defense of animals against bacterial infection. Lipopolysaccharide (LPS) of gram-negative bacteria is a representative of such glycoconjugates. LPS was first discovered as a potent bacterial toxin and named endotoxin but was soon found to exhibit immunostimulating activity. By the use of our synthetic pure preparations, the lipophilic partial structure of LPS, designated lipid A, proved to be the active entity responsible for both endotoxic and immunostimulating activities of LPS. This paper deals with our recent chemical synthesis and functional study of lipid A and related compounds. Synthesis is described of its various structural analogues, radio-labeled compound and Re-type LPS that contains two additional sugar moieties linked to lipid A.

DOI： 10.1002/jccs.200200071

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide (LPS). MD-2 is associated with TLR4 and imparts LPS responsiveness to it. Little is known, however, as to whether MD-2 directly regulates LPS recognition by TLR4. To address the issue, we took advantage of a species-specific pharmacology of lipid IVa, an analogue of lipid A. Lipid IVa acted agonistically on mouse (m) TLR4/MD-2 but not on human (h) TLR4/MD-2. Lipid IVa antagonized the agonistic effect of lipid A on hTLR4/MD-2. We examined the chimeric complex consisting of mTLR4 and hMD-2 to ask whether species specificity is conferred by TLR4 or MD-2. hMD-2 was clearly distinct from mMD-2 in the way of influencing LPS recognition by mTLR4. hMD-2 conferred on mTLR4 responsiveness to lipid A but not to lipid IVa. Moreover, lipid IVa acted as a lipid A antagonist on mTLR4 that is associated with hMD-2. Collectively, MD-2 directly influences the fine specificity of TLR4.

DOI： 10.1093/intimm/13.12.1595

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHEMICAL SOC JAPAN  

Both endotoxic and antagonistic [H-3]-labeled 2-(phosphonooxy)ethyl (PE) analogs of lipid A were synthesized with high purity and high specific radioactivity. Lipid A-binding proteins were detected by using the endotoxic analog of hexaacyl Escherichia coli-type designated [H-3] PE-506. The plasma membrane fractions from peritoneal macrophages derived from LPS-responder C3H/HeN mice and LPS-hyporesponder C3H/HeJ mice were separated by SDS-PAGE and transferred onto nitrocellulose membranes. The membranes were then incubated with the [H-3] PE-506. Several [H-3] PE506 binding proteins were detected in both C3H/HeN and C3H/HeJ macrophages. Unlabeled hexaacyl lipid A inhibited the interaction between [H-3] PE-506 and these proteins. The result suggests that there exist multiple binding sites for lipid A on macrophages. LPS-induced change in the profile of the cell surface lipid A binding proteins was observed in C3H/HeN macrophages, but not in C3H/HeJ macrophages, by preincubation of macrophages with LPS.

DOI： 10.1246/bcsj.74.2189

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

New efficient synthesis of lipid A, an immunostimulating glycoconjugate of bacteria, was achieved for the construction of lipid A library by using synthesis based on affinity separation (SAS), where the compounds possessing a barbituric acid (BA)-tag are selectively and rapidly purified by interaction with an artificial receptor for BA. Glycosylation of a glycosyl acceptor possessing the BA-tag with a 4'-phosphorylated N-Troc glucosaminyl trichloroacetimidate gave the disaccharide 4'-phosphate, wh ich was purified by the affinity separation. Successive removal of protective groups and introduction of acyl groups were then effected and the synthetic intermediate at each step was purified by the affinity separation. Cleavage of the tag and subsequent deprotection afforded Escherichia coli lipid A. SAS enabled the rapid preparation of lipid A, therefore, proved to be a promising method for synthesis of other complex glycoconjugates.

DOI： 10.1055/s-2001-18109

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Helicobacter pylori, a Gram-negative spiral rod shape pathogen closely associated with gastroduodenal diseases, has many interesting properties. The key features of the bacterium may be variation and natural transformation. It is well known that H. pylori has multiple genotypes, and often change its morphology and its infective activity during cultivation. The lipopolysaccharide (LPS) located on the outer membrane of H. pylori has also unique features and variability. The present study is done by focusing on the structural diversity and change for lipid A, which is the essential part for the immunobiological activity of LPS, to evaluate the relationship between the structure of lipid A, its immunobiological activities, the infective activity of the bacterium, and varied diseases. Quick screening procedure was first established using negative mode of ESI-TOF/MS and MALDI-TOF/MS combined with the modified TLC blotting. Then, the procedure was applied to so far 13 kinds of H. pylori obtained from different strains or from batches under different culture conditions. It was elucidated that at least 5 different structures of lipid A exist, indicating the structural variability of lipid A. Also it was found the structure was changed by the cultivation. The chemical syntheses were performed for the major lipid A structures and the cytokine inducing activity was evaluated on 3 kinds of H. pylori lipid A. All three lipid As possessed very weak, almost no, activities for the production of pro-inflammatory cytokine, except for the weak but distinct interleukin-6 inducing activity of one structure (2a). However, interestingly, all three lipid As showed high interleukin-18 inducing activity. The synthetic compound showed exactly same activities to those of natural ones. Since 2a was not detected in non-infective H. pylori strains, this structure might have key role for the infection. More study is in progress.

DOI： 10.24496/tennenyuki.43.0_383

CiNii Books

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHEMICAL SOC JAPAN  

During the course of a conformational study of lipid A, which is a bioactive entity of lipopolysaccharide of the Gram-negative bacterial cell surface, the molecular conformation of its tetraacyl biosynthetic precursor in dimethyl sulfoxide was unambiguously determined by means of NMR using both 6-C-13-labeled and nonlabeled synthetic specimens. The conformation of the hydrophilic moiety was determined by an NMR analysis based on the spin-coupling constants and nuclear Overhauser enhancement data around the glycosidic linkage. The whole molecular shape of the glycolipid was then elaborated with the aid of molecular mechanics calculations.

DOI： 10.1246/bcsj.74.1455

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PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

DOI： 10.1002/1521-3773(20010417)40:8<1475::AID-ANIE1475>3.0.CO;2-V

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CiNii Books

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Lipopolysaccharide (LPS) is a glycoconjugate located at the so-called outer membrane of Gram-negative bacterial cell surface and exhibits multiple and potent biological activities including both toxic and beneficial ones. LPS is generally composed of a polysaccharide portion and an acylated glucosamine disaccharide termed lipid A which is responsible for the biological activities of LPS. Re lipopolysaccharide (Re LPS) from E. coli Re mutant is one of the structurally most simple LPS found on living bacterial cell surface, being composed of only two moles of 3-deoxy-D-manno-2-octurosonic acid (Kdo) and lipid A. For precise investigation of effects of the additional Kdo residue(s) on the bioactivities and conformation, Re LPS has been successfully synthesized for the first time. The synthesis started from D-mannose and D-glucosamine which were converted into appropriately protected Kdo and lipid A components, respectively. The desired tetrasaccharide backbone consisting of Kdo-disaccharide and lipid A was constructed by stepwise condensations of these saccharide building blocks under elaborated efficient conditions and functional group manipulations in 0.9% total yield for 23 steps followed by efficient purification by liquid-liquid partition column chromatography. The synthetic preparation was identical in all respects with a natural counterpart. By employing the same synthetic strategy, several partial structures of Re LPS were also synthesized for precise functional studies. Biological activities as well as conformational studies by NMR will also be discussed in comparison with lipid A.

DOI： 10.24496/tennenyuki.42.0_115

CiNii Books

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Synthesis of lipid A 1 isolated from Helicobacter pylori strain 206-1 has been achieved in 2.2% total yield through 14 steps from D-glucosamine by employing a p-(trifluoromethyl)benzyl group for protection of the hydroxy group on the 3-hydroxy fatty acid residue. The synthetic specimen was identical with the natural counterpart in chromatographic, spectroscopic, and biological aspects. A structural analogue 2 which lacks the ethanolamine residue of 1 was also synthesized, and 2 was found to exhibit less potent IL-1 beta-inducing activity than 1. (C) 2000 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4039(00)01158-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Lipopolysaccharides (LPS, endotoxin) represent a major virulence factor of Gram-negative bacteria, which can cause septic shock in mammals, including man. The lipid anchor of LPS to the bacterial outer membrane, lipid A, exhibits a peculiar chemical structure, harbours the &apos;endotoxic principle&apos; of LPS and is also responsible for the expression of pathophysiological effects. Chemically modified lipid A can be endotoxically inactive, but may express strong antagonistic activity against endotoxically active LPS. By applying orientation measurements with attenuated total reflectance (ATR) infrared spectroscopy on hydrated lipid A samples, we show here that these different biological activities are directly correlated to the intrinsic conformation of lipid A. Bisphosphoryl-hexaacyl lipid A molecules with an asymmetric (4/2) distribution of the acyl chains linked to the diglucosamine backbone have a large tilt angle (&gt; 45 degrees) of the diglucosamine backbone with respect to the membrane surface, a conical molecular shape (larger cross-section of the hydrophobic than the hydrophilic moiety), and are endotoxically highly active. Monophosphoryl hexaacyl lipid A has a smaller tilt angle, and the conical shape is less expressed in favour of a more cylindrical shape. This correlates with decreasing endotoxic activity. Penta- and tetraacyl lipid A or hexaacyl lipid A with a symmetric acyl chain distribution (3/3) have a small tilt angle (&lt; 25 degrees) and a cylindrical shape and are endotoxically inactive, but may be antagonistic.

DOI： 10.1046/j.1432-1033.2000.01326.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

Lipopolysaccharide (LPS) is the main inducer of shock and death in Gram-negative sepsis. Recent evidence suggests that LPS-induced signal transduction begins with CD14-mediated activation of 1 or more Toll-like receptors (TLRs). The lipid A analogues lipid IVa and Rhodobacter sphaeroides lipid A (RSLA) exhibit an uncommon species-specific pharmacology Both compounds inhibit the effects of LPS in human cells but display LPS-mimetic activity in hamster cells. We transfected human TLR4 or human TLR2 into hamster fibroblasts to determine if either of these LPS signal transducers is responsible for the species-specific pharmacology RSLA and lipid IVa strongly induced NF-KB activity and IL-6 release in Chinese hamster ovary fibroblasts expressing CD14 (CHO/CD14), but these compounds antagonized LPS antagonists in CHO/CD14 fibroblasts that overexpressed human TLR4. No such antagonism occurred in cells overexpressing human TLR2. We cloned TLR4 from hamster macrophages and found that human THP-1 cells expressing the hamster TLR4 responded to Lipid IVa as an LPS mimetic, as if they were hamster in origin. Hence, cells heterologously overexpressing TLR4 from different species acquired a pharmacological phenotype with respect to recognition of lipid A substructures that corresponded to the species from which the TLR4 transgene originated. These data suggest that TLR4 is the central lipid A-recognition protein in the LPS receptor complex.

DOI： 10.1172/JCI8541

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

Investigations are reported into the interaction of lipid A, the &apos;endotoxic principle&apos; of bacterial lipopolysaccharide (LPS), with phospholipid membranes in the absence and presence of an acute-phase lipid transport protein, lipopolysaccharide-binding protein (LBP) applying Fourier-transform infrared (FTIR) and fluorescence resonance energy transfer (FRET) spectroscopy. In the absence of LBP, intermixing of phospholipids with lipid A takes place on the time-scale of hours, while in the presence of LBP this process takes place in the order of minutes. A comparison of chemically different lipid A shows that a prerequisite for the intercalation of lipid A into the phospholipid membrane is a sufficiently high negative charge density of lipid A. Variations in the lipid A acyl chain fluidity may modulate the intercalation, whereas the type of lipid A aggregate structure has no influence on the intercalation.The intercalation is a necessary, but not sufficient prerequisite for cell activation. Only lipid A with a conical molecular shape and a tilt angle of more than 40 degrees of the backbone with respect to the direction of the acyl chains induces cytokine induction in human mononuclear cells, while lipid A with a cylindrical shape and a small tilt angle does not exhibit this biological activity but may act antagonistically. This antagonistic effect may be explained by blocking of the binding-sites of the putative signal-transducing protein, possibly an ion channel, by the antagonist.

DOI： 10.1039/b004188m

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

To elucidate the mechanism of the biological events caused by bacterial endotoxin (lipopolysac-charide, LPS), isotope and fluorescence labelings were effected on lipid A, which is the partial structure of LPS essential for its bioactivity. The labelings were performed by means of chemical synthesis, and physicochemical as well as biological functions of the labeled derivatives were evaluated. 6-^<13>C-Labeled derivatives were synthesized of a biosynthetic precursor of lipid A (6-^<13>C-2) and its analogue with shorter (C10) acyl chains (6-^<13>C-3). NMR study of the biosynthetic precursor 2 using ^<13>C-labeled and unlabeled specimens enabled us to figure out its supramolecule structure formed by self-assembly. By contrast, the short-acyl analogue 3 was found to form no aggregate. Molecular modeling revealed the origin of this striking behavioral and conformational difference: unnatural C10 length for the acyl moieties is not sufficient to obtain stabilization by hydrophobic interaction. Because it has already shown that the short-acyl analogue 3 no longer retains the biological activity of the biosynthetic precursor 2, it is strongly suggested such a supramolecule-forming ability relates with the biological activity of lipid A analogues. The fluorescence-labeled lipid A analogue 5 was next synthesized to obtain a deeper insight on the self-assembly of lipid A. BODIPY^[○!R] was employed as a fluorescence group, and the labeling was effected on the phosphonooxyethyl (PE) analogue 4 wherein the chemically labile glycosyl phosphate of lipid A is replaced with the stable 2-(phosphonooxy)ethyl group. The synthesis was achieved using allyl-type groups for the persistent protection of all active functionalities to afford the highly pure final product. The labeled analogue 5 was found to retain definite activities of lipid A1. Fluorescence spectra indicated the critical micelle concentration of 5 being below 0.46nM. From these experiments it can be clearly concluded that the labeled lipid A analogue 5 forms aggregate around the concentration range where it exhibits the biological activities. To identify the possible receptor(s) on the competent animal cells, tritium-labeling was effected on the ethylene glycol moiety of the PE analogue 4 of lipid A. Careful two-step oxidation of the ally group and partition chromatographic purification after final deprotection led to complete removal of over-oxidized by-products and eventually enabled us to obtain a highly pure (>98% radiochemical purity) preparation of ^3H-4 with high specific radio activity (62GBq/mmol). Using the ^3H-labeled and unlabeled PE analogues, four binding proteins were detected in macrophages from both LPS-responder C3H/HeN mice and LPS-hyporesponder C3H/HeJ mice.

DOI： 10.24496/tennenyuki.41.0_133

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHEMICAL SOC JAPAN  

The synthesis of regiospecifically C-13-labeled compounds of a biosynthetic precursor of lipid A and its analogue with shorter acyl chains is described. D-(6-C-13)Glucose was converted into a suitably protected glucosamine derivative via 1,6-anhydro-beta-D-(6-C-13)glucose. After coupling with glycosyl donors, the desired compounds were synthesized through a 6-step reaction sequence. The total yields were 1.7% for the biosynthetic precursor, and 6.4% for the short acyl analogue, respectively, for a total of 18 steps from D-(6-C-13)glucose.

DOI： 10.1246/bcsj.72.1857

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

A fluorescence-labeled phosphonooxyethyl (PE) analogue of lipid A has been successfully synthesized in 15 steps from D-glucosamine derivative 2 in total 16% yield. The analogue exhibits Limulus activity and cytokine-inducing activity similar to the natural lipopolysaccharide and the unlabeled PE analogue of lipid A. (C) 1999 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4039(99)00937-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The spiroketals containing a benzyloxymethyl moiety at the C8 position showed the most potent apoptosis-inducing activity, whereas its analogous compounds lacking any substituent at C8 or possessing ones other than the benzyloxymethyl moiety at C8 were all much less active, These results strongly suggest an important role of the benzyloxymethyl moiety linked to the C8 oxygen atom. (C) 1999 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0960-894X(99)00309-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHEMICAL SOC JAPAN  

Lipid A and its two chemically stable analogues, wherein the glycosidic phosphoryl groups in lipid A is replaced with 2-(phosphonooxy)ethyl or carboxymethyl groups, have been synthesized by an improved and divergent route via a common allyl glycoside intermediate in which the 4-hydroxy group was protected as a benzyl ether. The total yields were more than 20% for 11 or 12 steps starting from allyl 4,6-O-benzylidene-2-deoxy-2- (trichloroethoxycarbonylamino)-D-glucopyranoside. These synthetic chemically stable analogues induce interleukin-6 and tumor necrosis factor alpha in human peripheral whole blood cells with potencies comparable to those by natural-type synthetic lipid A. The Limulus activities of both analogues were found to be even stronger than the activity of the natural-type one.

DOI： 10.1246/bcsj.72.1377

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MANEY PUBLISHING LTD  

In order to investigate precise structural requirements for expression of the biological activity of lipid A, new structural analogs were synthesized via improved, highly efficient preparative routes. The number and chain length of the fatty acyl groups proved to have crucial influence on the biological activity. For the study of conformation relevant to activity of lipid A by means of NMR spectrometry, lipid A analogs [C-13]-labeled at the 6-position were then synthesized starting from 6-[C-13]-glucose. Precise analysis of J(CH) and NOE data disclosed a particular molecular conformation and characteristic supramolecular assembly in an aqueous SDS micelle solution of the tetraacyl biosynthetic precursor molecule. The observed mode of assembly may reflect the actual behavior of lipid A molecules in the cell surface outer membrane of living bacteria. A biologically inactive, artificial, tetra-acyl analog having shorter acyl chains exhibits,by contrast, distinct conformations with no sign of supramolecule formation. The acyl moieties in lipid A are thus found to play an important role in regulating the overall conformation of the hydrophilic backbone.

DOI： 10.1177/09680519990050012001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG  

We describe herein a new tritylation procedure of alcohols using benzyl trityl ether and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, The reaction involves oxidative abstraction of one of the benzylic protons of benzyl trityl ether, followed by transformation of the generated benzyl trityl ether cation into a complex of benzaldehyde and trityl cation. The present procedure proceeds under mild neutral conditions to afford trityl ethers in generally good yields for primary alcohols, and in acceptable yields for several secondary alcohols.

DOI： 10.1055/s-1998-1777

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Novel lipid A analogues which possess four (R)-3-hydroxyacyl moieties of shorter chain length were synthesized via a new divergent synthetic route in order to clarify the effect of the chain length of acyl groups to the biological activity: a disaccharide 4'-phosphate was first constructed as a common synthetic intermediate and all acyl moieties were then introduced step by step to the respective positions. The hydroxy group in acyl moieties was protected with a benzyl group by novel 1-pot reductive alkylation using benzaldehyde, TMS2O, TMSOTf, and Et3SiH. Both the glycosyl donor and acceptor were synthesized by using the new method recently reported by ourselves for the regioselective reductive opening of 4,6-O-benzylidene glucosamine derivatives with BH3 . Me2NH and BF3 . OEt2. In this reaction, a 3-O-allyloxycarbonylated 4,6-O-benzylidene compound in CH3CN afforded the 6-O-benzylated product selectively, which was then converted to a glycosyl trichloroacetimidate used as the donor. The 4-O-benzylated acceptor was synthesized by the same reductive opening of a 3-O-p-methoxybenzylated compound in CH2Cl2. A disaccharide 4'-phosphate was synthesized by coupling of the imidate donor and the acceptor using TMSOTf as a catalyst. (R)-3-Benzyloxyacyl groups were then introduced to the 3,3',2 and 2' positions followed by 1-O-phosphorylation and subsequent deprotection by Pd/H-2 afforded the desired lipid A analogues. The present divergent route opens an efficient way toward the synthesis of lipid A libraries. Biological tests (inhibition of IL-6 induction) clearly showed the critical importance of the chain length of the acyl moieties in lipid A to the activity. (C) 1998 Published by Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4020(98)00133-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The effects of tautomycin and its derivatives on protein phosphatases PP1 and PP2A and their apoptosis-inducing activity toward human leukemia Jurkat cells were examined, and the relationship between chemical structure and function was discussed. Among the compounds we examined, tautomycin was the most potent inhibitor and the most effective inducer of apoptosis. It inhibited PP1 and PP2A enzymatic activity concentration-dependently with IC50 values of 20 and 75 pM, respectively, in the presence of 0.01% Brij-35, and an LC50 value of 1 mu M. Esterification of the anhydride moiety of tautomycin markedly increased the IC50 for the protein phosphatases. The C-1-C-7, fragment of tautomycin had no inhibitory effect, but the fragment containing the C-22-C-26 moiety was inhibitory. These results suggest that the C-22-C-26 moiety is essential for inhibition of protein phosphatase activity and that the anhydride moiety enhances the inhibition. However, the esterification of the anhydride did not decrease, nor did the inclusion of the C-22-C-26 moiety increase the apoptosis inducing activity. On the other hand, the C-1-C-18 moiety of tautomycin was essential for induction of apoptosis, and the conformation and the arrangement of functionalities of the C-18-C-26 carbon chain affected the apoptosis activity. However, modification of C-1-C-18, C-1-C-21, or C-1-C-26 compounds had little effect on phosphatase inhibitory activity. Our results strongly suggest that different moieties of tautomycin are involved in protein phosphatase inhibition and induction of apoptosis. (C) 1998 Elsevier Science Inc.

DOI： 10.1016/S0006-2952(97)00539-X

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Two large subunits for synthesis of tautomycetin have been synthesized. Efficient construction of the dienone moiety has been achieved by regioselective hydrostannylation of an internal alkyne and subsequent Stille coupling. (C) 1997 Elsevier Science Ltd.

DOI： 10.1016/S0040-4039(97)10100-9

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Tautomycetin 1, an antifungal agent from Streptomyces griseochromogenes shows a distinctive biological and structural similarity to tautomycin 2, which is known as a potent inhibitor of protein phosphatases (PP) type 1 and 2A. Although inhibitory activity of 1 to PP was not reported, it strongly suggests that 1 is also an inhibitor of PP1 and PP2A and that the structural difference of 1 and 2 is exchangeable. In order to obtain pertinent data for this hypothesis and to develop a specific inhibitor for PP1, we studied a total synthesis of 1 and conformational analysis of right fragments of 1 and 2. Biological activities of tautomycin analogs were also examined. The right half of tautomycetin were constructied by asymmetric crotylboration as key reactions. Efficient construction of dienone moiety has been achieved by a regioselective hydrostannylation of internal alkyne and the subsequent Stille coupling. Thus, two large subunits 3, 4 for synthesis of 1 were synthesized. Both molecular mechanics calculations and ^1H-NMR data exhibited that tautomycetin right half is present as "bent conformers". Most populated conformer of the tautomycetin right half showed a distinct similarity to the one found in the right half of tautomycin. Effects of tautomycin and its derivatives on protein phosphatases PP1 and PP2A and their apoptosis-inducing activity on human leukemia Jurkat cells were examined and the relationship between chemical structure and function was discussed.

DOI： 10.24496/tennenyuki.39.0_433

CiNii Books

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Lipopolysaccharide (LPS) is a component of cell surface architecture of Gram-negative bacteria. It exhibits both toxic and beneficial bioactivities for higher animals. The actual bioactive principle of LPS is glycolipid called lipid A (1) which is the partial structure present at the reducing end of LPS. It is also known that the biosynthetic precursor 2 of lipid A inhibits the bioactivity of LPS and lipid A (1). Although an interaction between lipid A portion of LPS and certain receptor on macrophage cell is expected to play an important role for bioactivities, the identification of the receptor and their binding manner still remain to be studied. So we planned to synthesize ^3H-, ^<13>C-, and fluorescence-labeled lipid A analogues, which will be useful for the binding study, in different synthetic pathways. Allyl-type protecting groups were employed for the final protecting groups in the present synthetic study of fluorescence-labeled lipid A. The fluorescence (BODIPY^[○!R]) group was introduced to 6'-O-position of lipid A using glycine as a linker after the formation of disaccharide backbone (13→14). Radio-labeling was found to be effected on the ethylene glycol linker to the stable phosphonooxyethyl analogue of lipid A by NaB^3H_4 reduction at the final synthetic stage. 6-^<13>C-Labeled glucose (26) was used as the starting material for the synthesis of ^<13>C-labeled analogue. An efficient synthetic pathway toward suitably protected glucosamine 34 was developed via 1,6-anhydro-β-glucopyranose derivatives 28-32.

DOI： 10.24496/tennenyuki.39.0_403

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Novel lipid A analogues were synthesized in order to investigate the structural principles responsible for the biological activity of lipid A. Syntheses were achieved via divergent routes where various compounds were prepared from common synthetic intermediates. 1. In order to investigate the role of 1-O-phosphoryl group for the activity of lipid A, the 1-O-carboxymethyl analogues 4 and 5 were synthesized from disaccharide allyl glycosides which also serve as the common synthetic intermediates to natural lipid A. Ozonolysis of the allyl glycosides 8a,b afforded the formylmethyl glycosides 9a,b, which were then oxidized by NaClO_2 to give the desired carboxymethyl analogues 4 and 5, respectively. The 1-O-phosphonooxyethyl analogue 3 was synthesized more conveniently than our own previous route by reduction of the same formylmethyl glycoside 9a followed by phosphorylation. The E. coli-type analogue 4 showed strong IL-6 inducing activity and the biosynthetic-precursor-type analogue 5 exhibited antagonistic activity both with potency comparable to the respective natural type counterparts. These results showed the anionic moiety at 1-position is very important but monoanionic charge is sufficient for the expression of the activity. 2. In order to clarify the effect of the chain length of the acyl groups to the biological activity, the syntheses of precursor-type analogues which possess four (R)-3-hydroxyacyl moieties of shorter chains were effected via a new divergent synthetic route: a disaccharide 4'-phosphate was first constructed as a common synthetic intermediate and all acyl moieties were then introduced step by step to the respective positions. The hydroxy group in acyl moieties was protected with benzyl group by 1-pot reductive alkylation using benzaldehyde, TMS_2O, TMSOTf, and Et_3SiH. Both the glycosyl donor and the acceptor were synthesized by using novel method for the regioselective reductive opening of 4,6-O-benzylidene glucosamine derivatives with BH_3・Me_2NH and BF_3・OEt_2. On this reaction, the 3-O-allyloxycarbonylated compound in CH_3CN afforded the 6-O-benzylated product selectively, which was then converted to a glycosyl trichloroacetimidate as the donor. The 4-O-benzylated acceptor was synthesized by the same reductive opening of a 3-O-p-methoxybenzylated compound in CH_2Cl_2. A disaccharide 4'-phosphate was synthesized by coupling of the imidate donor and the acceptor using TMSOTf as a catalyst. Stepwise introduction of (R)-3-benzyloxyacyl groups at 3, 3', 2 and 2' positions followed by 1-O-phosphorylation and subsequent deprotection by Pd/H_2 afforded the desired lipid A analogues. The present divergent route opens an efficient way toward the synthesis of lipid A libraries. Biological tests of the synthetic analogues clearly showed the critical importance of the chain length of the acyl moieties in lipid A to its biological activity.

DOI： 10.24496/tennenyuki.39.0_397

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE BIOCHEMICAL SOC  

The chemical structure of a novel lipid A, which was obtained as a major component from lipopolysaccharide of Hebicobacter pylori strain 206-1, was determined to be a glucosamine beta(1-6) disaccharide 1-(2-aminoethyl)phosphate acylated by (R)-3-hydroxyoctadecanoic acid and (R)-3-(octadecanoyloxy)octadecanoic acid at the 2- and 2'-position, respectively, The absence of a phosphoryl group at the 4'-position and fatty acyl groups at the 3- and 3'-position, and the stoichiometric presence of 2-aminoethyl phosphate at the 1-position are unique features, distinguishing it from the lipid A of enterobacteria.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHEMICAL SOC JAPAN  

Synthesis of unnatural analogues, that contain (S)-3-hydroxytetradecanoyl moieties in place of the corresponding natural (R)-isomers, of both lipid A and its biosynthetic precursor, designated precursor Ia or lipid IVA, has been achieved through our recently developed procedure. (S)-3-Hydroxytetradecanoic acid was prepared from its racemate through the optical resolution by the use of a lipase and subsequent fractional recrystallization. The (S)-acyl analogue of lipid A exhibited slightly stronger interleukin-6 inducing activity than the corresponding natural lipid A, and the (S)-acyl analogue of the biosynthetic precursor was far more active than the natural precursor in inhibiting the induction of interleukin-6 by lipopolysaccharide.

DOI： 10.1246/bcsj.70.1441

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHEMICAL SOC JAPAN  

A biosynthetic precursor of lipid A has been synthesized by an improved efficient method. Two appropriately modified acyl-substituted glucosamine units were synthesized from D-glucosamine using (R)-3-(benzyloxy)tetradecanoic acid and then coupled by the Lewis acid-promoted glycosidation via the corresponding trichloroacetimidate. Glycosyl phosphorylation and hydrogenolytic deprotection, followed by purification by liquid-liquid partition chromatography, afforded the target compound in 2.9% total yield through 13 steps from N-Troc-D-glucosamine.

DOI： 10.1246/bcsj.70.1435

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG  

Here described is the reduction of 4,6-O-benzylidene functionalities of D-glucose or D-glucosamine with various protecting groups by borane dimethylamine complex and boron trifluoride etherate. The 4-O-benzyl products were selectively obtained when the reaction was carried out in dichloromethane for substrates with 3-O-benzyl groups. In contrast, the reaction in acetonitrile provided the 6-O-benzyl products predominantly for substrates 3-O-protected in other forms than a benzyl ether.

DOI： 10.1055/s-1996-5724

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC SYNTHETIC ORGANIC CHEM JPN  

Recent synthetic work on typical cell surface glycoconjugates of bacteria which activate the immunological system of higher animals is described. Lipid A, previously proved to be the active entity of lipopolysaccharide of Gram-negative bacteria, was subjected to further study and novel efficient routes were established for its structural analogs and a H-3-labeled derivative. Proposed structures of lipoteichoic acids from Gram-positive bacteria were also synthesized to lead to the conclusion that not the major components corresponding to the proposed structures but other minor ones are responsible for the activity.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

DOI： 10.1021/jo960081a

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG  

A radio-labeled bioactive lipid A derivative was synthesized for the first time by H-3-labeling of a phosphonooxyethyl (PE) analogue. H-3-Labeling was effected via oxidation of the distal hydroxyl group of the ethylene glycol unit of a disaccharide intermediate and subsequent reduction of the resulting aldehyde by (NaBH4)-H-3. Phosphorylation of the labeled alcohol and deprotection gave the target compound. The glycosidation of an ethylene glycol unit with a thioglycoside was promoted by PhIO-SnCl4-AgClO4 to give the alpha-glycoside selectively.

DOI： 10.1055/s-1996-5394

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Strategies for the synthesis of a dialkylmaleic anhydride segment of tautomycin and tautomycetin are presented, The most difficult point was the stereocontrolled construction of the tetrasubstituted olefin, The maleate-type olefin construction through dehydration proved not to be adoptable because the corresponding beta-hydroxyimine or aldol precursors were extremely unstable even under neutral conditions, suffering the retro-aldol-type decomposition, The Horner-Wadsworth-Emmons reaction on the alpha-ketoester with an appropriate protecting group had acceptable levels of diastereoselectivity giving rise to the dialkylmaleate diester, which was further led to the segment used in the synthesis of tautomycin and tautomycetin, In such the strategy, functional group protections were important in the olefination reaction and the final anhydride formation.

DOI： 10.1271/bbb.59.2104

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Synthesis of an analog of a biosynthetic precursor of lipid A containing four (S)-3-hydroxytetradecanoic acids was effected via an improved synthetic route to investigate the relationship between the bioactivity and the chirality of the 3-hydroxy fatty acid residues in lipid A. The S-analog inhibited endotoxin-induced interleukin-6 (IL-6) production from human peripheral whole blood cells more strongly than the natural-type biosynthetic precursor with (R)-hydroxy acids, a known antagonist of LPS-induced cytokine release in human peripheral blood mononuclear cells.

DOI： 10.1016/0040-4039(95)01433-0

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A convergent stereocontrolled synthesis of the antifungal antibiotic tautomycin, a potent protein phosphatases inhibitor, has been achieved first via key aldol coupling of two large subunits, a right-hand C-1-C-21 ketone and a left-hand aldehyde (left from C-22). The C-1-C-10 segment was synthesized through a remote stereochemical control process using a spiroketal template. After joining with the C-11-C-18 segment, the spiroketal moiety was selectively constructed. Then the right-hand C-1-C-21 ketone was synthesized via Roush asymmetric crotylboration. The left-hand aldehyde was prepared from a C-21-C-26 Segment and a dialkylmaleic anhydride segment. Completely stereoselective assemblage of the two subunits, the right-hand and the left-hand, was achieved by employing the Mukaiyama aldol reaction. Further functional group manipulations including desilylation, oxidation at C-2, and deprotection of tert-butyl ester with concomitant anhydride formation provided tautomycin which was identical with the natural product. As a preliminary study, derivatizations and degradation of the natural product were also examined to support the total synthesis.

DOI： 10.1021/jo00121a026

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Syntheses of 5-methyl-1,7-dioxaspiro[5.5]undecane 4 and its three congeners 5, 6, and 7 (alpha-methylspiroketals), and their reductive ring opening using aluminum hydride or silane - Lewis acid system have been investigated. Each spiroketal was synthesized through stereocontrolled acetalization with 42 - 96% diastereomeric excess (de). The diisobutylaluminum hydride reduction of alpha-methylspiroketals proceeded via the tight oxocarbenium ion pair complex wherein the C - O bond which located at the opposite site against the C(alpha) - methyl bond was cleaved affording a configuration-retentive product with 50 - 100% de.
The regioselectivity in the silane - Lewis acid reduction of the simplest monomethylspiroketal 4 was controlled by the equilibration of the two possible oxocarbenium ionic intermediates. On the other hand, dimethylspiroketal 5 and siloxyspiroketal 6 showed moderate to high regio- and stereoselectivity (10 - 100% de), that originated from regioselective formation of the oxocarbenium ionic species and the subsequent stereoselective hydride attack In these cases, the coordination site of the Lewis acid was controlled by the steric interaction of the methyl group on C(alpha) with the Lewis acid. To the resultant oxocarbenium ion, stereoelectronically-favored axial hydride attack occurred with high stereoselection. The reduction of benzyloxyspiroketal 7 also exhibited good selectivity (62 - 100% de) while the outcome was opposite to those of 5 and 6. Such a dramatic change could be attributed to the bidentate chelation of the Lewis acid to both the benzyl ether and the neighboring acetal oxygens. The whole procedure, the thermodynamic spiroketalization and the subsequent reductive ring opening, could be regarded as a remote stereochemical control using the spiroketal templates.

DOI： 10.1016/0040-4020(95)00288-J

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An efficient synthesis of three homochiral beta-hydroxy fatty acid derivatives, which have been utilized in our total synthesis of lipid A, is reported. The synthesis features Sharpless asymmetric dihydroxylation of an unsaturated ester, regioselective conversion of a diol into acyloxy chlorides, and a reductive removal of the chloro group.

DOI： 10.1016/0957-4166(95)00106-Y

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Language：English   Publisher：GEORG THIEME VERLAG  

A reliable synthetic scheme to produce the CD-ring of grayanotoxins, the toxic principles contained in the leaves of the various plants of the family Ericaceae, in an optically active form was explored.

DOI： 10.1055/s-1994-23011

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An efficient six-step degradation method for the protein phosphatase inhibitor, tautomycin (1), was developed in order to synthesize various analogues of 1 for their biological evaluation. This route allows rapid and multi-gram access to key intermediate 2 in the total synthesis of 1.

DOI： 10.1271/bbb.58.1933

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The Diels-Alder reaction of methyl (2Z,4S)-4-(benzyloxy)-2-pentenoate (6) with 1-[(trimethylsilyl)oxy]-1,3-butadiene took place with complete facial selectivity to give the epimeric mixture of the cycloadducts 8 and 9 (2:1). The absolute configuration of 8 and 9 is the mirror image of that of the C-ring of grayanotoxins, the main toxic substances in plant leaves belonging to the family Ericaceae.

DOI： 10.1055/s-1994-23010

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Total synthesis of(-)-grayanotoxin III (3), a unique tetracyclic diterpene isolated from the leaves of various plants of the family Ericaceae, has been successfully accomplished featuring the highly stereoselective cyclization reactions induced by SmI2.

DOI： 10.1021/jo00098a009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The total synthesis of tautomycin 1 has been achieved via key aldol condensation of the Left-wing 2 and the Right-wing 3.

DOI： 10.1016/S0040-4039(00)76974-7

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Highly regio- and stereoselective reductions of the spiroketals have been achieved by DIBAH and silane-Lewis acid. The key factors of these selectivities were attributed to steric hindrance of alpha-methyl group at spiroketal and to vicinal ether oxygens for bidentate chelation.

DOI： 10.1016/S0040-4039(00)73980-3

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A stereocontrolled synthesis of C(1)-C(18) fragment of tautomycin is accomplished employing asymmetric crotylboration, selective reduction of spiroketal, and addition of crotylstannane as the key steps.

DOI： 10.1016/S0040-4039(00)74091-3

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Grayanotoxins (1-4), toxic principles isolated from leaves of various plants of family Ericaceae, have been shown to increase specifically membrane permeability to sodium cation in sodium-dependent excitable membranes. These diterpenes are characterized by the A-nor-B-homo-kaurane skeleton, unique tetracyclic carbon framework, and by the dense arrangement of hydroxyl groups. Effective synthetic routes to the CD-, A-, and B-rings of grayanotoxins has been successfully developed. Construction of CD-Ring. A reliable synthetic scheme to produce the CD-ring, a diol-γ-lactone 17, in an optically active form was explored. Stereoselective formation of the C-ring was performed through enantioselective Diels-Alder reaction of an α, β-unsaturated ester 10, prepared from L-ethyl lactate, stereocontrolled alkylation of a β-ketoester 13, and regio- and stereoselective reduction of a keto-γ-lactone 14. The D-ring was constructed via radical cyclization of a hydroxy-γ-lactone 9 and stereoselective iodohydrin formation of an olefine-γ-lactone 16. Construction of A-Ring. Connection of the CD- and A-rings was examined. It turned out that cross Aldol reaction of the acyclic precursor of the A-ring, aldehyde 7 and the CD-ring, methylketone 8 took place cleanly, giving an α, β-unsaturated ketone 18. Thus, elaboration of the A-ring was studied using model compounds. Stereocontrolled cyclization of the A-ring meditated by samarium(II) iodide was achieved by employing an allylsulfide 19 as a starting material to afford an alcohol 20. Construction of B-Ring. The tertiary hydroxyl group of the B-ring was introduced by stereocontrolled epoxidation of a homoallylalcohol 24, synthesized from grayanotoxin II (2), followed by reduction, giving rise to a diol 25. Ring closure reaction that lead directly to the vicinal cis-diol moiety of the B-ring was also investigated. Samarium(II) iodide induced pinacol coupling reaction of ketoaldehyde 5, prepared from grayanotoxin III (3), was found to occur in a stereoselective manner to afford a triol 26.

DOI： 10.24496/tennenyuki.33.0_16

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SPRINGER WIEN  

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Micronesian marine sponge Lendenfeldia chondrodes contains structurally diverse neuroactive metabolites such as dysiherbaine, neodysiherbaine, dysibetaine, dysibetaine CPa and CPb, and cribronic acid, which have received significant attention from the synthetic community as structural motifs for developing novel neuroactive compounds. It is also of our considerable interest to use these metabolites as a probe for investigating functions of synaptic receptors. In the present study, we established a synthetic route to dysibetaine CPa (1) in racemic form, which is amenable to the analog synthesis, to study the biological function as well as the structure-activity relationships. Dysibetaine CPa (1) is a betaine consists of a quaternary ammonium group and two carboxyl groups, located on a novel 1,2,3-trisubstituted cyclopropane ring. From the synthetic point of view, differentiation of the functional groups on the cyclopropane ring is essential for the total synthesis but proved to be challenging during our study because of the instability of the synthetic intermediates. Upon considerable experimentation, we discovered that the cyclopropane ring was readily constructed by the reaction of N-(4-nitrophenyl)maleimide with sulfonium ylide 3. Reductive opening of the cyclopropane-fused imide 22 with NaBH_4 proceeded chemoselectively, giving rise to hydroxyamide 23. The amide was converted to ethyl ester over two steps, and then quaternary ammonium group was introduced by way of bromide 6'. Finally, acidic hydrolysis of two esters was effected by hydrochloric acid to achieve the total synthesis of dysibetaine CPa ((±ア)-1). Total yield was 4.5% for 12 steps. Furthermore, synthesis of five analogs was performed in the present study. Our route for the racemates, thus established here, will be also expanded to the asymmetric synthesis to determine the absolute stereochemistry of 1. Preliminary study indicated that all synthetic compounds did not induce noticeable behavioral change when 20 μg was administrated in mice intracerebroventricularly, as was observed with natural product.

DOI： 10.24496/tennenyuki.53.0_643

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Ionotropic glutamate receptors (iGluRs) are involved in higher brain functions such as memory and learning, nociception, and a number of brain disorders. Here, we report the synthesis of twelve artificial glutamate analogs whose core structure was inspired by two marine-derived excitatory amino acids, dysiherbaine and kainia acid. Four 7-oxznorbornenes, 2a-2d, were prepared in two steps, starting from and Ugi four component coupling reaction followed by spontaneous Diels-Alder reaction between 2-furfural, 3-iodoacrylic acid, 4-methoxybenzylamine, and benzyl isocyanide. An unprecedented domino metathesis reaction with less reactive vinyl acetate as a cross metathesis substrate was then performed with the Hoveyda-Grubbs second-generation catalyst, to successfully deliver four heterotricycles 3a-3d in good yiels. After functional group transformations followed by diversification at the C-ring, twelve artificial glutamate analogs 6a-6d, 7a-7d, 8a-8d were synthesized in total 7.2-25.8% yield for 13-15 steps. Mice in vivo assays indicated that all analogs are biologically active; namely, 6b, 7a, 7b, and 8b produce hyperactivity in injected i.c.v., whereas other analogs induce hypoactiity in the animals. In vitro electrophysiological assays showed that some hypoactive analogs inhibit spontaneous excitatory synaptic currents in hippocampal neurons and glutamate-evoked currents from recombinant AMPA receptors. With these pharmacological profiles, synthesis of other analogs werer further performed, and pyrrolidone dicarboxylic acid analog IKM-159 was discovered as a more potent, AMPA receptor-selective antagonist.

DOI： 10.24496/tennenyuki.52.0_85

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

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Language：Japanese   Publishing type：Book review, literature introduction, etc.   Publisher：SOC SYNTHETIC ORGANIC CHEM JPN  

Azaspiracids (AZAs) are a group of shellfish toxin responsible for the poisoning called "azaspiracid poisoning (AZP)" prevailed in a coastal region of north Europe to northwest Africa since 1995. To establish the molecular basis including its chemical structure and its mode of biological action, several synthetic studies have been developed on azaspiracid-1 (AZA-1). In this review, studies on the syntheses of the FGHI- and EFGHI-ring domains corresponding to a lower half of AZA-1, reported by groups of Forsyth, Evans, Nicolaou, and us, are summarized. Retrosynthetic analysis, fragment synthesis and their assembly, and stereoselective construction of the unique spiroaminal HI-ring domain are main topics of this review. Furthermore, total syntheses successfully made by Evans and Nicolaou groups are described.

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (other)   Publisher：The Society of Synthetic Organic Chemistry, Japan  

DOI： 10.5059/yukigoseikyokaishi.66.836

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Dysiherbaine (DH, 1) and its congener neodysiherbaine A (2), isolated from the Micronesian marine sponge, Dysidea herbacea, are remarkable excitatory amino acids with potent convulsant activity. DH activates the AMPA and kainate classes of ionotropic glutamate receptors, with a higher affinity for the latter. Furthermore, it has been revealed that DH had extremely high affinity for GluR5 and GluR6 kainate receptor subunits. Due to these intriguing pharmacological properties to kainite receptors, DH and its designed analogues are anticipated to serve as useful tools for understanding the complex functions of glutamate receptors in the central nervous system. In this presentation, we describe an efficient total synthesis of dysiherbaine. In addition, we report preparation and preliminary biological evaluation of several DH analogues to elucidate the detailed structure-activity relationship profile. A key intermediate 15 was synthesized by two approaches. The first synthetic route utilized compound 6 as the starting point, and the cis-oriented amino alcohol functionality on the tetrahydropyran ring was installed by using an S_N2 cyclization of N-Boc protected amino alcohol 12. An alternative and even more efficient synthetic approach to 15 featured stereoselective introduction of an amino group at C8 by iodoaminocyclization prior to constructing the bicyclic ether skeleton. The amino acid appendage was efficiently constructed by a catalytic asymmetric hydrogenation of enamide ester 24. The synthetic route developed here provided access to several DH analogues, including 9-epi-dysiherbaine (26a), 9-deoxydysiherbaine (26b), 9-O-methyldysiherbaine (26c), and N-ethyldysiherbaine (26d). The preliminary biological evaluation of these variants will be presented.

DOI： 10.24496/tennenyuki.49.0_691

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Language：English   Publishing type：Article, review, commentary, editorial, etc. (bulletin of university, research institution)   Publisher：Graduate School of Agricultural Science, Tohoku University  

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Other Link： http://hdl.handle.net/10097/40401

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Language：Japanese   Publisher：日本農芸化学会  

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Dysiherbaine (DH, 1) and its congener neodysiherbaine A (2), isolated from the Micronesian marine sponge, Dysidea herbacea, are novel excitatory amino acids with potent convulsant activity. DH activates non-NMDA type glutamate receptors [AMPA and kainic acid (KA) receptors] with considerable preference over KA receptors. Moreover, it has been shown that DH binds to the GluR5 and GluR6 KA receptor subunits with high affinity. Due to these intriguing pharmacological properties to KA receptors, DH and its designed analogues are anticipated to serve as useful tools for understanding the structure and functions of glutamate receptors in the central nervous system. In order to reveal the detailed structure-activity relationship profiles of DH, we undertook a diverted synthesis of structural analogues of DH. In this paper, we report the synthesis of simplified analogue 3,8,9-epi-neodysiherbaine A (4a), 8-epi-neodysiherbaine A (4b), 8-deoxyneodysiherbaine A (4c) and 9-deoxyneodysiherbaine A (4d) from a common intermediate 5. The synthesis of 5 started with C-glycosylation of allylsilane 9 with diacetyl-L-arabinal (10), which led to C-glycoside 8 as the sole product. Chemo- and stereoselective dihydroxylation using (DHQD)_2AQN and subsequent epoxidation delivered epoxy alcohol 7, which underwent epoxide opening/5-exo ring-closure during chromatography on silica gel, leading to bicyclic ether core 12. Stereoselective construction of the amino acid chain was efficiently realized by DuPHOS-mediated asymmetric hydrogenation of enamido ester 17 to generate key intermediate 5 via 18. Global deprotection of 5 by acid hydrolysis furnished analogue 4a. Selective deprotection of the acetonide group of 5 was achieved by using DDQ to afford diol 19, which was further converted to other analogues (3 and 4b-d) via cyclic sulfate 20 and thiocarbonate 24. The toxicity of analogues 4a-d were tested on mice. Intracerebral injection of analogue 4a did not induce any convulsant behavior even at higher dose (20μg/mouse), whereas that of 4b induced a sleeper effect. Analogues 4c and 4d were found to show convulsant activity although the potency was much weaker than that of the natural DH (1). In the radioligand binding assay using rat synaptic membrane preparation, 4b displaced [^3H]KA and [^3H]AMPA with IC_<50> values of 24.1±6.8μM and 9.7±2.3μM, respectively. In contrast, analogue 4a did not displace these radioligand from receptors even at 100μM. In addition, detailed pharmacological studies revealed that simplified analogue 3 is a selective antagonist for GluR5 KA receptors. Further neurophysiological studies of analogues are underway and will be described.

DOI： 10.24496/tennenyuki.47.0_49

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Language：English   Publisher：GEORG THIEME VERLAG KG  

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Language：Japanese   Publisher：The Society of Syhthetic Organic Chemistry, Japan  

The first synthesis of the antifungal antibiotic tautomycin, a potent protein phosphatase inhibitor, has been achieved &lt;I&gt;via&lt;/I&gt; aldol coupling of two large subunits, a right-hand C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;21&lt;/SUB&gt; ketone and a left-hand aldehyde (left from C&lt;SUB&gt;22&lt;/SUB&gt;). The C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;10&lt;/SUB&gt; segment was synthesized through a remote stereochemical control process using a spiroketal template After joining with the C&lt;SUB&gt;11&lt;/SUB&gt;-C&lt;SUB&gt;18&lt;/SUB&gt; segment, the spiroketal moiety was selectively constructed. Then the right-hand C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;21&lt;/SUB&gt; ketone was synthesized via Roush...

DOI： 10.5059/yukigoseikyokaishi.53.1123

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Tautomycin (1) was first isolated in 1987 by Isono and co-workers and the full stereostructure was established recently. This compound is a potent inhibitor of protein phosphatases type 1 and type 2A. Here we describe the synthetic studies of 1. Synthesis of the C1-C10 segment. We applied the newly developed methodology for the synthesis of this segment. This methodology involves the selective spiroketal formation using thermodynamic equilibration and its regio- and stereoselective reduction. These reaction proceeds in high selectivity, and the reduction product 15A was leaded to the aldehy...

DOI： 10.24496/tennenyuki.35.0_120

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Event date： 2020.12

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

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Event date： 2020.10

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Country：Japan  

File： 2020 CSJ 要旨9.pdf

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Venue：横浜  

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Venue：熱海  

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Venue：船橋  

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Venue：東京都新宿区  

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Venue：北海道虻田郡ニセコ町  

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Venue：北海道虻田郡ニセコ町  

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Venue：小金井  

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Venue：Kyoto  

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Venue：東京都江戸川区  

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Venue：東京都文京区  

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Venue：札幌市、札幌市民ホール  

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Venue：札幌、北海道大学  

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Venue：東京都江戸川区、タワーホール船堀  

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Venue：東京都江戸川区、タワーホール船堀  

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Venue：東京都豊島区、学習院大学  

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Venue：東京都豊島区、学習院大学  

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Venue：札幌市、北海道大学  

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Venue：横浜市、新横浜フジビューホテル  

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Venue：船橋、日本大学理工学部船橋キャンパス  

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Venue：船橋、日本大学理工学部船橋キャンパス  

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Venue：千葉、千葉大学西千葉キャンパス  

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Venue：野田、東京理科大学  

IKM-159 is a hybrid of two neuroactive natural products designed and synthesized in our laboratory. Reasonably, IKM-159 was later identified as an antagonist selective to subtypes of AMPA-type ionotropic glutamate receptor. To study the structure-activity relationships, and to develop probes for the receptor, we synthesized new analogs of IKM-159 bearing dioxane ring for the C-ring by the novel three-component oxa-Michael reaction. Results for the mice in vivo assay will be also reported.

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Venue：横浜、慶應義塾大学  

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Venue：Rose Garden Hotel, Yangon, Myanmar  

File： Abstract_oikawa.pdf

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Venue：熱海、富士フイルム和光純薬(株) 湯河原研修所  

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Venue：神戸、甲南大学岡本キャンパス  

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Venue：神戸、甲南大学岡本キャンパス  

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Venue：東京都千代田区、麹町田村ビル  

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Venue：札幌、北海道大学  

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Venue：倉敷、倉敷市芸文館  

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Venue：新潟、新潟大学五十嵐キャンパス  

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Venue：仙台  

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Language：English   Presentation type：Oral presentation (invited, special)  

Venue：函館、北海道大学水産科学研究院  

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Language：English   Presentation type：Poster presentation  

Venue：広島、広島国際会議場  

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Language：English   Presentation type：Oral presentation (general)  

Venue：船橋、日本大学理工学部船橋キャンパス  

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Language：Japanese   Presentation type：Poster presentation  

Venue：東京都江戸川区、タワーホール船堀  

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Language：Japanese   Presentation type：Poster presentation  

Venue：高知、高知県立県民文化ホール  

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Language：Japanese   Presentation type：Poster presentation  

Venue：高知、高知県立県民文化ホール  

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Language：English   Presentation type：Oral presentation (invited, special)  

Venue：Bayview Hotel Langkawi, Langkawi, Malaysia  

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：長岡、長岡技術科学大学  

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Language：Japanese   Presentation type：Poster presentation  

Venue：長崎、長崎ブリックホール  

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Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：八王子、工学院大学  

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Language：Japanese   Presentation type：Poster presentation  

Venue：久留米、久留米シティプラザ  

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：横浜、パシフィコ横浜  

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：千葉、千葉大学西千葉キャンパス  

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Language：Japanese   Presentation type：Poster presentation  

Venue：名古屋、名古屋大学 坂田・平田ホール  

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Language：Japanese   Presentation type：Poster presentation  

Venue：名古屋、名古屋大学 坂田・平田ホール  

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京、東京ビッグサイト  

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：長岡、長岡技術科学大学  

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Language：English   Presentation type：Oral presentation (general)  

Venue：野田、東京理科大学  

Aculeine B (ACU-B) is a peptide-polyamine conjugate isolated from a marine sponge collected in Iriomote, Okinawa, Japan. ACU-B is toxic to cultured cancer cells, and it has been suggested that the toxicity is based on a specific interaction between the long-chain polyamine moiety and cell surface molecules. Since ACU?B may be of use for 1) development of a new anticancer drug, and/or 2) delivery of drugs into cells, we have started functional analyses of ACU?B based on synthetic organic chemistry. Herein we will report our efforts toward total synthesis of pACU?B, which is the N?terminal partial structure of ACU?B, and the analogs. Results on the structure?activity relationships study of ACU?B analogs will be also presented.

File： MM_CSJ予稿原稿_mo_wo-track.pdf

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Language：English   Presentation type：Poster presentation  

Venue：野田、東京理科大学  

To design the key steps in multi-step synthesis of complex amino acids, we herein propose our strategy based on DFT calculation for analysis of the selectivities and the structures.

File： 20200110-0111_mo_abs.pdf

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：野田、東京理科大学  

Selective cleavage of the amide bond is of use to generate the fragments of structurally complex natural product to 1) analyze the structure, and to 2) investigate the structure?activity relationships. In this study, we focused on N-acyl-β-aminoalcohol motif, frequently found in some natural products and pharmaceutical agents. Two-step cleavage of the amide by derivatization of the motif into N-acyloxazolidinone via imidazolyl carbamate followed by N-deacylation under mild conditions will be reported.

File： 2020春季年会_予稿_RAK.pdf

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：船橋  

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Language：Japanese   Presentation type：Poster presentation  

Venue：札幌  

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Language：Japanese   Presentation type：Poster presentation  

Venue：札幌  

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Language：Japanese   Presentation type：Poster presentation  

Venue：高知  

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：船橋  

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：横浜  

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