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井貫晋輔

徳島大学

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リサーチマップ・
Jグローバル
KAKEN
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2025年6月6日更新

職名: 教授
電話: 研究者総覧に該当データはありませんでした。
電子メール: sinuki@tokushima-u.ac.jp
学歴: 2002/4: 京都大学薬学部 ( - 2006. 3.)
2006/4: 京都大学大学院薬学研究科博士前期課程 ( - 2008. 3.)
2008/4: 京都大学大学院薬学研究科博士後期課程 ( - 2011. 3.)
学位: 博士(薬学) (京都大学) (2011年3月)
職歴・経歴: 2024/7: 徳島大学教授, 大学院医歯薬学研究部

専門分野・研究分野: ライフサイエンス (Life sciences) [薬系化学、創薬科学 (Pharmaceuticals - chemistry and drug development)]

研究者総覧で最新データを確認する

2025年6月6日更新

専門分野・研究分野: ライフサイエンス (Life sciences) [薬系化学、創薬科学 (Pharmaceuticals - chemistry and drug development)]
担当経験のある授業科目: ゲノム創薬特論 (大学院)
創薬化学特論 (大学院)
創薬科学演習 (大学院)
天然医薬資源学 (学部)
専攻公開ゼミナール (大学院)
有機化学5(生体分子) (学部)
生薬学実習 (学部)
薬学科学特論Ⅱ (大学院)
薬科学演習1 (大学院)
薬科学特別研究 (大学院)
指導経験: 研究者総覧に該当データはありませんでした。

研究者総覧で最新データを確認する

2025年6月6日更新

専門分野・研究分野: ライフサイエンス (Life sciences) [薬系化学、創薬科学 (Pharmaceuticals - chemistry and drug development)]

研究テーマ: 研究者総覧に該当データはありませんでした。

著書

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論文

Takuro Matsuoka, Ryosuke Takasaki, Hiroki Akiba, Kosuke Ogata, Akira Hattori, Norihito Arichi, Hideaki Kakeya, Sho Yamasaki, Yasushi Ishihama, Hiroaki Ohno and Shinsuke Inuki :
Visible light-mediated photocatalytic coupling between tetrazoles and carboxylic acids for biomolecule labelling.,
Chemical Communications, 61, 34, 6320-6323, 2025.

(要約): Photocatalytic biomolecular labelling is gaining attention as a foundational technique for analyzing biological phenomena. However, photocatalytic reactions compatible with physiological conditions remain limited. Here, we present a photocatalytic reaction of diaryltetrazoles to generate nitrile imines, which readily couple with carboxylic acids in aqueous environments. This reaction is applied for photocatalyst-dependent labelling of proteins and cells.
(キーワード): Carboxylic Acids / Catalysis / Light / Tetrazoles / Photochemical Processes / Nitriles / Humans / Imines / Molecular Structure
(出版サイトへのリンク): ● Publication site (DOI): 10.1039/d4cc04452e
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 40166963; ● Search Scopus @ Elsevier (PMID): 40166963; ● Search Scopus @ Elsevier (DOI): 10.1039/d4cc04452e

(DOI: 10.1039/d4cc04452e, PubMed: 40166963) Aoi Takahara, Toru Nakatsu, Kazushige Hirata, Hironori Hayashi, Kumi Kawaji, Keisuke Aoki, Shinsuke Inuki, Hiroaki Ohno, Hiroaki Kato, Eiichi Kodama and Shinya Oishi :
Elucidation of Postfusion Structures of the Measles Virus F Protein for the Structure-Based Design of Fusion Inhibitors.,
Journal of Medicinal Chemistry, 68, 3, 3123-3133, 2025.

(要約): Measles is a highly infectious disease and remains a major cause of childhood mortality worldwide. In some cases, the measles virus (MV) induces subacute sclerosing panencephalitis within several years of the acute infection. The infection of the target cells by MV is mediated by the F protein, in which two heptad repeat regions, HR1 and HR2, form a six-helix bundle before membrane fusion. We previously reported anti-MV peptides, which were designed from the HR region of the MV F protein. Here, we characterized the essential interactions between the HR1 and HR2 regions on the postfusion six-helix bundles of synthetic HR1 and HR2 peptides by crystallographic studies. Based on the crystal structures, we identified the minimal α-helix sequence for antiviral activity. Additionally, optimizing HR2 peptides by introducing α-helix-inducible motifs and maintaining key hydrogen bond networks at the N- and C-terminal regions led to the identification of highly potent antiviral peptides.
(キーワード): Measles virus / Viral Fusion Proteins / Antiviral Agents / Drug Design / Humans / Structure-Activity Relationship / Viral Fusion Protein Inhibitors / Crystallography, X-Ray / Models, Molecular / Peptides / Amino Acid Sequence / Animals
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.jmedchem.4c02337
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39887040; ● Search Scopus @ Elsevier (PMID): 39887040; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.jmedchem.4c02337

(DOI: 10.1021/acs.jmedchem.4c02337, PubMed: 39887040) Hidenori Shimizu, Junki Miyamoto, Keiko Hisa, Ryuji Ohue-Kitano, Hiromi Takada, Mayu Yamano, Akari Nishida, Daiki Sasahara, Yuki Masujima, Keita Watanabe, Shota Nishikawa, Sakura Takahashi, Takako Ikeda, Yuya Nakajima, Naofumi Yoshida, Chiaki Matsuzaki, Takuya Kageyama, Ibuki Hayashi, Akari Matsuki, Ryo Akashi, Seiichi Kitahama, Masako Ueyama, Takumi Murakami, Shinsuke Inuki, Junichiro Irie, Noriko Satoh-Asahara, Hirokazu Toju, Hiroshi Mori, Shinji Nakaoka, Tomoya Yamashita, Atsushi Toyoda, Kenji Yamamoto, Hiroaki Ohno, Takane Katayama, Hiroshi Itoh and Ikuo Kimura :
Sucrose-preferring gut microbes prevent host obesity by producing exopolysaccharides.,
Nature Communications, 16, 1, 2025.

(要約): Commensal bacteria affect host health by producing various metabolites from dietary carbohydrates via bacterial glycometabolism; however, the underlying mechanism of action remains unclear. Here, we identified Streptococcus salivarius as a unique anti-obesity commensal bacterium. We found that S. salivarius may prevent host obesity caused by excess sucrose intake via the exopolysaccharide (EPS) -short-chain fatty acid (SCFA) -carbohydrate metabolic axis in male mice. Healthy human donor-derived S. salivarius produced high EPS levels from sucrose but not from other sugars. S. salivarius abundance was significantly decreased in human donors with obesity compared with that in healthy donors, and the EPS-SCFA bacterial carbohydrate metabolic process was attenuated. Our findings reveal an important mechanism by which host-commensal interactions in glycometabolism affect energy regulation, suggesting an approach for preventing lifestyle-related diseases via prebiotics and probiotics by targeting bacteria and EPS metabolites.
(キーワード): Obesity / Animals / Gastrointestinal Microbiome / Humans / Male / Polysaccharides, Bacterial / Mice / Sucrose / Fatty Acids, Volatile / Mice, Inbred C57BL / Symbiosis / Adult / Streptococcus / Female
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s41467-025-56470-0
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39880823; ● Search Scopus @ Elsevier (PMID): 39880823; ● Search Scopus @ Elsevier (DOI): 10.1038/s41467-025-56470-0

(DOI: 10.1038/s41467-025-56470-0, PubMed: 39880823) Kodai Sueyoshi, Junichiro Kishi, Shinsuke Inuki, Takanori Matsumaru and Yukari Fujimoto :
Highly Selective Cytokine Induction of Nitrated Lipid-Modified α-GalCer Derivatives Demonstrating High Binding Affinity to the Lipid Antigen Presenting Molecule CD1d.,
Chemistry - A European Journal, 31, 6, 2025.

(要約): -π interactions, leading to the distinctive function in cytokine induction and selectivity.
(キーワード): Antigens, CD1d / Galactosylceramides / Cytokines / Natural Killer T-Cells / Animals / Antigen Presentation / Humans / Mice / Glycolipids / Hydrogen Bonding / Lipids
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/chem.202403871
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39632752; ● Search Scopus @ Elsevier (PMID): 39632752; ● Search Scopus @ Elsevier (DOI): 10.1002/chem.202403871

(DOI: 10.1002/chem.202403871, PubMed: 39632752) Daiki Hasegawa, Atsuhito Tsuji, C Luca Greiner, Norihito Arichi, Shinsuke Inuki and Hiroaki Ohno :
Synthesis of Azocine-Fused Indoles via Gold(I)-Catalyzed Cyclization of Azido-alkynes.,
The Journal of Organic Chemistry, 90, 1, 925-930, 2024.

(要約): Herein, we report a gold(I)-catalyzed cascade cyclization of azido-alkynes bearing an enol ester moiety, leading to indole-fused eight-membered rings. This method allows for the one-step construction of indole and tetrahydroazocin-4-one via an α-imino gold carbene intermediate. The resulting scaffold would be useful for accessing natural products with an eight-membered ring-fused indole moiety.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.joc.4c02704
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39740203; ● Search Scopus @ Elsevier (PMID): 39740203; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.joc.4c02704

(DOI: 10.1021/acs.joc.4c02704, PubMed: 39740203) Yuki Sakai, Minori Asa, Mika Hirose, Wakana Kusuhara, Nagatoshi Fujiwara, Hiroto Tamashima, Takahiro Ikazaki, Shiori Oka, Kota Kuraba, Kentaro Tanaka, Takashi Yoshiyama, Masamichi Nagae, Yoshihiko Hoshino, Daisuke Motooka, Ildiko Rhijn Van, Xiuyuan Lu, Eri Ishikawa, Branch D Moody, Takayuki Kato, Shinsuke Inuki, Go Hirai and Sho Yamasaki :
A conserved human CD4+ T cell subset recognizing the mycobacterial adjuvant trehalose monomycolate.,
The Journal of Clinical Investigation, 135, 6, 2024.

(要約): Mycobacterium tuberculosis causes human tuberculosis (TB). As mycobacteria are protected by a thick lipid cell wall, humans have developed immune responses against diverse mycobacterial lipids. Most of these immunostimulatory lipids are known as adjuvants acting through innate immune receptors, such as C-type lectin receptors. Although a few mycobacterial lipid antigens activate unconventional T cells, the antigenicity of most adjuvantic lipids is unknown. Here, we identified that trehalose monomycolate (TMM), an abundant mycobacterial adjuvant, activated human T cells bearing a unique αβ T cell receptor (αβTCR). This recognition was restricted by CD1b, a monomorphic antigen-presenting molecule conserved in primates but not mice. Single-cell TCR-RNA-Seq using newly established CD1b-TMM tetramers revealed that TMM-specific T cells were present as CD4+ effector memory T cells in the periphery of uninfected donors but expressed IFN-γ, TNF, and anti-mycobacterial effectors upon TMM stimulation. TMM-specific T cells were detected in cord blood and PBMCs of donors without bacillus Calmette-Guérin vaccination but were expanded in patients with active TB. A cryo-electron microscopy study of CD1b-TMM-TCR complexes revealed unique antigen recognition by conserved features of TCRs, positively charged CDR3α, and long CDR3β regions. These results indicate that humans have a commonly shared and preformed CD4+ T cell subset recognizing a typical mycobacterial adjuvant as an antigen. Furthermore, the dual role of TMM justifies reconsideration of the mechanism of action of adjuvants.
(キーワード): Humans / Adjuvants, Immunologic / Mycobacterium tuberculosis / CD4-Positive T-Lymphocytes / Antigens, CD1 / Receptors, Antigen, T-Cell, alpha-beta / Glycolipids / Animals / Mice / Female / Tuberculosis / T-Lymphocyte Subsets / Male / Cord Factors
(出版サイトへのリンク): ● Publication site (DOI): 10.1172/JCI185443
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39718834; ● Search Scopus @ Elsevier (PMID): 39718834; ● Search Scopus @ Elsevier (DOI): 10.1172/JCI185443

(DOI: 10.1172/JCI185443, PubMed: 39718834) Ryosuke Takasaki, Emi Ito, Masamichi Nagae, Yuki Takahashi, Takuro Matsuoka, Wakana Yasue, Norihito Arichi, Hiroaki Ohno, Sho Yamasaki and Shinsuke Inuki :
Development of Ribityllumazine Analogue as Mucosal-Associated Invariant T Cell Ligands.,
Journal of the American Chemical Society, 146, 43, 29964-29976, 2024.

(要約): Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells abundant in human tissues that play a significant role in defense against bacterial and viral infections and in tissue repair. MAIT cells are activated by recognizing microbial-derived small-molecule ligands presented by the MHC class I related-1 protein. Although several MAIT cell modulators have been identified in the past decade, potent and chemically stable ligands remain limited. Herein, we carried out a structure-activity relationship study of ribityllumazine derivatives and found a chemically stable MAIT cell ligand with a pteridine core and a 2-oxopropyl group as the Lys-reactive group. The ligand showed high potency in a cocultivation assay using model cell lines of antigen-presenting cells and MAIT cells. The X-ray crystallographic analysis revealed the binding mode of the ligand to MR1 and the T cell receptor, indicating that it forms a covalent bond with MR1 via Schiff base formation. Furthermore, we found that the ligand stimulated proliferation of human MAIT cells in human peripheral blood mononuclear cells and showed an adjuvant effect in mice. Our developed ligand is one of the most potent among chemically stable MAIT cell ligands, contributing to accelerating therapeutic applications of MAIT cells.
(キーワード): Mucosal-Associated Invariant T Cells / Humans / Ligands / Animals / Mice / Structure-Activity Relationship / Crystallography, X-Ray / Models, Molecular / Histocompatibility Antigens Class I / Molecular Structure / Ribitol / Uracil
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/jacs.4c12997
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39432319; ● Search Scopus @ Elsevier (PMID): 39432319; ● Search Scopus @ Elsevier (DOI): 10.1021/jacs.4c12997

(DOI: 10.1021/jacs.4c12997, PubMed: 39432319) Norihito Arichi, Tsuyoshi Amano, Shuhan Wu, Shinsuke Inuki and Hiroaki Ohno :
Synthesis of Sulfilimines via Visible-Light-Mediated Triplet Energy Transfer to Sulfonyl Azides.,
Chemistry - A European Journal, 30, 48, 2024.

(要約): Sulfilimines and their derivatives have garnered considerable interest in both synthetic and medicinal chemistry. Photochemical nitrene transfer to sulfides is known as a conventional synthetic approach to sulfilimines. However, the existing methods have a limited substrate scope stemming from the incompatibility of singlet nitrene intermediates with nucleophilic functional groups. Herein, we report the synthesis of N-sulfonyl sulfilimines via visible-light-mediated energy transfer to sulfonyl azides, uncovering the previously overlooked reactivity of triplet nitrenes with sulfides. This reaction features broad functional group tolerance, water compatibility, and amenability to the late-stage functionalization of drugs. Thus, this work represents an important example of energy transfer chemistry that overcomes challenges in traditional synthetic methods.
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/chem.202401842
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38923056; ● Search Scopus @ Elsevier (PMID): 38923056; ● Search Scopus @ Elsevier (DOI): 10.1002/chem.202401842

(DOI: 10.1002/chem.202401842, PubMed: 38923056) Keisuke Aoki, Kayuu Maeda, Shinsuke Inuki, Hiroaki Ohno, Motohiro Nonaka and Shinya Oishi :
Chemical Synthesis of Interleukin-6 for Mirror-Image Screening.,
Bioconjugate Chemistry, 35, 8, 1190-1199, 2024.

(要約): Interleukin-6 (IL-6), a multifunctional cytokine, is an attractive therapeutic target for immunological and inflammatory diseases. We investigated the chemical synthesis of IL-6 and its enantiomer (d-IL-6) using a sequential N-to-C native chemical ligation strategy from six peptide segments. Solubilizing Trt-K₁₀ tags improved the intermediate solubility and served as protecting groups during the metal-free desulfurization to facilitate the synthesis of full-length IL-6 protein. Synthetic l-IL-6 and recombinant IL-6 exhibited nearly identical structural and binding properties. The symmetrical binding property of d-IL-6 was also demonstrated by functional analysis using IL-6-binding peptides. The resulting functional d-IL-6 was employed to screen a phage-displayed antibody fragment library, leading to the identification of several d-IL-6-binding single-domain antibodies. This work will contribute to the development of novel, potent IL-6 inhibitors without the adverse effects of undesired immune activation.
(キーワード): Interleukin-6 / Peptide Library / Humans / Stereoisomerism / Peptides / Recombinant Proteins / Models, Molecular / Amino Acid Sequence / Solubility
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.bioconjchem.4c00204
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39042943; ● Search Scopus @ Elsevier (PMID): 39042943; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.bioconjchem.4c00204

(DOI: 10.1021/acs.bioconjchem.4c00204, PubMed: 39042943) Naoki Hashimoto, Junichi Taguchi, Takumi Kasagi, Norihito Arichi, Shinsuke Inuki and Hiroaki Ohno :
Construction of the Akuammiline Alkaloid Core Structure via Stereoselective E-Ring Formation.,
The Journal of Organic Chemistry, 89, 14, 10388-10392, 2024.

(要約): Construction of the core structure of akuammiline alkaloids with three-dimensional cage-like structures for their diversity-oriented synthesis was investigated. Extensive exploration centered around the introduction of nitrogen functional groups and construction of the E-ring in an intramolecular or intermolecular manner revealed that a Claisen rearrangement approach involving intramolecular amination provided a common precursor, potentially facilitating divergent access to various types of akuammiline alkaloids.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.joc.4c01105
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38952036; ● Search Scopus @ Elsevier (PMID): 38952036; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.joc.4c01105

(DOI: 10.1021/acs.joc.4c01105, PubMed: 38952036) Yuki Yoshida, Haruka Takeuchi, Norihito Arichi, Shinya Oishi, Hiroaki Ohno and Shinsuke Inuki :
Approach to Spirocyclohexadienes via Visible LightMediated ipsoCyclization of Amino Acid Derivatives with N(2Phenyl)benzoyl Groups,
Asian Journal of Organic Chemistry, 13, 2024.

(要約): <jats:title>Abstract</jats:title><jats:p>Spirocycles are important structural motifs, found in natural and pharmaceutical compounds, which have attracted considerable interest in modern drug discovery research. Herein, we describe the development of a visible light‐mediated <jats:italic>ipso</jats:italic>‐cyclization of amino acid derivatives with <jats:italic>N</jats:italic>‐(2‐phenyl)benzoyl groups, allowing easy access to a variety of spirocyclohexadienes. The addition of water was found to be beneficial in promoting the reaction progress. Investigation of the substrate scope revealed that incorporating an electron‐donating moiety at the 3′‐position of the biphenyl group resulted in a more favorable outcome for spirocycle formation.</jats:p>
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/ajoc.202400140
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1871991017834777088; ● Search Scopus @ Elsevier (DOI): 10.1002/ajoc.202400140

(DOI: 10.1002/ajoc.202400140, CiNii: 1871991017834777088) Naoya Iwamoto, Takuma Kai, Shinsuke Inuki, Hiroaki Ohno, Hitoshi Maeda, Hiroshi Watanabe, Toru Maruyama and Shinya Oishi :
Mirror-Image Human Serum Albumin Domain III as a Tool for Analyzing Site II-Dependent Molecular Recognition.,
Bioconjugate Chemistry, 35, 6, 816-825, 2024.

(要約): Human serum albumin (HSA) as a drug carrier can significantly improve the pharmacokinetic profiles of short-lived therapeutics. Conjugation of albumin-binding moieties (ABMs) to therapeutic agents may prolong their serum half-life by promoting their association with endogenous HSA. To discover a new molecular class of ABMs from mirror-image chemical space, a preparation protocol for bioactive HSA domain III and its d-enantiomer (d-HSA domain III) was established. Structural and functional analyses suggested that the synthetic protein enantiomers exhibited mirror-image structures and stereoselective neonatal fragement crystallizable receptor (FcRn) recognition. Additionally, the ligand-binding properties of synthetic l-HSA domain III were comparable with those of site II in native HSA, as confirmed using site II-selective fluorescent probes and an esterase substrate. Synthetic d-HSA domain III is an attractive tool for analyzing the site II-dependent molecular recognition properties of HSA.
(キーワード): Humans / Serum Albumin, Human / Binding Sites / Protein Domains / Stereoisomerism / Protein Binding / Models, Molecular / Fluorescent Dyes
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.bioconjchem.4c00150
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38781049; ● Search Scopus @ Elsevier (PMID): 38781049; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.bioconjchem.4c00150

(DOI: 10.1021/acs.bioconjchem.4c00150, PubMed: 38781049) Keisuke Aoki, Katsuaki Higashi, Sakiho Oda, Asako Manabe, Kayuu Maeda, Jyoji Morise, Shogo Oka, Shinsuke Inuki, Hiroaki Ohno, Shinya Oishi and Motohiro Nonaka :
Engineering a Low-Immunogenic Mirror-Image VHH against Vascular Endothelial Growth Factor.,
ACS Chemical Biology, 19, 5, 1194-1205, 2024.

(要約): Immunogenicity is a major caveat of protein therapeutics. In particular, the long-term administration of protein therapeutic agents leads to the generation of antidrug antibodies (ADAs), which reduce drug efficacy while eliciting adverse events. One promising solution to this issue is the use of mirror-image proteins consisting of d-amino acids, which are resistant to proteolytic degradation in immune cells. We have recently reported the chemical synthesis of the enantiomeric form of the variable domain of the antibody heavy chain (d-VHH). However, identifying mirror-image antibodies capable of binding to natural ligands remains challenging. In this study, we developed a novel screening platform to identify a d-VHH specific for vascular endothelial growth factor A (VEGF-A). We performed mirror-image screening of two newly constructed synthetic VHH libraries displayed on T7 phage and identified VHH sequences that effectively bound to the mirror-image VEGF-A target (d-VEGF-A). We subsequently synthesized a d-VHH candidate that preferentially bound the native VEGF-A (l-VEGF-A) with submicromolar affinity. Furthermore, immunization studies in mice demonstrated that this d-VHH elicited no ADAs, unlike its corresponding l-VHH. Our findings highlight the utility of this novel d-VHH screening platform in the development of protein therapeutics exhibiting both reduced immunogenicity and improved efficacy.
(キーワード): Vascular Endothelial Growth Factor A / Animals / Mice / Humans / Protein Engineering / Immunoglobulin Heavy Chains / Peptide Library
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acschembio.4c00197
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38695546; ● Search Scopus @ Elsevier (PMID): 38695546; ● Search Scopus @ Elsevier (DOI): 10.1021/acschembio.4c00197

(DOI: 10.1021/acschembio.4c00197, PubMed: 38695546) Shinsuke Inuki, Junki Miyamoto, Naoki Hashimoto, Hidenori Shimizu, Hitomi Tabuchi, Atsuko Kawai, C Luca Greiner, Ikuo Kimura and Hiroaki Ohno :
Structure-activity relationship studies of tetrahydroquinolone derivatives as GPR41 modulators.,
Bioorganic & Medicinal Chemistry Letters, 107, 129758, 2024.

(要約): GPR41, a G protein-coupled receptor, serves as a sensor for short-chain fatty acids and plays a crucial role in regulating multiple physiological processes such as the maintenance of metabolic and immune homeostasis. Therefore, the modulation of GPR41 has garnered attention as a potential strategy for the treatment of various disorders. We conducted a structure-activity relationship study on a lead tetrahydroquinolone derivative bearing a 2-(trifluoromethoxy)benzene group that displayed antagonistic activity toward GPR41. Modification of the aryl group attached to the furan moiety revealed that derivatives containing di- or trifluorobenzene, instead of 2-(trifluoromethoxy)benzene, exhibited agonistic activity toward GPR41, comparable with the reported agonistic modulator AR420626. These results suggest that the aryl group plays a pivotal role in regulating the activity of compounds toward GPR41, providing valuable insights for the design of GPR41 modulators.
(キーワード): Structure-Activity Relationship / Receptors, G-Protein-Coupled / Humans / Molecular Structure / Quinolones / Dose-Response Relationship, Drug / Receptors, Cell Surface
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.bmcl.2024.129758
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38641152; ● Search Scopus @ Elsevier (PMID): 38641152; ● Search Scopus @ Elsevier (DOI): 10.1016/j.bmcl.2024.129758

(DOI: 10.1016/j.bmcl.2024.129758, PubMed: 38641152) Keisuke Aoki, Shugo Tsuda, Naoko Ogata, Michiyo Kataoka, Jumpei Sasaki, Shinsuke Inuki, Hiroaki Ohno, Koichi Watashi, Taku Yoshiya and Shinya Oishi :
Synthesis of the full-length hepatitis B virus core protein and its capsid formation.,
Organic & Biomolecular Chemistry, 22, 11, 2218-2225, 2024.

(要約): Chronic infection with hepatitis B virus (HBV) is a major cause of cirrhosis and liver cancer. Capsid assembly modulators can induce error-prone assembly of HBV core proteins to prevent the formation of infectious virions, representing promising candidates for treating chronic HBV infections. To explore novel capsid assembly modulators from unexplored mirror-image libraries of natural products, we have investigated the synthetic process of the HBV core protein for preparing the mirror-image target protein. In this report, the chemical synthesis of full-length HBV core protein (Cp183) containing an arginine-rich nucleic acid-binding domain at the C-terminus is presented. Sequential ligations using four peptide segments enabled the synthesis of Cp183 via convergent and C-to-N direction approaches. After refolding under appropriate conditions, followed by the addition of nucleic acid, the synthetic Cp183 assembled into capsid-like particles.
(キーワード): Humans / Capsid / Capsid Proteins / Hepatitis B virus / Hepatitis B / Viral Core Proteins / Nucleic Acids / Virus Replication / Antiviral Agents
(出版サイトへのリンク): ● Publication site (DOI): 10.1039/d3ob02099a
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38358380; ● Search Scopus @ Elsevier (PMID): 38358380; ● Search Scopus @ Elsevier (DOI): 10.1039/d3ob02099a

(DOI: 10.1039/d3ob02099a, PubMed: 38358380) Ayuta Yamaguchi, Naoki Obiya, Norihito Arichi, Shinya Oishi, Hiroaki Ohno and Shinsuke Inuki :
Synthesis of labionin and avionin precursors via a nitrogen-centred-radical-triggered 1,5-HAT reaction of Tris derivatives.,
Organic & Biomolecular Chemistry, 22, 10, 2049-2055, 2024.

(要約): Labionin and avionin are non-proteinogenic amino acids containing 2,4-diamino-2-(mercaptomethyl)pentanedioic acid that forms the core structures of spirocyclic peptides including labyrinthopeptin A2 and microvionin, respectively. We have developed a diastereoselective synthetic route to labionin and avionin precursors. This route highlights the formation of the quaternary carbon stereocenter of an α,α-disubstituted amino acid via a regioselective 1,5-HAT reaction of a Tris derivative.
(出版サイトへのリンク): ● Publication site (DOI): 10.1039/d3ob02037a
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38362729; ● Search Scopus @ Elsevier (PMID): 38362729; ● Search Scopus @ Elsevier (DOI): 10.1039/d3ob02037a

(DOI: 10.1039/d3ob02037a, PubMed: 38362729) Emi Ito, Shinsuke Inuki, Yoshihiro Izumi, Masatomo Takahashi, Yuki Dambayashi, Lisa Ciacchi, Wael Awad, Ami Takeyama, Kensuke Shibata, Shotaro Mori, W Jeffrey Y Mak, P David Fairlie, Takeshi Bamba, Eri Ishikawa, Masamichi Nagae, Jamie Rossjohn and Sho Yamasaki :
Sulfated bile acid is a host-derived ligand for MAIT cells.,
Science Immunology, 9, 91, eade6924, 2024.

(要約): Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize bacterial riboflavin-based metabolites as activating antigens. Although MAIT cells are found in tissues, it is unknown whether any host tissue-derived antigens exist. Here, we report that a sulfated bile acid, cholic acid 7-sulfate (CA7S), binds the nonclassical MHC class I protein MR1 and is recognized by MAIT cells. CA7S is a host-derived metabolite whose levels were reduced by more than 98% in germ-free mice. Deletion of the sulfotransferase 2a family of enzymes (Sult2a1-8) responsible for CA7S synthesis reduced the number of thymic MAIT cells in mice. Moreover, recognition of CA7S induced MAIT cell survival and the expression of a homeostatic gene signature. By contrast, recognition of a previously described foreign antigen, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), drove MAIT cell proliferation and the expression of inflammatory genes. Thus, CA7S is an endogenous antigen for MAIT cells, which promotes their development and function.
(キーワード): Animals / Mice / Mucosal-Associated Invariant T Cells / Bile Acids and Salts / Ligands / Sulfates / Minor Histocompatibility Antigens / Antigens
(出版サイトへのリンク): ● Publication site (DOI): 10.1126/sciimmunol.ade6924
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38277465; ● Search Scopus @ Elsevier (PMID): 38277465; ● Search Scopus @ Elsevier (DOI): 10.1126/sciimmunol.ade6924

(DOI: 10.1126/sciimmunol.ade6924, PubMed: 38277465) Naoya Iwamoto, Jumpei Sasaki, Saya Ohno, Keisuke Aoki, Yusuke Usui, Shinsuke Inuki, Hiroaki Ohno and Shinya Oishi :
Synthetic studies on the extracellular domain of the T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) using Trt-K10 solubilizing tags,
Bioorganic & Medicinal Chemistry, 99, 117585, 2023.

(要約): The T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an inhibitory immunoreceptor expressed on lymphocytes that serves as a promising target for cancer immunotherapy. In this study, facile synthetic protocols to produce the extracellular domain of TIGIT were investigated for applications of TIGIT in mirror-image screening. During the synthesis via sequential native chemical ligations, we encountered problems with significantly poor solubility of the ligated products. Introducing trityl-type solubilizing auxiliaries, which also functioned as temporary protecting groups for cysteine residues, facilitated a flexible order of ligations and efficient purification protocols. After refolding under appropriate conditions, the synthetic TIGIT showed a sufficient affinity toward its target ligand CD155.
(キーワード): T-Lymphocytes / Immunoglobulins / Receptors, Immunologic / Immunotherapy / Tyrosine
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.bmc.2023.117585
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38219557; ● Search Scopus @ Elsevier (PMID): 38219557; ● Search Scopus @ Elsevier (DOI): 10.1016/j.bmc.2023.117585

(DOI: 10.1016/j.bmc.2023.117585, PubMed: 38219557) Naoki Hashimoto, Junichi Taguchi, Norihito Arichi, Shinsuke Inuki and Hiroaki Ohno :
Gold(I)-Catalyzed Cascade Cyclization of Alkynyl Indoles for the Stereoselective Construction of the Quaternary Carbon Center of Akuammiline Alkaloids.,
The Journal of Organic Chemistry, 88, 24, 17306-17321, 2023.

(要約): A gold-catalyzed cyclization reaction of alkynyl-indoles has been developed for the stereoselective construction of the quaternary carbon center of fused indolines. This reaction efficiently produces fused indolines via diastereoselective 6-endo-dig cyclization controlled by a bulky TIPS group, followed by nucleophilic attack of the carboxy group on the resulting imine. The lactone moiety of the fused indoline can be reductively cleaved to produce a tricyclic indoline, which could be useful for the synthesis of akuammiline alkaloids.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.joc.3c02142
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38051730; ● Search Scopus @ Elsevier (PMID): 38051730; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.joc.3c02142

(DOI: 10.1021/acs.joc.3c02142, PubMed: 38051730) Toshiki Ochiai, Tensei Inukai, Manato Akiyama, Kairi Furui, Masahito Ohue, Nobuaki Matsumori, Shinsuke Inuki, Motonari Uesugi, Toshiaki Sunazuka, Kazuya Kikuchi, Hideaki Kakeya and Yasubumi Sakakibara :
Variational autoencoder-based chemical latent space for large molecular structures with 3D complexity.,
Communications Chemistry, 6, 1, 2023.

(要約): The structural diversity of chemical libraries, which are systematic collections of compounds that have potential to bind to biomolecules, can be represented by chemical latent space. A chemical latent space is a projection of a compound structure into a mathematical space based on several molecular features, and it can express structural diversity within a compound library in order to explore a broader chemical space and generate novel compound structures for drug candidates. In this study, we developed a deep-learning method, called NP-VAE (Natural Product-oriented Variational Autoencoder), based on variational autoencoder for managing hard-to-analyze datasets from DrugBank and large molecular structures such as natural compounds with chirality, an essential factor in the 3D complexity of compounds. NP-VAE was successful in constructing the chemical latent space from large-sized compounds that were unable to be handled in existing methods, achieving higher reconstruction accuracy, and demonstrating stable performance as a generative model across various indices. Furthermore, by exploring the acquired latent space, we succeeded in comprehensively analyzing a compound library containing natural compounds and generating novel compound structures with optimized functions.
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s42004-023-01054-6
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37973971; ● Search Scopus @ Elsevier (PMID): 37973971; ● Search Scopus @ Elsevier (DOI): 10.1038/s42004-023-01054-6

(DOI: 10.1038/s42004-023-01054-6, PubMed: 37973971) Keisuke Aoki, Asako Manabe, Hiroyuki Kimura, Yohei Katoh, Shinsuke Inuki, Hiroaki Ohno, Motohiro Nonaka and Shinya Oishi :
Mirror-Image Single-Domain Antibody for a Novel Nonimmunogenic Drug Scaffold.,
Bioconjugate Chemistry, 34, 11, 2055-2065, 2023.

(要約): Immunogenic responses by protein therapeutics often lead to reduced therapeutic effects and/or adverse effects via the generation of neutralizing antibodies and/or antidrug antibodies (ADA). Mirror-image proteins of the variable domain of the heavy chain of the heavy chain antibody (VHH) are potential novel protein therapeutics with high-affinity binding to target proteins and reduced immunogenicity because these mirror-image VHHs (d-VHHs) are less susceptible to proteolytic degradation in antigen-presenting cells (APCs). In this study, we investigated the preparation protocols of d-VHHs and their biological properties, including stereoselective target binding and immunogenicity. Initially, we established a facile synthetic process of two model VHHs [anti-GFP VHH and PMP12A2h1 (monomeric VHH of caplacizumab)] and their mirror-image proteins by three-step native chemical ligations (NCLs) from four peptide segments. The folded synthetic VHHs (l-anti-GFP VHH and l-PMP12A2h1) bound to the target proteins (EGFP and vWF-A1 domain, respectively), while their mirror-image proteins (d-anti-GFP VHH and d-PMP12A2h1) showed no binding to the native proteins. For biodistribution studies, l-VHH and d-VHH with single radioactive indium diethylenetriamine-pentaacid (¹¹¹In-DTPA) labeling at the C-terminus were designed and synthesized by the established protocol. The distribution profiles were essentially similar between l-VHH and d-VHH, in which the probes accumulated in the kidney within 15 min after intravenous administration in mice, because of the small molecular size of VHHs. Comparative assessment of the immunogenicity responses revealed that d-VHH-induced levels of ADA generation were significantly lower than those of native VHH, regardless of the peptide sequences and administration routes. The resulting scaffold investigated should be applicable in the design of d-VHHs with various C-terminal CDR3 sequences, which can be identified by screening using display technologies.
(キーワード): Mice / Animals / Single-Domain Antibodies / Pharmaceutical Preparations / Tissue Distribution / Immunoglobulin Heavy Chains / Antibodies, Neutralizing / Camelids, New World
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.bioconjchem.3c00372
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37883660; ● Search Scopus @ Elsevier (PMID): 37883660; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.bioconjchem.3c00372

(DOI: 10.1021/acs.bioconjchem.3c00372, PubMed: 37883660) Naoya Iwamoto, Yukino Sato, Asako Manabe, Shinsuke Inuki, Hiroaki Ohno, Motohiro Nonaka and Shinya Oishi :
Design and Synthesis of Monobody Variants with Low Immunogenicity.,
ACS Medicinal Chemistry Letters, 14, 11, 1596-1601, 2023.

(要約): Mirror-image proteins (d-proteins) are promising scaffolds for drug discovery because of their high proteolytic stability and low immunogenic properties. Facile and reproducible processes for the preparation of functional d-proteins are required for their application in therapeutic biologics. In this study, we designed and synthesized a novel monobody variant with two cysteine substitutions that facilitate the synthetic process via sequential native chemical ligations and improve protein stability by disulfide bond formation. The synthetic anti-GFP monobody in this model study exhibited good binding affinity to the target enhanced green fluorescent protein. In vivo administration of the synthetic anti-GFP monobody (l-monobody) to mice induced antidrug antibody (ADA) production, whereas no ADA production was observed following immunization with the mirror-image anti-GFP monobody (d-monobody). These results suggest that the synthetic d-monobody is a non-antibody protein scaffold with low immunogenic properties.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acsmedchemlett.3c00342
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37974939; ● Search Scopus @ Elsevier (PMID): 37974939; ● Search Scopus @ Elsevier (DOI): 10.1021/acsmedchemlett.3c00342

(DOI: 10.1021/acsmedchemlett.3c00342, PubMed: 37974939) Rikito Suzuki, R Daphne Mattos, Takashi Kitamura, Rina Tsujioka, Kazuya Kobayashi, Shinsuke Inuki, Hiroaki Ohno, E Jane Ishmael, L Kerry McPhail and Shinya Oishi :
Design of Synthetic Surrogates for the Macrolactone Linker Motif in Coibamide A.,
ACS Medicinal Chemistry Letters, 14, 10, 1344-1350, 2023.

(要約): A marine cyanobacterial cyclic depsipeptide, coibamide A (CbA), inhibits the mammalian protein secretory pathway by blocking the Sec61 translocon, which is an emerging drug target for cancer and other chronic diseases. In our previous structure-activity relationship study of CbA, the macrolactone ester linker was replaced with alkyl/alkenyl surrogates to provide synthetically accessible macrocyclic scaffolds. To optimize the cellular bioactivity profile of CbA analogues, novel lysine mimetics having β- and ε-methyl groups have now been designed and synthesized by a stereoselective route. A significant increase in cytotoxicity was observed upon introduction of these two methyl groups, corresponding to the d-MeAla α-methyl and MeThr β-methyl of CbA. All synthetic products retained the ability to inhibit secretion of a model Sec61 substrate. Tandem evaluation of secretory function inhibition in living cells and cytotoxicity was an effective strategy to assess the impact of structural modifications to the linker for ring closure.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acsmedchemlett.3c00232
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37849553; ● Search Scopus @ Elsevier (PMID): 37849553; ● Search Scopus @ Elsevier (DOI): 10.1021/acsmedchemlett.3c00232

(DOI: 10.1021/acsmedchemlett.3c00232, PubMed: 37849553) Takuro Matsuoka, Akira Hattori, Shinya Oishi, Mitsugu Araki, Biao Ma, Toshiki Fujii, Norihito Arichi, Yasushi Okuno, Hideaki Kakeya, Sho Yamasaki, Hiroaki Ohno and Shinsuke Inuki :
Establishment of an MR1 Presentation Reporter Screening System and Identification of Phenylpropanoid Derivatives as MR1 Ligands.,
Journal of Medicinal Chemistry, 66, 17, 12520-12535, 2023.

(要約): Mucosal-associated invariant T (MAIT) cells are innate-like T cells that are modulated by ligands presented on MHC class I-related proteins (MR1). These cells have attracted attention as potential drug targets because of their involvement in the initial response to infection and various disorders. Herein, we have established the MR1 presentation reporter assay system employing split-luciferase, which enables the efficient exploration of MR1 ligands. Using our screening system, we identified phenylpropanoid derivatives as MR1 ligands, including coniferyl aldehyde, which have an ability to inhibit the MR1-MAIT cell axis. Further, the structure-activity relationship study of coniferyl aldehyde analogs revealed the key structural features of ligands required for MR1 recognition. These results will contribute to identifying a broad range of endogenous and exogenous MR1 ligands and to developing novel MAIT cell modulators.
(キーワード): Ligands / Acrolein / Biological Assay / Structure-Activity Relationship
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.jmedchem.3c01122
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37638616; ● Search Scopus @ Elsevier (PMID): 37638616; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.jmedchem.3c01122

(DOI: 10.1021/acs.jmedchem.3c01122, PubMed: 37638616) Shiori Oka, Miyuki Watanabe, Emi Ito, Ami Takeyama, Takuro Matsuoka, Masatomo Takahashi, Yoshihiro Izumi, Norihito Arichi, Hiroaki Ohno, Sho Yamasaki and Shinsuke Inuki :
Archaeal Glycerolipids Are Recognized by C-Type Lectin Receptor Mincle.,
Journal of the American Chemical Society, 145, 33, 18538-18548, 2023.

(要約): Recently, various metabolites derived from host microbes have been reported to modulate the immune system, with potential involvement in health or diseases. Archaea, prokaryotic organisms, are present in the human body, but their connection with the host is largely unknown when compared to other microorganisms such as bacteria. This study focused on unique glycerolipids from symbiotic methanogenic archaea and evaluated their activities toward an innate immune receptor. The results revealed that archaeal lipids were recognized by the C-type lectin receptor Mincle and induced immune responses. A concurrent structure-activity relationship study identified the key structural features of archaeal lipids required for recognition by Mincle. Subsequent gene expression profiling suggested qualitative differences between the symbiotic archaeal lipid and the pathogenic bacteria-derived lipid. These findings have broad implications for understanding the function of symbiotic archaea in host health and diseases.
(キーワード): Humans / Archaea / Lectins, C-Type / Receptors, Immunologic / Structure-Activity Relationship / Lipids
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/jacs.3c05473
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37555666; ● Search Scopus @ Elsevier (PMID): 37555666; ● Search Scopus @ Elsevier (DOI): 10.1021/jacs.3c05473

(DOI: 10.1021/jacs.3c05473, PubMed: 37555666) Hitomi Tsuno, Jingfeng Shen, Hiroki Komatsu, Norihito Arichi, Shinsuke Inuki and Hiroaki Ohno :
Gold(I)-Catalyzed Bis-Cyclization of Allenynes for the Synthesis of Strained and Planar Polycyclic Compounds.,
Angewandte Chemie International Edition, 62, 35, 2023.

(要約): A gold-catalyzed cascade cyclization of naphthalene-tethered allenynes gave strained fused phenanthrene derivatives. The reaction proceeds through the nucleophilic reaction of an alkyne with the activated allene to generate a vinyl cation intermediate, followed by arylation with a tethered naphthalene ring to form the 4H-cyclopenta[def]phenanthrene (CPP) scaffold. When using aryl-substituted substrates on the alkyne terminus, the gold-catalyzed reaction produced dibenzofluorene derivatives along with the CPP derivatives. Selective formation of CPP and dibenzofluorene derivatives depending on the reaction conditions is also presented.
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/anie.202307532
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37401836; ● Search Scopus @ Elsevier (PMID): 37401836; ● Search Scopus @ Elsevier (DOI): 10.1002/anie.202307532

(DOI: 10.1002/anie.202307532, PubMed: 37401836) C. Luca Greiner, Norihito Arichi, Shinsuke Inuki and Hiroaki Ohno :
Alkoxymigration onto α-Imino Gold Carbenes for Constructing Propellane-Type Indolines,
Asian Journal of Organic Chemistry, 12, 7, e202300232, 2023.

(出版サイトへのリンク): ● Publication site (DOI): 10.1002/ajoc.202300232
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1050297372150652032; ● Summary page in Scopus @ Elsevier: 2-s2.0-85163783215

(DOI: 10.1002/ajoc.202300232, CiNii: 1050297372150652032, Elsevier: Scopus) Yuki Yoshida, Haruka Takeuchi, Kohei Nakagawa, Toshiki Fujii, Norihito Arichi, Shinya Oishi, Hiroaki Ohno and Shinsuke Inuki :
Construction of a Bicyclo[2.2.2]octene Skeleton via a Visible-Light-Mediated Radical Cascade Reaction of Amino Acid Derivatives with N-(2-Phenyl)benzoyl Groups,
Organic Letters, 25, 26, 4846-4851, 2023.

(要約): to enable the direct construction of bicyclo[2.2.2]octene structures. Isotopic labeling experiments suggested that intramolecular hydrogen atom transfer is involved in the cascade processes.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.orglett.3c01586
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37366566; ● Search Scopus @ Elsevier (PMID): 37366566; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.orglett.3c01586

(DOI: 10.1021/acs.orglett.3c01586, PubMed: 37366566) Atsuhito Tsuji, Takahiro Masuya, Norihito Arichi, Shinsuke Inuki, Masatoshi Murai, Hideto Miyoshi and Hiroaki Ohno :
Discovery of Bis-sulfonamides as Novel Inhibitors of Mitochondrial NADH-Quinone Oxidoreductase (Complex I).,
ACS Medicinal Chemistry Letters, 14, 2, 211-216, 2023.

(要約): Mitochondrial oxidative phosphorylation (OXPHOS) is an essential cellular metabolic process that generates ATP. The enzymes involved in OXPHOS are considered to be promising druggable targets. Through screening of an in-house synthetic library with bovine heart submitochondrial particles, we identified a unique symmetric bis-sulfonamide, KPYC01112 (1) as an inhibitor targeting NADH-quinone oxidoreductase (complex I). Structural modifications of KPYC01112 (1) led to the discovery of the more potent inhibitors 32 and 35 possessing long alkyl chains (IC₅₀ = 0.017 and 0.014 μM, respectively). A photoaffinity labeling experiment using a newly synthesized photoreactive bis-sulfonamide ([¹²⁵I]-43) revealed that it binds to the 49-kDa, PSST, and ND1 subunits which make up the quinone-accessing cavity of complex I.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acsmedchemlett.2c00504
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 36793437; ● Search Scopus @ Elsevier (PMID): 36793437; ● Search Scopus @ Elsevier (DOI): 10.1021/acsmedchemlett.2c00504

(DOI: 10.1021/acsmedchemlett.2c00504, PubMed: 36793437) Junki Miyamoto, Hidenori Shimizu, Keiko Hisa, Chiaki Matsuzaki, Shinsuke Inuki, Yuna Ando, Akari Nishida, Ayano Izumi, Mayu Yamano, Chihiro Ushiroda, Junichiro Irie, Takane Katayama, Hiroaki Ohno, Hiroshi Itoh, Kenji Yamamoto and Ikuo Kimura :
Host metabolic benefits of prebiotic exopolysaccharides produced by Leuconostoc mesenteroides.,
Gut Microbes, 15, 1, 2161271, 2023.

(要約): Fermented foods demonstrate remarkable health benefits owing to probiotic bacteria or microproducts produced via bacterial fermentation. Fermented foods are produced by the fermentative action of several lactic acid bacteria, including Leuconostoc mesenteroides; however, the exact mechanism of action of these foods remains unclear. Here, we observed that prebiotics associated with L. mesenteroides-produced exopolysaccharides (EPS) demonstrate substantial host metabolic benefits. L. mesenteroides-produced EPS is an indigestible α-glucan, and intake of the purified form of EPS improved glucose metabolism and energy homeostasis through EPS-derived gut microbial short-chain fatty acids, and changed gut microbial composition. Our findings reveal an important mechanism that accounts for the effects of diet, prebiotics, and probiotics on energy homeostasis and suggests an approach for preventing lifestyle-related diseases by targeting bacterial EPS.
(キーワード): Prebiotics / Leuconostoc mesenteroides / Gastrointestinal Microbiome / Probiotics / Lactobacillales / Bacteria / Fermentation
(出版サイトへのリンク): ● Publication site (DOI): 10.1080/19490976.2022.2161271
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 36604628; ● Search Scopus @ Elsevier (PMID): 36604628; ● Search Scopus @ Elsevier (DOI): 10.1080/19490976.2022.2161271

(DOI: 10.1080/19490976.2022.2161271, PubMed: 36604628) C Luca Greiner, Norihito Arichi, Shinsuke Inuki and Hiroaki Ohno :
Gold(I)-Catalyzed Benzylic C(sp3 )-H Functionalizations: Divergent Synthesis of Indole[a]- and [b]-Fused Polycycles.,
Angewandte Chemie International Edition, 62, 3, e202213653, 2022.

(要約): Phenyl azides substituted by an (alkylphenyl)ethynyl group facilitate benzylic sp³ (C-H) functionalization in the presence of a JohnPhosAu catalyst, resulting in indole-fused tetra- and pentacycles via divergent N- or C-cyclization. The chemoselectivity is influenced depending on the counter-anion, the electron density of the α-imino gold(I) carbene, and the alkyl groups stabilizing the benzylic carbocation originating from a 1,5-hydride shift. An isotopic labeling experiment demonstrates the involvement of an indolylgold(I) species resulting from a tautomerization that is much faster than the deauration. The formation of a benzylic sp³ (C-H) functionalization leading to an indole-fused seven-membered ring is also demonstrated.
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/anie.202213653
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 36255174; ● Search Scopus @ Elsevier (PMID): 36255174; ● Search Scopus @ Elsevier (DOI): 10.1002/anie.202213653

(DOI: 10.1002/anie.202213653, PubMed: 36255174) Aki Yamamoto, Yuki Takahashi, Shinsuke Inuki, Shumpei Nakagawa, Kodai Nakao, Hiroaki Ohno, Masao Doi and Yoshinobu Takakura :
The identification of novel small extracellular vesicle (sEV) production modulators using luciferase-based sEV quantification method.,
Journal of Extracellular Biology, 1, 9, 2022.

(要約): Small extracellular vesicles (sEVs) are nano-sized vesicles secreted from various cells that contain bioactive metabolites and function as key regulators for intercellular communication. sEVs modulate diverse biological and pathological processes in the body, and the amount of circulating sEVs has been reported to correlate with certain disease progression. Therefore, the identification of small molecular compounds that can control sEV production may become a novel therapeutic strategy. In this study, a rapid, highly sensitive sEV quantification method utilizing fusion proteins consisting of Gaussia luciferase (gLuc) reporter protein and sEV markers (CD63 and CD82) was developed. A total of 480 compounds were screened to identify potent inducers and inhibitors of gLuc activity. Two novel compounds, KPYC08425 and KPYC12163, showed significant and dose-dependent changes in gLuc activity with minimal cytotoxicity based on the LDH assay. The efficacy of these two compounds was further evaluated by protein quantification of the isolated sEVs. Further evaluation of KPYC12163 suggested that the autolysosomal pathway may be involved in its inhibitory effect on sEV production.
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/jex2.62
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38938770; ● Search Scopus @ Elsevier (PMID): 38938770; ● Search Scopus @ Elsevier (DOI): 10.1002/jex2.62

(DOI: 10.1002/jex2.62, PubMed: 38938770) Moeri Yagi, Simon Miller, Yoshiko Nagai, Shinsuke Inuki, Ayato Sato and Tsuyoshi Hirota :
A methylbenzimidazole derivative regulates mammalian circadian rhythms by targeting Cryptochrome proteins.,
F1000Research, 11, 1016, 2022.

(要約): Background: Impairment of the circadian clock has been associated with numerous diseases, including sleep disorders and metabolic disease. Although small molecules that modulate clock function may form the basis of drug discovery of clock-related diseases, only a few compounds that selectively target core clock proteins have been identified. Three scaffolds were previously discovered as small-molecule activators of the clock protein Cryptochrome (CRY), and they have been providing powerful tools to understand and control the circadian clock system. Identifying new scaffolds will expand the possibilities of drug discovery. Methods: A methylbenzimidazole derivative TH401 identified from cell-based circadian screens was characterized. Effects of TH401 on circadian rhythms were evaluated in cellular assays. Functional assays and X-ray crystallography were used to elucidate the effects of the compound on CRY1 and CRY2 isoforms. Results: TH401 lengthened the period of circadian rhythms and stabilized both CRY1 and CRY2. The compound repressed Per2 reporter activity, which was reduced by Cry1 or Cry2 knockout and abolished by Cry1/Cry2 double knockout, indicating the dependence on CRY isoforms. Thermal shift assays showed slightly higher interaction of TH401 with CRY2 over CRY1. The crystal structure of CRY1 in complex with TH401 revealed a conformational change of the gatekeeper W399, which is involved in isoform-selectivity determination. Conclusions: The present study identified a new small molecule TH401 that targets both CRY isoforms. This compound has expanded the chemical diversity of CRY activators, and will ultimately aid in the development of therapeutics against circadian clock-related disorders.
(キーワード): Animals / Cryptochromes / Circadian Rhythm / Circadian Clocks / Mammals / Protein Isoforms
(出版サイトへのリンク): ● Publication site (DOI): 10.12688/f1000research.124658.2
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 36226040; ● Search Scopus @ Elsevier (PMID): 36226040; ● Search Scopus @ Elsevier (DOI): 10.12688/f1000research.124658.2

(DOI: 10.12688/f1000research.124658.2, PubMed: 36226040) Shinsuke Inuki, Hitomi Tabuchi, Chiaki Matsuzaki, Yasunori Yonejima, Keiko Hisa, Ikuo Kimura, Kenji Yamamoto and Hiroaki Ohno :
Chemical Synthesis and Evaluation of Exopolysaccharide Fragments Produced by Leuconostoc mesenteroides Strain NTM048.,
Chemical & Pharmaceutical Bulletin, 70, 2, 155-161, 2022.

(要約): Exopolysaccharides (EPSs) occur widely in natural products made by bacteria, fungi and algae. Some EPSs have intriguing biological properties such as anticancer and immunomodulatory activities. Our group has recently found that EPSs generated from Leuconostoc mesenteroides ssp. mesenteroides strain NTM048 (NTM048 EPS) enhanced a production of mucosal immunoglobulin A (IgA) of mouse. Herein, we described the synthesis and evaluation of the tetrasaccharide fragments of NTM048 EPS to obtain information about the molecular mechanism responsible for the IgA-inducing activity.
(キーワード): Biological Products / Carbohydrate Conformation / Leuconostoc / Polysaccharides
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/cpb.c21-00919
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 35110436; ● Search Scopus @ Elsevier (PMID): 35110436; ● Search Scopus @ Elsevier (DOI): 10.1248/cpb.c21-00919

(DOI: 10.1248/cpb.c21-00919, PubMed: 35110436) Takashi Kitamura, Rikito Suzuki, Shinsuke Inuki, Hiroaki Ohno, L Kerry McPhail and Shinya Oishi :
Design of Coibamide A Mimetics with Improved Cellular Bioactivity.,
ACS Medicinal Chemistry Letters, 13, 1, 105-110, 2021.

(要約): Coibamide A, a cyclic depsipeptide isolated from a Panamanian marine cyanobacterium, shows potent cytotoxic activity via the inhibition of the Sec61 translocon. We designed a coibamide A mimetic in which the ester linkage between MeThr and d-MeAla in coibamide A was replaced with an alkyl linker to provide a stable macrocyclic scaffold possessing a MeLys(Me) residue. Taking advantage of a facile solid-phase synthetic approach, an structure-activity relationship (SAR) study of the newly designed macrocyclic structure was performed, with a focus on altering the pattern of N-methyl substitution and amino acid configurations. Overall, the simplified macrocyclic scaffold with an alkyl linker resulted in a significantly reduced cytotoxicity. Instead, more potent coibamide A derivatives with a β-(4-biphenylyl)alanine (Bph) group were identified after the optimization of the Tyr(Me) position in the original macrocyclic scaffold of coibamide A based on the characteristic apratoxin A substructures. The similar SAR between coibamide A and apratoxin A suggests that the binding site of the Tyr(Me) side chain at the luminal end of Sec61α may be shared.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acsmedchemlett.1c00591
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 35059129; ● Search Scopus @ Elsevier (PMID): 35059129; ● Search Scopus @ Elsevier (DOI): 10.1021/acsmedchemlett.1c00591

(DOI: 10.1021/acsmedchemlett.1c00591, PubMed: 35059129) Hiroki Komatsu, Takaya Ikeuchi, Hitomi Tsuno, Norihito Arichi, Kosuke Yasui, Shinya Oishi, Shinsuke Inuki, Aiko Fukazawa and Hiroaki Ohno :
Construction of Tricyclic Nitrogen Heterocycles by a Gold(I)-Catalyzed Cascade Cyclization of Allenynes and Application to Polycyclic π-Electron Systems.,
Angewandte Chemie International Edition, 60, 52, 27019-27025, 2021.

(要約): A novel approach to the direct construction of tricyclic nitrogen heterocycles based on gold-catalyzed cascade cyclization of aminoallenynes is described. The expected biscyclization reaction of hydroxyisobutyryl-protected aminoallenynes was efficiently promoted by a catalytic amount of BrettPhosAuNTf₂ in the presence of iPrOH to produce 1,2-dihydrobenzo[cd]indole derivatives in good yields. When the reaction was combined with Friedel-Crafts acylation or palladium-catalyzed N-arylation, the resulting tricyclic products were efficiently converted into nitrogen-containing polycyclic aromatic compounds (N-PACs) with highly conjugated ϖ-electron systems. A newly obtained hexacyclic indolium salt showed characteristic concentration-dependent absorption and emission properties.
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/anie.202111267
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34590766; ● Search Scopus @ Elsevier (PMID): 34590766; ● Search Scopus @ Elsevier (DOI): 10.1002/anie.202111267

(DOI: 10.1002/anie.202111267, PubMed: 34590766) C Luca Greiner, Shinsuke Inuki, Norihito Arichi, Shinya Oishi, Rikito Suzuki, Tomohiro Iwai, Masaya Sawamura, K A Stephen Hashmi and Hiroaki Ohno :
Access to Indole-Fused Benzannulated Medium-Sized Rings through a Gold(I)-Catalyzed Cascade Cyclization of Azido-Alkynes.,
Chemistry - A European Journal, 27, 51, 12992-12997, 2021.

(要約): Because benzannulated and indole-fused medium-sized rings are found in many bioactive compounds, combining these fragments might lead to unexplored areas of biologically relevant and uncovered chemical space. Herein is shown that α-imino gold carbene chemistry can play an important role in solving the difficulty in the formation of medium-sized rings. Namely, phenylene-tethered azido-alkynes undergo arylative cyclization through the formation of a gold carbene intermediate to afford benzannulated indole-fused medium-sized tetracycles. The reactions allow a range of different aryl substitution patterns and efficient access to these otherwise difficult-to-obtain medium-sized rings. This study also demonstrates the feasibility of the semihollow-shaped C-dtbm ligand for the construction of a nine-membered ring.
(キーワード): Alkynes / Catalysis / Cyclization / Gold / Indoles
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/chem.202101824
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34110644; ● Search Scopus @ Elsevier (PMID): 34110644; ● Search Scopus @ Elsevier (DOI): 10.1002/chem.202101824

(DOI: 10.1002/chem.202101824, PubMed: 34110644) Ayuta Yamaguchi, Shinsuke Inuki, Katsumi Ohta, Shinya Oishi, Akira Asai and Hiroaki Ohno :
IDENTIFICATION OF A NOVEL INDOLEAMINE 2,3-DIOXYGENASE INHIBITOR BEARING AN EIGHT-MEMBERED RING FUSED INDOLE SCAFFOLD AND ITS STRUCTURE-ACTIVITY RELATIONSHIP,
Heterocycles, 103, 331-347, 2021.

(出版サイトへのリンク): ● Publication site (DOI): 10.3987/COM-20-S(K)17
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1522543656062849664; ● Summary page in Scopus @ Elsevier: 2-s2.0-85108350257

(DOI: 10.3987/COM-20-S(K)17, CiNii: 1522543656062849664, Elsevier: Scopus) Takuro Matsuoka, Chihiro Motozono, Akira Hattori, Hideaki Kakeya, Sho Yamasaki, Shinya Oishi, Hiroaki Ohno and Shinsuke Inuki :
The effects of 5-OP-RU stereochemistry on its stability and MAIT-MR1 axis.,
ChemBioChem, 22, 4, 672-678, 2020.

(要約): Mucosal-associated invariant T (MAIT) cells are an abundant subset of innate-like T lymphocytes. MAIT cells are activated by microbial riboflavin-derived antigens, such as 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), when presented by the major histocompatibility complex (MHC) class I-related protein (MR1). We have synthesized all stereoisomers of 5-OP-RU to investigate the effects of its stereochemistry on the MR1-dependent MAIT cell activation and MR1 upregulation. The analysis of MAIT cell activation by these 5-OP-RU isomers revealed that the stereocenters at the 2'- and 3'-OH groups in the ribityl tail are crucial for the recognition of MAIT-TCR, whereas that of 4'-OH group does not significantly affect the regulation of MAIT cell activity. Furthermore, kinetic analysis of complex formation between the ligands and MR1 suggested that 5-OP-RU forms a covalent bond to MR1 in cells within 1 hour. These findings provide guidelines for designing ligands that regulate MAIT cell functions.
(キーワード): Histocompatibility Antigens Class I / Humans / Kinetics / Ligands / Lymphocyte Activation / Minor Histocompatibility Antigens / Mucosal-Associated Invariant T Cells / Ribitol / Stereoisomerism / Structure-Activity Relationship / Uracil
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/cbic.202000466
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33034934; ● Search Scopus @ Elsevier (PMID): 33034934; ● Search Scopus @ Elsevier (DOI): 10.1002/cbic.202000466

(DOI: 10.1002/cbic.202000466, PubMed: 33034934) Shinsuke Inuki, Natsumi Hirata, Emi Kashiwabara, Junichiro Kishi, Toshihiko Aiba, Toshiaki Teratani, Wataru Nakamura, Yoshimi Kojima, Toru Maruyama, Takanori Kanai and Yukari Fujimoto :
Polar functional group-containing glycolipid CD1d ligands modulate cytokine-biasing responses and prevent experimental colitis.,
Scientific Reports, 10, 1, 2020.

(要約): The MHC class I-like molecule CD1d is a nonpolymorphic antigen-presenting glycoprotein, and its ligands include glycolipids, such as α-GalCer. The complexes between CD1d and ligands activate natural killer T cells by T cell receptor recognition, leading to the secretion of various cytokines (IFN-γ, IL-4, IL-17A, etc.). Herein, we report structure-activity relationship studies of α-GalCer derivatives containing various functional groups in their lipid acyl chains. Several derivatives have been identified as potent CD1d ligands displaying higher cytokine induction levels and/or unique cytokine polarization. The studies also indicated that flexibility of the lipid moiety can affect the binding affinity, the total cytokine production level and/or cytokine biasing. Based on our immunological evaluation and investigation of physicochemical properties, we chose bisamide- and Bz amide-containing derivatives 2 and 3, and evaluated their in vivo efficacy in a DSS-induced model of ulcerative colitis. The derivative 3 that exhibits Th2- and Th17-biasing responses, demonstrated significant protective effects against intestinal inflammation in the DSS-induced model, after a single intraperitoneal injection.
(キーワード): Animals / Antigens, CD1d / Colitis, Ulcerative / Cytokines / Disease Models, Animal / Drug Design / Galactosylceramides / Glycolipids / Ligands / Mice / Solubility / Structure-Activity Relationship / Water
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s41598-020-72280-4
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32978421; ● Search Scopus @ Elsevier (PMID): 32978421; ● Search Scopus @ Elsevier (DOI): 10.1038/s41598-020-72280-4

(DOI: 10.1038/s41598-020-72280-4, PubMed: 32978421) Haruka Takeuchi, Shinsuke Inuki, Kohei Nakagawa, Takaaki Kawabe, Atsuhiko Ichimura, Shinya Oishi and Hiroaki Ohno :
Total Synthesis of Zephycarinatines via Photocatalytic Reductive Radical ipso-Cyclization.,
Angewandte Chemie International Edition, 59, 47, 21210-21215, 2020.

(要約): We report herein a nonbiomimetic strategy for the total synthesis of the plicamine-type alkaloids zephycarinatines C and D. The key feature of the synthesis is a stereoselective reductive radical ipso-cyclization using visible-light-mediated photoredox catalysis. This cyclization enabled the construction of a 6,6-spirocyclic core structure through the addition of a carbon-centered radical onto the aromatic ring. Biological evaluation of zephycarinatines and their derivatives revealed that the synthetic derivative with a keto group displays moderate inhibitory activity against LPS-induced NO production. This approach could offer future opportunities to expand the chemical diversity of plicamine-type alkaloids as well as providing useful intermediates for their syntheses.
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/anie.202009399
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32770565; ● Search Scopus @ Elsevier (PMID): 32770565; ● Search Scopus @ Elsevier (DOI): 10.1002/anie.202009399

(DOI: 10.1002/anie.202009399, PubMed: 32770565) Junpei Matsuoka, Shinsuke Inuki, Yuka Matsuda, Yoichi Miyamoto, Mayumi Otani, Masahiro Oka, Shinya Oishi and Hiroaki Ohno :
Total Synthesis of Dictyodendrins A-F by the Gold-Catalyzed Cascade Cyclization of Conjugated Diyne with Pyrrole.,
Chemistry - A European Journal, 26, 49, 2020.

(要約): Invited for the cover of this issue is Hiroaki Ohno and co-workers at Kyoto University and National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN). The image depicts gold catalysis which promotes the domino reaction to push the switch for the diversity-directed total synthesis. Read the full text of the article at 10.1002/chem.202001950.
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/chem.202002563
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32776584; ● Search Scopus @ Elsevier (PMID): 32776584; ● Search Scopus @ Elsevier (DOI): 10.1002/chem.202002563

(DOI: 10.1002/chem.202002563, PubMed: 32776584) Junpei Matsuoka, Shinsuke Inuki, Yuka Matsuda, Yoichi Miyamoto, Mayumi Otani, Masahiro Oka, Shinya Oishi and Hiroaki Ohno :
Total Synthesis of Dictyodendrins A-F by the Gold-Catalyzed Cascade Cyclization of Conjugated Diyne with Pyrrole.,
Chemistry - A European Journal, 26, 49, 11150-11157, 2020.

(要約): The total synthesis of dictyodendrins A-F was achieved by using the gold(I)-catalyzed annulation of a conjugated diyne with N-Boc-pyrrole for direct construction of the pyrrolo[2,3-c]carbazole scaffold. Late-stage functionalization of the resulting pyrrolo[2,3-c]carbazole to introduce various substituents provided divergent access to dictyodendrins. Some dictyodendrin analogues exhibited inhibitory activities toward CDK2/CycA2 and GSK3.
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/chem.202001950
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32364649; ● Search Scopus @ Elsevier (PMID): 32364649; ● Search Scopus @ Elsevier (DOI): 10.1002/chem.202001950

(DOI: 10.1002/chem.202001950, PubMed: 32364649) Takuro Matsuoka, Shinsuke Inuki, Takashi Miyagawa, Shinya Oishi and Hiroaki Ohno :
Total Synthesis of (+)-Polyoxamic Acid via Visible-Light-Mediated Photocatalytic β-Scission and 1,5-Hydrogen Atom Transfer of Glucose Derivative.,
The Journal of Organic Chemistry, 85, 12, 8271-8278, 2020.

(要約): A total synthesis of polyoxamic acid has been achieved. The key feature of the synthetic route is a visible-light-mediated β-scission and carbon-to-carbon 1,5-hydrogen atom transfer (1,5-HAT) to provide the functionalized alditol under mild conditions. This type of carbon-to-carbon 1,5-HAT initiated by C(sp³)-centered radicals has been scarcely reported. Furthermore, the reaction was adapted for flow chemistry, facilitating the total synthesis of polyoxamic acid.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.joc.0c00910
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32425047; ● Search Scopus @ Elsevier (PMID): 32425047; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.joc.0c00910

(DOI: 10.1021/acs.joc.0c00910, PubMed: 32425047) Junichiro Kishi, Shinsuke Inuki, Emi Kashiwabara, Takehiro Suzuki, Naoshi Dohmae and Yukari Fujimoto :
Design and Discovery of Covalent α-GalCer Derivatives as Potent CD1d Ligands.,
ACS Chemical Biology, 15, 2, 353-359, 2020.

(要約): CD1d is a nonpolymorphic antigen-presenting protein responsible for the regulation of natural killer T (NKT) cell activation. α-Galactosyl ceramide (α-GalCer, KRN7000) is the representative CD1d ligand that can bind to the CD1d protein. The resulting complex is recognized by the T cell receptors of the NKT cell, inducing various immune responses. Previous structure-activity relationship studies of α-GalCer have revealed that the ability of NKT cells to induce cytokines depends on the ligand structure, and in particular, ligands that form more stable complexes with CD1d display potent activity. We focused on the Cys residue of the large hydrophobic pockets of CD1d (A' pocket) and developed α-GalCer derivatives containing groups that can form covalent bonds. The assay results revealed that these ligands displayed higher levels of cytokine production and Th2 cell-type cytokine polarization response. Furthermore, the LC-MS/MS analysis indicated that the chloroacetylamide-containing ligand was covalently bound to Cys12 of CD1d, which suggests that the enhanced activities result from the formation of a stable CD1d-ligand complex. To our knowledge, this is the first ligand that allows covalent bond formation to CD1d under physiological conditions.
(キーワード): Acetamides / Acrylamides / Animals / Antigens, CD1d / Cysteine / Drug Design / Drug Discovery / Galactosylceramides / Interferon-gamma / Interleukin-4 / Ligands / Lymphocyte Activation / Mice / Molecular Docking Simulation / Natural Killer T-Cells / Protein Binding
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acschembio.9b00700
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31939653; ● Search Scopus @ Elsevier (PMID): 31939653; ● Search Scopus @ Elsevier (DOI): 10.1021/acschembio.9b00700

(DOI: 10.1021/acschembio.9b00700, PubMed: 31939653) Ayuta Yamaguchi, Shinsuke Inuki, Yusuke Tokimizu, Shinya Oishi and Hiroaki Ohno :
Gold(I)-Catalyzed Cascade Cyclization of Anilines with Diynes: Controllable Formation of Eight-Membered Ring-Fused Indoles and Propellane-Type Indolines.,
The Journal of Organic Chemistry, 85, 4, 2543-2559, 2020.

(要約): Heterocycle-fused indoles or indolines are distributed widely in a variety of natural products, bioactive agents, and pharmaceuticals. Herein, we describe the development of gold-catalyzed cascade reactions of anilines with diynes to form eight-membered ring-fused indoles and propellane-type indolines, both of which proceed through an intramolecular 5-endo-dig hydroamination followed by an 8-endo-dig cycloisomerization. Controllable formation of eight-membered ring-fused indoles and propellane-type indolines was achieved through selection of the ligands and/or solvents. Protic solvents such as alcohols or IPr ligand favored the formation of eight-membered ring-fused indoles, whereas the use of Buchwald's type ligands and/or nonpolar solvents gave propellane-type indoline predominantly. This reaction provides rapid access to two types of fused nitrogen heterocycles from simple aniline derivatives.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.joc.9b03256
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31913037; ● Search Scopus @ Elsevier (PMID): 31913037; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.joc.9b03256

(DOI: 10.1021/acs.joc.9b03256, PubMed: 31913037) Shinsuke Inuki :
Elucidation of Biological Mechanisms Using Synthetic Natural Products and Their Derivatives,
Journal of the Pharmaceutical Society of Japan, 140, 4, 455-470, 2020.

(要約): Natural products are useful sources in the search for biochemical probes and drug leads because of their unique biological activities. However, synthetic studies or functional analyses of polycyclic complex natural products or conjugated lipids (e.g., glycolipids) are often hampered because of their synthesis and handling are challenging. On the basis of rational designs, synthetic studies, and chemical modifications, natural products need to be optimized to more potent compounds with improved activities, selectivities and/or physical properties. We have been synthesizing natural products and their derivatives for the elucidation of their biological mechanisms and discovery of drug leads. This review describes three topics for developing functional compounds derived from natural products for prospective involvement in pharmaceutical research: 1) direct construction of the ergot alkaloid scaffold by palladium catalyzed domino cyclization of amino allenes; 2) identification of novel sphingosine kinase inhibitors through a structure-activity relationship study of jaspine B; and 3) design, synthesis and biological evaluation of novel CD1d glycolipid ligands containing modified lipid moieties.
(キーワード): Alkadienes / Antigens, CD1d / Biological Products / Catalysis / Chemical Phenomena / Cyclization / Drug Development / Ergot Alkaloids / Glycolipids / Ligands / Palladium / Phosphotransferases (Alcohol Group Acceptor) / Structure-Activity Relationship
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/yakushi.19-00206
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32238625; ● Search Scopus @ Elsevier (PMID): 32238625; ● Search Scopus @ Elsevier (DOI): 10.1248/yakushi.19-00206

(DOI: 10.1248/yakushi.19-00206, PubMed: 32238625) Makoto Tokunaga, Yoichi Miyamoto, Tatsuya Suzuki, Mayumi Otani, Shinsuke Inuki, Tsuyoshi Esaki, Chioko Nagao, Kenji Mizuguchi, Hiroaki Ohno, Yoshihiro Yoneda, Toru Okamoto, Masahiro Oka and Yoshiharu Matsuura :
Novel anti-flavivirus drugs targeting the nucleolar distribution of core protein.,
Virology, 541, 41-51, 2019.

(要約): The risk of infectious diseases caused by Flavivirus is increasing globally. Here, we developed a novel high-throughput screening (HTS) system to evaluate the inhibitory effects of compounds targeting the nuclear localization of the flavivirus core protein. We screened 4000 compounds based on their ability to inhibit the nuclear localization of the core protein, and identified over 20 compounds including inhibitors for cyclin dependent kinase and glycogen synthase kinase. The efficacy of the identified compounds to suppress viral growth was validated in a cell-based infection system. Remarkably, the nucleolus morphology was affected by the treatment with the compounds, suggesting that the nucleolus function is critical for viral propagation. The present HTS system provides a useful strategy for the identification of antivirals against flavivirus by targeting the nucleolar localization of the core protein.
(キーワード): Active Transport, Cell Nucleus / Antiviral Agents / Cell Nucleolus / Cyclin-Dependent Kinases / Flavivirus / HEK293 Cells / High-Throughput Screening Assays / Humans / Viral Core Proteins
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.virol.2019.11.015
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31826845; ● Search Scopus @ Elsevier (PMID): 31826845; ● Search Scopus @ Elsevier (DOI): 10.1016/j.virol.2019.11.015

(DOI: 10.1016/j.virol.2019.11.015, PubMed: 31826845) Shinsuke Inuki, Keisuke Sato, Naoto Zui, Ryosuke Yamaguchi, Takanori Matsumaru and Yukari Fujimoto :
Synthetic Studies on FNC-RED and Its Analogues Containing an All syn-Cyclopentanetetrol Moiety,
The Journal of Organic Chemistry, 84, 19, 12680-12685, 2019.

(要約): FNC-RED exhibits innate immune receptor Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD2) stimulatory activity. We have developed a divergent synthetic route to FNC-RED derivatives containing various alkyl side chains. Key features of the synthetic study include stepwise palladium catalyzed cross-coupling reactions and the construction of an all syn-cyclopentanetetrol moiety.
(キーワード): Catalysis / Cyclopentanes / Molecular Conformation / Organic Chemicals / Palladium / Pyridones
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.joc.9b02101
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31507185; ● Search Scopus @ Elsevier (PMID): 31507185; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.joc.9b02101

(DOI: 10.1021/acs.joc.9b02101, PubMed: 31507185) Takashi Miyagawa, Shinsuke Inuki, Shinya Oishi and Hiroaki Ohno :
Construction of Quaternary Carbon Stereocenter of α-Tertiary Amine through Remote C-H Functionalization of Tris Derivatives: Enantioselective Total Synthesis of Myriocin.,
Organic Letters, 21, 14, 5485-5490, 2019.

(要約): We describe the development of a strategy for the construction of the quaternary carbon stereocenter of α-tertiary amines. This strategy highlights a site-selective C-H functionalization involving an alkoxy-radical-triggered 1,5-hydrogen transfer (1,5-HAT) reaction of a conformationally fixed spiro-compound derived from trishydroxymethylaminomethane (Tris). The utilization of this strategy enabled an enantioselective total synthesis of myriocin, a naturally occurring sphingosine analog that displays potent immunosuppressive activity.
(キーワード): Amines / Carbon / Catalysis / Chemistry Techniques, Synthetic / Fatty Acids, Monounsaturated / Stereoisomerism / Tromethamine
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.orglett.9b01778
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31287325; ● Search Scopus @ Elsevier (PMID): 31287325; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.orglett.9b01778

(DOI: 10.1021/acs.orglett.9b01778, PubMed: 31287325) Junpei Matsuoka, Hiroshi Kumagai, Shinsuke Inuki, Shinya Oishi and Hiroaki Ohno :
Construction of the Pyrrolo[2,3-d]carbazole Core of Spiroindoline Alkaloids by Gold-Catalyzed Cascade Cyclization of Ynamide.,
The Journal of Organic Chemistry, 84, 14, 9358-9363, 2019.

(要約): We achieved direct construction of the common pyrrolo[2,3-d]carbazole core of aspidosperma and malagasy alkaloids by a gold-catalyzed cascade cyclization of ynamide. This reaction involves intramolecular cyclization from indole to ynamide followed by trapping of the resulting iminium intermediate. Through the use of chiral gold complexes, an enantiomerically enriched pyrrolo[2,3-d]carbazole was obtained in up to 74% ee. This methodology was successfully applied to the asymmetric formal synthesis of vindorosine.
(キーワード): Alkaloids / Catalysis / Gold / Models, Molecular / Molecular Structure / Spiro Compounds / Vinblastine
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.joc.9b01149
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31244165; ● Search Scopus @ Elsevier (PMID): 31244165; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.joc.9b01149

(DOI: 10.1021/acs.joc.9b01149, PubMed: 31244165) Takaya Ikeuchi, Shinsuke Inuki, Shinya Oishi and Hiroaki Ohno :
Gold(I)-Catalyzed Cascade Cyclization Reactions of Allenynes for the Synthesis of Fused Cyclopropanes and Acenaphthenes.,
Angewandte Chemie International Edition, 58, 23, 7792-7796, 2019.

(要約): A gold-catalyzed reaction of phenylene-tethered allenynes with benzofurans gave 1-(naphth-1-yl)cyclopropa[b]benzofuran derivatives, whereas the reaction of 1-allenyl-2-ethynyl-3-methylbenzene derivatives in the absence of benzofurans gave acenaphthenes in good yields. These results can be rationalized by nucleophilic attack of the alkyne moiety on an activated allene to form a vinyl cation intermediate.
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/anie.201903384
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30985049; ● Search Scopus @ Elsevier (PMID): 30985049; ● Search Scopus @ Elsevier (DOI): 10.1002/anie.201903384

(DOI: 10.1002/anie.201903384, PubMed: 30985049) Koki Yamamoto, Shinsuke Inuki, Hiroaki Ohno and Shinya Oishi :
Scaffold hopping of fused piperidine-type NK3 receptor antagonists to reduce environmental impact.,
Bioorganic & Medicinal Chemistry, 27, 10, 2019-2026, 2019.

(要約): Neurokinin-3 receptor (NK3R) plays a pivotal role in the release of gonadotropin-releasing hormone in the hypothalamus-pituitary-gonadal (HPG) axis. To develop novel NK3R antagonists with less environmental toxicity, a series of heterocyclic scaffolds for the triazolopiperazine substructure in an NK3R antagonist fezolinetant were designed and synthesized. An isoxazolo[3,4-c]piperidine derivative exhibited moderate NK3R antagonistic activity and favorable properties that were decomposable under environmental conditions.
(キーワード): Crystallography, X-Ray / Heterocyclic Compounds, 2-Ring / Inhibitory Concentration 50 / Molecular Conformation / Photolysis / Piperidines / Receptors, Neurokinin-3 / Structure-Activity Relationship / Sunlight / Thiadiazoles
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.bmc.2019.03.059
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30975505; ● Search Scopus @ Elsevier (PMID): 30975505; ● Search Scopus @ Elsevier (DOI): 10.1016/j.bmc.2019.03.059

(DOI: 10.1016/j.bmc.2019.03.059, PubMed: 30975505) Junichiro Kishi, Shinsuke Inuki, Natsumi Hirata, Emi Kashiwabara, Daisuke Yoshidome, Osamu Ichihara and Yukari Fujimoto :
Structure-activity relationship studies of Bz amide-containing α-GalCer derivatives as natural killer T cell modulators.,
Bioorganic & Medicinal Chemistry Letters, 29, 8, 970-973, 2019.

(要約): CD1d is a non-polymorphic antigen-presenting glycoprotein that recognizes glycolipids as ligands. Ligands bind to the hydrophobic grooves of CD1d, and the resulting ligand-CD1d complexes activate natural killer T (NKT) cells by means of T cell receptor recognition, leading to the secretion of various cytokines. However, details of the ligand recognition mechanism of a large hydrophobic ligand binding pocket and the relationship between cytokine induction and ligand structure are unclear. We report the synthesis of α-GalCer derivatives containing a Bz amide group having various substituting groups in the ceramide moiety, and the analysis of the structure-activity relationships. The assays reveal that the Bz amide-containing CD1d ligands function as NKT cell modulators displaying Th2 cytokine biasing responses. Furthermore, molecular dynamics simulation studies suggest that the phenyl groups can interact with the aromatic amino acid residues in the lipid binding pocket of CD1d.
(キーワード): Amides / Animals / Antigens, CD1d / Benzene / Binding Sites / Cells, Cultured / Cytokines / Galactosylceramides / Ligands / Mice / Molecular Dynamics Simulation / Natural Killer T-Cells / Protein Structure, Tertiary / Structure-Activity Relationship
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.bmcl.2019.02.018
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30824201; ● Search Scopus @ Elsevier (PMID): 30824201; ● Search Scopus @ Elsevier (DOI): 10.1016/j.bmcl.2019.02.018

(DOI: 10.1016/j.bmcl.2019.02.018, PubMed: 30824201) Koki Yamamoto, Yasushi Yoshikawa, Masahito Ohue, Shinsuke Inuki, Hiroaki Ohno and Shinya Oishi :
Synthesis of Triazolo- and Oxadiazolopiperazines by Gold(I)-Catalyzed Domino Cyclization: Application to the Design of a Mitogen Activated Protein (MAP) Kinase Inhibitor.,
Organic Letters, 21, 2, 373-377, 2018.

(要約): An efficient method for the synthesis of [1,2,4]triazolo[4,3- a]piperazine derivatives was established based on a gold(I)-catalyzed domino cyclization of an amidrazone substrate with a terminal alkyne. The amidoxime congeners were converted into [1,2,4]oxadiazolo[4,5- a]piperazine derivatives in the presence of a gold catalyst. The oxadiazolopiperazine is a promising scaffold for the design of novel inhibitors against p38 mitogen activated protein kinase (MAP kinase).
(キーワード): Aza Compounds / Catalysis / Cyclization / Enzyme Inhibitors / Gold / Mitogen-Activated Protein Kinases / Protein Kinase Inhibitors / Triazoles
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.orglett.8b03500
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30596417; ● Search Scopus @ Elsevier (PMID): 30596417; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.orglett.8b03500

(DOI: 10.1021/acs.orglett.8b03500, PubMed: 30596417) Yuiki Kawada, Shunsuke Ohmura, Misaki Kobayashi, Wataru Nojo, Masaki Kondo, Yuka Matsuda, Junpei Matsuoka, Shinsuke Inuki, Shinya Oishi, Chao Wang, Tatsuo Saito, Masanobu Uchiyama, Takanori Suzuki and Hiroaki Ohno :
Direct synthesis of aryl-annulated [c]carbazoles by gold(i)-catalysed cascade reaction of azide-diynes and arenes.,
Chemical Science, 9, 44, 8416-8425, 2018.

(要約): The gold-catalysed annulation of conjugated alkynes bearing an azido group with arenes gave annulated [c]carbazoles. Using benzene, pyrrole, and indole derivatives as the nucleophiles, benzo[c]-, pyrrolo[2,3-c]-, and indolo[2,3-c]carbazoles were produced, respectively. The reaction proceeded through pyrrole and benzene ring construction accompanied by the formation of two carbon-carbon and one carbon-nitrogen bond and the cleavage of two aromatic C-H bonds. The mechanism of the reaction with pyrrole was investigated by density functional theory calculations. N,N'-dimethylated indolo[2,3-c]carbazole showed dual ultraviolet-visible-near-infrared and fluorescence spectral changes upon electrolysis.
(出版サイトへのリンク): ● Publication site (DOI): 10.1039/c8sc03525c
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30542591; ● Summary page in Scopus @ Elsevier: 2-s2.0-85056621020

(DOI: 10.1039/c8sc03525c, PubMed: 30542591, Elsevier: Scopus) Naoka Hamada, Ayuta Yamaguchi, Shinsuke Inuki, Shinya Oishi and Hiroaki Ohno :
Gold(I)-Catalyzed Oxidative Cascade Cyclization of 1,4-Diyn-3-ones for the Construction of Tropone-Fused Furan Scaffolds.,
Organic Letters, 20, 15, 4401-4405, 2018.

(要約): -catalyzed intramolecular carbon-carbon bond formation, is also presented.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.orglett.8b01524
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30036068; ● Search Scopus @ Elsevier (PMID): 30036068; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.orglett.8b01524

(DOI: 10.1021/acs.orglett.8b01524, PubMed: 30036068) Shinsuke Inuki, Emi Kashiwabara, Natsumi Hirata, Junichiro Kishi, Etsuko Nabika and Yukari Fujimoto :
Potent Th2 Cytokine Bias of Natural Killer T Cell by CD1d Glycolipid Ligands: Anchoring Effect of Polar Groups in the Lipid Component.,
Angewandte Chemie International Edition, 57, 31, 9655-9659, 2018.

(要約): Th2-biasing CD1d ligands are attractive potential candidates for adjuvants and therapeutic drugs. However, the number of potent ligands is limited, and their biasing mechanism remain unclear. Herein, a series of novel Th2-biasing CD1d glycolipid ligands, based on modification of their lipid part, have been identified. These have shown high binding affinities and efficient Th2 cytokine production. Importantly, the truncated acyl chain containing variants still retain their binding affinities and agonistic activities, which can be associated with an "anchoring effect," that is, formation of a buried hydrogen bond between a polar group on the acyl chain and the CD1d lipid-binding pocket. The analysis indicated that the appearance rates of ligand-CD1d complexes on the cell surface were involved in Th2-biasing responses. The designed ligands, having the anchor in the shorter lipid part, are one of the most potent Th2-biasing ligands among the known ligands.
(キーワード): Antigens, CD1d / Cytokines / Humans / Hydrogen Bonding / Ligands / Lipids / Molecular Structure / Natural Killer T-Cells / Th2 Cells
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/anie.201802983
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29863807; ● Search Scopus @ Elsevier (PMID): 29863807; ● Search Scopus @ Elsevier (DOI): 10.1002/anie.201802983

(DOI: 10.1002/anie.201802983, PubMed: 29863807) Yohei Arai, Kouhei Yokoyama, Yuki Kawahara, Qi Feng, Ippei Ohta, Atsushi Shimoyama, Shinsuke Inuki, Koichi Fukase, Kazuya Kabayama and Yukari Fujimoto :
Time-lapse monitoring of TLR2 ligand internalization with newly developed fluorescent probes.,
Organic & Biomolecular Chemistry, 16, 20, 3824-3830, 2018.

(要約): As a mammalian toll-like receptor family member protein, TLR2 recognizes lipoproteins from bacteria and modulates the immune response by inducing the expression of various cytokines. We have developed fluorescence-labeled TLR2 ligands with either hydrophilic or hydrophobic fluorescence groups. The labeled ligands maintained the inflammatory IL-6 induction activity and enabled us to observe the internalization and colocalization of the TLR2 ligands using live-cell imaging. The time-lapse monitoring in the live-cell imaging of the fluorescence-labeled TLR2 ligand showed that TLR2/CD14 expression in the host cells enhanced the internalization of TLR2 ligand molecules.
(出版サイトへのリンク): ● Publication site (DOI): 10.1039/c7ob03205f
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29745411; ● Search Scopus @ Elsevier (PMID): 29745411; ● Search Scopus @ Elsevier (DOI): 10.1039/c7ob03205f

(DOI: 10.1039/c7ob03205f, PubMed: 29745411) Yuka Kobayashi, Masaru Hoshino, Tomoshi Kameda, Kazuya Kobayashi, Kenichi Akaji, Shinsuke Inuki, Hiroaki Ohno and Shinya Oishi :
Use of a Compact Tripodal Tris(bipyridine) Ligand to Stabilize a Single-Metal-Centered Chirality: Stereoselective Coordination of Iron(II) and Ruthenium(II) on a Semirigid Hexapeptide Macrocycle.,
Inorganic Chemistry, 57, 9, 5475-5485, 2018.

(要約): Fe(II)-coordinating hexapeptides containing three 2,2'-bipyridine moieties as side chains were designed and synthesized. A cyclic hexapeptide having three [(2,2'-bipyridin)-5-yl]-d-alanine (d-Bpa5) residues, in which d-Bpa5 and Gly are alternately arranged with 3-fold rotational symmetry, coordinated with Fe(II) to form a 1:1 octahedral Fe(II)-peptide complex with a single facial-Λ configuration of the metal-centered chirality. NMR spectroscopy and molecular dynamics simulations revealed that the Fe(II)-peptide complex has an apparent C₃-symmetric conformations on the NMR time scale, while the peptide backbone is subject to dynamic conformational exchange between three asymmetric β/γ conformations and one C₃-symmetric γ/γ/γ conformation. The semirigid cyclic hexapeptide preferentially arranged these conformations of the small octahedral Fe(II)-bipyridine complex, as well as the Ru(II) congener, to underpin the single configuration of the metal-centered chirality.
(キーワード): 2,2'-Dipyridyl / Ferrous Compounds / Ligands / Macrocyclic Compounds / Molecular Structure / Ruthenium / Stereoisomerism
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.inorgchem.8b00416
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29634246; ● Search Scopus @ Elsevier (PMID): 29634246; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.inorgchem.8b00416

(DOI: 10.1021/acs.inorgchem.8b00416, PubMed: 29634246) Takashi Miyagawa, Shinsuke Inuki, Maho Honda, Shinya Nakamura, Isao Nakanishi, Nobutaka Fujii, Shinya Oishi and Hiroaki Ohno :
Synthesis of jaspine B regioisomers through palladium-catalyzed stereoselective tetrahydrofuran formation: Insight into the ligand recognition of sphingosine kinases,
Tetrahedron, 74, 15, 1802-1809, 2018.

(要約): Abstract We recently reported a structure-activity relationship study of 4-epi-jaspine B derivatives toward sphingosine kinase (SphK) and identified selective inhibitors of two SphK isoforms. In this study, we designed and synthesized jaspine B regioisomers on the basis of palladium-catalyzed tetrahydrofuran formation and late-stage cross metathesis reactions to investigate the influence of the substitution position of functional groups on SphK inhibition. Evaluation of the jaspine B regioisomers SphK inhibitory activities revealed that several of these compounds exhibited comparable SphK1/2 inhibitory potency to that of 4-epi-jaspine B.
(キーワード): Organic Chemistry / Drug Discovery / Biochemistry
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.tet.2018.02.042
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1360004232525522304; ● Search Scopus @ Elsevier (DOI): 10.1016/j.tet.2018.02.042

(DOI: 10.1016/j.tet.2018.02.042, CiNii: 1360004232525522304) Yohei Arai, Shinsuke Inuki and Yukari Fujimoto :
Site-specific effect of polar functional group-modification in lipids of TLR2 ligands for modulating the ligand immunostimulatory activity.,
Bioorganic & Medicinal Chemistry Letters, 28, 9, 1638-1641, 2018.

(要約): Toll-like receptor 2 (TLR2), a member of the TLR innate immune receptor family, recognizes lipoproteins from bacteria and modulates the immune response by inducing the expression of various cytokines. TLR2 has a large hydrophobic pocket that recognizes long fatty acyl groups on TLR2 ligands. However, few studies have focused on the property of the hydrophobic TLR2 pocket. Based on the X-ray crystal structure of TLR2, small polar regions were found in the hydrophobic TLR2 pocket. Interactions between the polar residues and ligands were explored here by designing and synthesizing a Pam₂CSK₄ derivative of the TLR2 ligands, containing an amide group within the lipid moiety. We evaluated the binding affinities and immunomodulatory activities of these ligands. Results suggested that the amide groups in the lipid chain interacted with the polar residues in the hydrophobic lipid-binding pocket of TLR2.
(キーワード): Adjuvants, Immunologic / Animals / Cytokines / Dose-Response Relationship, Drug / Humans / Hydrophobic and Hydrophilic Interactions / Ligands / Lipids / Macrophages / Mice / Molecular Structure / RAW 264.7 Cells / Structure-Activity Relationship / Toll-Like Receptor 2
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.bmcl.2018.03.042
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29598910; ● Search Scopus @ Elsevier (PMID): 29598910; ● Search Scopus @ Elsevier (DOI): 10.1016/j.bmcl.2018.03.042

(DOI: 10.1016/j.bmcl.2018.03.042, PubMed: 29598910) Masato Kaneda, Shinsuke Inuki, Hiroaki Ohno and Shinya Oishi :
Total Synthesis and Stereochemical Revision of Stereocalpin A: Mirror-Image Approach for Stereochemical Assignments of the Peptide-Polyketide Macrocycle.,
The Journal of Organic Chemistry, 83, 6, 3047-3060, 2018.

(要約): Stereocalpin A is a cyclic depsipeptide with cytotoxic activity isolated from the Antarctic lichen Stereocaulon alpinum. Although a number of synthetic investigations of the unprecedented 12-membered macrocycle of stereocalpin A with a dipeptide segment and a polyketide substructure have been conducted, the configurational assignment has not been completed. In this study, we achieved the first total synthesis and stereochemical revision of stereocalpin A. To facilitate the comprehensive assessment of eight possible stereocalpin A isomers, four stereoisomers of polyketide precursors were conjugated with l-Phe-l-MePhe and d-Phe-d-MePhe dipeptides (MePhe: N-methylphenylalanine) to provide four possible isomers and four mirror-image structures of the remaining isomers, respectively. The comparative NMR analysis of a series of stereoisomers revealed that stereocalpin A possesses 2 R,4 S,5 R-configurations, which is unique among the related 12-membered hybrid peptide-polyketide natural products reported recently. The NOE correlations in the polyketide substructure of stereocalpin A were also retrospectively analyzed among the eight possible stereoisomers.
(キーワード): Chemistry Techniques, Synthetic / Depsipeptides / Polyketides / Stereoisomerism
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.joc.8b00118
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29470088; ● Search Scopus @ Elsevier (PMID): 29470088; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.joc.8b00118

(DOI: 10.1021/acs.joc.8b00118, PubMed: 29470088) Shinsuke Inuki, Takashi Miyagawa, Shinya Oishi and Hiroaki Ohno :
Introduction of a Polar Functional Group to the Lipid Tail of 4-epi-Jaspine B Affects Sphingosine Kinase Isoform Selectivity.,
Chemical & Pharmaceutical Bulletin, 66, 9, 866-872, 2018.

(要約): Sphingosine kinases (SphKs) are key enzymes that regulate sphingosine 1-phosphate production levels, and are involved in a range of cellular processes. Focusing on a hydrophilic residue in the hydrophobic binding pocket of SphKs, we designed and synthesized 4-epi-jaspine B derivatives containing a polar functional group in the lipid tail. A biological evaluation revealed that the introduction of ether groups to the lipid tail of 4-epi-jaspine B modulated its isoform selectivity toward SphKs.
(キーワード): Binding Sites / Humans / Hydrophobic and Hydrophilic Interactions / Isoenzymes / Lipids / Molecular Conformation / Molecular Docking Simulation / Phosphotransferases (Alcohol Group Acceptor) / Protein Binding / Protein Kinase Inhibitors / Sphingosine / Stereoisomerism / Structure-Activity Relationship
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/cpb.c18-00366
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30175743; ● Search Scopus @ Elsevier (PMID): 30175743; ● Search Scopus @ Elsevier (DOI): 10.1248/cpb.c18-00366

(DOI: 10.1248/cpb.c18-00366, PubMed: 30175743) Shinsuke Inuki, Junichiro Kishi, Emi Kashiwabara, Toshihiko Aiba and Yukari Fujimoto :
Convergent Synthesis of Digalactosyl Diacylglycerols.,
Organic Letters, 19, 24, 6482-6485, 2017.

(要約): Efficient convergent chemical syntheses of digalactosyl diacylglycerols (DGDGs), which have both a galactose-galactose α(16)-linkage and a galactose-glycerol β-linkage along with a diacylglycerol containing various kinds of fatty acids, have been accomplished. In order to achieve a concise synthesis, we chose to use allylic protective groups as permanent protective groups. We have also achieved α- and β-selective glycosylations for the respective linkages with high yields as the key steps.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.orglett.7b03043
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29182339; ● Search Scopus @ Elsevier (PMID): 29182339; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.orglett.7b03043

(DOI: 10.1021/acs.orglett.7b03043, PubMed: 29182339) Qianqian Wang, Roberta Marchetti, Sladjana Prisic, Kentaro Ishii, Yohei Arai, Ippei Ohta, Shinsuke Inuki, Susumu Uchiyama, Alba Silipo, Antonio Molinaro, N Robert Husson, Koichi Fukase and Yukari Fujimoto :
A Comprehensive Study of the Interaction between Peptidoglycan Fragments and the Extracellular Domain of Mycobacterium tuberculosis Ser/Thr Kinase PknB.,
ChemBioChem, 18, 21, 2094-2098, 2017.

(要約): The Mycobacterium tuberculosis Ser/Thr kinase PknB is implicated in the regulation of bacterial cell growth and cell division. The intracellular kinase function of PknB is thought to be triggered by peptidoglycan (PGN) fragments that are recognized by the extracytoplasmic domain of PknB. The PGN in the cell wall of M. tuberculosis has several unusual modifications, including the presence of N-glycolyl groups (in addition to N-acetyl groups) in the muramic acid residues and amidation of d-Glu in the peptide chains. Using synthetic PGN fragments incorporating these diverse PGN structures, we analyzed their binding characters through biolayer interferometry (BLI), NMR spectroscopy, and native mass spectrometry (nMS) techniques. The results of BLI showed that muropeptides containing 1,6-anhydro-MurNAc and longer glycan chains exhibited higher binding potency and that the fourth amino acid of the peptide stem, d-Ala, was crucial for protein recognition. Saturation transfer difference (STD) NMR spectroscopy indicated the major involvement of the stem peptide region in the PASTA-PGN fragment binding. nMS suggested that the binding stoichiometry was 1:1. The data provide the first molecular basis for the specific interaction of PGN with PknB and firmly establish PGNs as the effective ligands of PknB.
(キーワード): Carbohydrate Conformation / Mycobacterium tuberculosis / Peptidoglycan / Protein Serine-Threonine Kinases
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/cbic.201700385
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28851116; ● Search Scopus @ Elsevier (PMID): 28851116; ● Search Scopus @ Elsevier (DOI): 10.1002/cbic.201700385

(DOI: 10.1002/cbic.201700385, PubMed: 28851116) Shinsuke Inuki, Ippei Ohta, Shunichi Ishibashi, Masayuki Takamatsu, Koichi Fukase and Yukari Fujimoto :
Total Synthesis of Cardiolipins Containing Chiral Cyclopropane Fatty Acids.,
The Journal of Organic Chemistry, 82, 15, 7832-7838, 2017.

(要約): Cardiolipin (CL) is a phospholipid located in both the eukaryotic mitochondrial inner membrane and the bacterial cell membrane. Some bacterial CLs are known to contain cyclopropane moieties in their acyl chains. Although the CLs are thought to be involved in the innate immune response, there have been few attempts at chemical synthesis of the CLs, and detailed studies of their biological activities are scarce. Thus, we have developed a synthetic route to CLs containing chiral cyclopropane moieties.
(キーワード): Cardiolipins / Cyclopropanes / Fatty Acids / Molecular Structure
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.joc.7b00945
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28682614; ● Search Scopus @ Elsevier (PMID): 28682614; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.joc.7b00945

(DOI: 10.1021/acs.joc.7b00945, PubMed: 28682614) Shinsuke Inuki, Toshihiko Aiba, Shota Kawakami, Taishin Akiyama, Jun-Ichiro Inoue and Yukari Fujimoto :
Chemical Synthesis of d-glycero-d-manno-Heptose 1,7-Bisphosphate and Evaluation of Its Ability to Modulate NF-κB Activation.,
Organic Letters, 19, 12, 3079-3082, 2017.

(要約): d-glycero-d-manno-Heptose 1,7-bisphosphate (HBP) is the precursor for heptose residues found in Gram-negative bacterial membrane surface glycoproteins and glycolipids. HBP β-anomer was recently reported to be a pathogen-associated molecular pattern (PAMP) that regulates TIFA-dependent immunity. Herein, we report the chemical synthesis of HBP α- and β-anomers, which highlights a C-7 carbon homologation via the Corey-Chaykovsky reaction, and the introduction of a phosphate group at the anomeric position using the Mitsunobu reaction. Furthermore, NF-κB reporter assaying revealed that HBP β-anomer activates the NF-κB signaling pathway.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.orglett.7b01158
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28541700; ● Search Scopus @ Elsevier (PMID): 28541700; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.orglett.7b01158

(DOI: 10.1021/acs.orglett.7b01158, PubMed: 28541700) Toshihiko Aiba, Sae Suehara, Siew-Ling Choy, Yuuki Maekawa, Hannelore Lotter, Toshiaki Murai, Shinsuke Inuki, Koichi Fukase and Yukari Fujimoto :
Employing BINOL-Phosphoroselenoyl Chloride for Selective Inositol Phosphorylation and Synthesis of Glycosyl Inositol Phospholipid from Entamoeba histolytica.,
Chemistry - A European Journal, 23, 34, 8304-8308, 2017.

(要約): The chemical synthesis of glycosyl inositol phospholipids from Entamoeba histolytica is reported. The key feature of this synthesis is a regioselective phosphorylation reaction that occurs through desymmetrization of a myo-inositol derivative with phosphoroselenoyl chloride. A new protecting-group strategy was developed that utilizes allyl and alloc groups to synthesize complex glycolipids bearing unsaturated lipids. These developments provided an efficient synthetic route for various complex inositol phospholipids and their analogues. Furthermore, the binding affinity of the synthetic inositol phospholipids with mouse CD1d molecules has been evaluated, as well as the immunostimulatory activity.
(キーワード): Entamoeba histolytica / Glycosylphosphatidylinositols / Naphthols / Phosphatidylinositols / Phosphorylation
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/chem.201701298
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28390155; ● Search Scopus @ Elsevier (PMID): 28390155; ● Search Scopus @ Elsevier (DOI): 10.1002/chem.201701298

(DOI: 10.1002/chem.201701298, PubMed: 28390155) Hiroaki Ohno, Maho Honda, Naoka Hamada, Jun Miyagaki, Akira Iwata, Kazuhiro Otsuki, Toru Maruyama, Shinya Nakamura, Isao Nakanishi, Shinsuke Inuki, Nobutaka Fujii and Shinya Oishi :
Identification of selective inhibitors of sphingosine kinases 1 and 2 through a structure-activity relationship study of 4-epi-jaspine B.,
Bioorganic & Medicinal Chemistry, 25, 12, 3046-3052, 2017.

(要約): We recently reported that 4-epi-jaspine B exhibits potent inhibitory activity towards sphingosine kinases (SphKs). In this study, we investigated the effects of modifying the 2-alkyl group, as well as the functional groups on the THF ring of 4-epi-jaspine B using a diversity-oriented synthesis approach based on a late-stage cross metathesis reaction. The introduction of a p-phenylene tether to the alkyl group was favored in most cases, whereas the replacement of a carbon atom with an oxygen atom led to a decrease in the inhibitory activity. Furthermore, the introduction of a bulky alkyl group at the terminus led to a slight increase in the inhibitory activity of this series towards SphKs compared with 4-epi-jaspine B (the Q values of compound 13 for SphK1 and SphK2 were 0.2 and 0.4, respectively). Based on this study, we identified two isoform selective inhibitors, including the m-phenylene derivative 4 [IC₅₀ (SphK1) ≥30μM; IC₅₀ (SphK2)=2.2μM] and the methyl ether derivative 22 [IC₅₀ (SphK1)=4.0μM; IC₅₀ (SphK2) ≥30μM].
(キーワード): Humans / Molecular Docking Simulation / Phosphotransferases (Alcohol Group Acceptor) / Protein Kinase Inhibitors / Sphingosine / Structure-Activity Relationship
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.bmc.2017.03.059
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28408190; ● Search Scopus @ Elsevier (PMID): 28408190; ● Search Scopus @ Elsevier (DOI): 10.1016/j.bmc.2017.03.059

(DOI: 10.1016/j.bmc.2017.03.059, PubMed: 28408190) Shinsuke Inuki, Keisuke Sato, Takahide Fukuyama, Ilhyong Ryu and Yukari Fujimoto :
Formal Total Synthesis of l-Ossamine via Decarboxylative Functionalization Using Visible-Light-Mediated Photoredox Catalysis in a Flow System.,
The Journal of Organic Chemistry, 82, 2, 1248-1253, 2017.

(要約): A formal total synthesis of l-ossamine was achieved. The key feature of the synthesis was the decarboxylative functionalization of a threonine derivative using visible-light-mediated photoredox catalysis. This reaction was implemented in a flow reactor, allowing for the efficient conversion to the desired product.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.joc.6b02531
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 27997795; ● Search Scopus @ Elsevier (PMID): 27997795; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.joc.6b02531

(DOI: 10.1021/acs.joc.6b02531, PubMed: 27997795) Zenyu Shiokawa, Emi Kashiwabara, Daisuke Yoshidome, Koichi Fukase, Shinsuke Inuki and Yukari Fujimoto :
Discovery of a Novel Scaffold as an Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Based on the Pyrrolopiperazinone Alkaloid, Longamide B.,
ChemMedChem, 11, 24, 2682-2689, 2016.

(要約): Indoleamine 2,3-dioxygenase 1 (IDO1) has emerged as a key target for cancer therapy, as IDO1 plays a critical role in the capacity of tumor cells to evade the immune system. The pyrrolopiperazinone alkaloid longamide B and its derivatives were identified as novel IDO1 inhibitors based on docking studies and small library synthesis. The thioamide derivative showed higher IDO1 inhibitory activity than longamide B, and displayed an activity similar to that of a representative IDO1 inhibitor, 1-methyl-tryptophan. These results suggest that the pyrrolopiperazinone scaffold of longamide B could be used in the development of IDO1 inhibitors.
(キーワード): Drug Discovery / Enzyme Activation / Enzyme Inhibitors / Indoleamine-Pyrrole 2,3,-Dioxygenase / Matrix Attachment Regions / Models, Molecular / Piperazines / Pyrazoles / Pyrroles
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/cmdc.201600446
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 27863031; ● Summary page in Scopus @ Elsevier: 2-s2.0-85006357076

(DOI: 10.1002/cmdc.201600446, PubMed: 27863031, Elsevier: Scopus) Shinsuke Inuki, Toshihiko Aiba, Natsumi Hirata, Osamu Ichihara, Daisuke Yoshidome, Shunsuke Kita, Katsumi Maenaka, Koichi Fukase and Yukari Fujimoto :
Isolated Polar Amino Acid Residues Modulate Lipid Binding in the Large Hydrophobic Cavity of CD1d.,
ACS Chemical Biology, 11, 11, 3132-3139, 2016.

(要約): The CD1d protein is a nonpolymorphic MHC class I-like protein that controls the activation of natural killer T (NKT) cells through the presentation of self- and foreign-lipid ligands, glycolipids, or phospholipids, leading to the secretion of various cytokines. The CD1d contains a large hydrophobic lipid binding pocket: the A' pocket of CD1d, which recognizes hydrophobic moieties of the ligands, such as long fatty acyl chains. Although lipid-protein interactions typically rely on hydrophobic interactions between lipid chains and the hydrophobic sites of proteins, we showed that the small polar regions located deep inside the hydrophobic A' pocket could be used for the modulation of the lipid binding. A series of the ligands, α-galactosyl ceramide (α-GalCer) derivatives containing polar groups in the acyl chain, was synthesized, and the structure-activity relationship studies demonstrated that simple modification from a methylene to an amide group in the long fatty acyl chain, when introduced at optimal positions, enhanced the CD1d recognition of the glycolipid ligands. Formation of hydrogen bonds between the amide group and the polar residues was supported by molecular dynamics (MD) simulations and WaterMap calculations. The computational studies suggest that localized hydrating water molecules may play an important role in the ligand recognition. Here, the results showed that confined polar residues in the large hydrophobic lipid binding pockets of the proteins could be potential targets to modulate the affinity for its ligands.
(キーワード): Animals / Antigen-Presenting Cells / Antigens, CD1d / Binding Sites / Cells, Cultured / Coculture Techniques / Hydrophobic and Hydrophilic Interactions / Interferon-gamma / Interleukin-4 / Lipids / Mice / Molecular Dynamics Simulation / Spleen
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acschembio.6b00674
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 27648599; ● Search Scopus @ Elsevier (PMID): 27648599; ● Search Scopus @ Elsevier (DOI): 10.1021/acschembio.6b00674

(DOI: 10.1021/acschembio.6b00674, PubMed: 27648599) Zenyu Shiokawa, Shinsuke Inuki, Koichi Fukase and Yukari Fujimoto :
Efficient Synthesis of ( )-Hanishin, ( )-Longamide B, and ( )-Longamide B Methyl Ester through Piperazinone Formation from 1,2-Cyclic Sulfamidates,
Synlett, 27, 04, 616-620, 2015.

(出版サイトへのリンク): ● Publication site (DOI): 10.1055/s-0035-1560988
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1360567183730401408; ● Search Scopus @ Elsevier (DOI): 10.1055/s-0035-1560988

(DOI: 10.1055/s-0035-1560988, CiNii: 1360567183730401408) Shinsuke Inuki, Keisuke Sato and Yukari Fujimoto :
Visible-light-mediated decarboxylative benzoyloxylation of β-hydroxy amino acids and its application to synthesis of functional 1,2-amino alcohol derivatives,
Tetrahedron Letters, 56, 42, 5787-5790, 2015.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.tetlet.2015.09.012
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1360567182481215616; ● Summary page in Scopus @ Elsevier: 2-s2.0-84941995425

(DOI: 10.1016/j.tetlet.2015.09.012, CiNii: 1360567182481215616, Elsevier: Scopus) Akira Iwata, Shinsuke Inuki, Shinya Oishi, Nobutaka Fujii and Hiroaki Ohno :
Convenient synthesis of spiroindole derivatives via palladium-catalyzed cyclization of propargyl chlorides,
Tetrahedron, 71, 37, 6580-6585, 2015.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.tet.2015.05.006
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1050282810795481856; ● Summary page in Scopus @ Elsevier: 2-s2.0-84938749658

(DOI: 10.1016/j.tet.2015.05.006, CiNii: 1050282810795481856, Elsevier: Scopus) Akira Iwata, Shinsuke Inuki, Shinya Oishi, Nobutaka Fujii and Hiroaki Ohno :
Synthesis of fused tetracyclic spiroindoles via palladium-catalysed cascade cyclisation.,
Chemical Communications, 50, 3, 298-300, 2014.

(要約): Efficient palladium-catalysed cascade cyclisation to form spiroindoles is developed. Treatment of indoles bearing a propargyl chloride side chain at the 3-position with various external nucleophiles in the presence of a catalytic amount of Pd2(dba)3·CHCl3/dppb and Cs2CO3 in THF gives fused tetracyclic spiroindoles in moderate to good yields.
(キーワード): Catalysis / Cyclization / Indoles / Nitrogen / Oxidation-Reduction / Palladium / Spiro Compounds
(出版サイトへのリンク): ● Publication site (DOI): 10.1039/c3cc46511j
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24247420; ● Search Scopus @ Elsevier (PMID): 24247420; ● Search Scopus @ Elsevier (DOI): 10.1039/c3cc46511j

(DOI: 10.1039/c3cc46511j, PubMed: 24247420) Yuji Yoshimitsu, Shinsuke Inuki, Shinya Oishi, Nobutaka Fujii and Hiroaki Ohno :
Palladium-catalyzed medium-ring formation for construction of the core structure of laurencia oxacycles: synthetic study of laurendecumallene B.,
Organic Letters, 15, 12, 3046-3049, 2013.

(要約): Palladium-catalyzed medium-ring formation from a cyclic propargyl carbonate via a ring-opening and -closing cascade proceeded at the central carbon atom of the propargyl unit to provide a tetrahydro-2H-oxocine derivative bearing the core structure of laurencia oxacycle. The synthetic application of this reaction to a possible laurendecumallene B precursor is also presented.
(キーワード): Acetogenins / Catalysis / Hydrocarbons, Brominated / Laurencia / Palladium / Stereoisomerism
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/ol401231y
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23721225; ● Search Scopus @ Elsevier (PMID): 23721225; ● Search Scopus @ Elsevier (DOI): 10.1021/ol401231y

(DOI: 10.1021/ol401231y, PubMed: 23721225) Yuji Yoshimitsu, Shinya Oishi, Jun Miyagaki, Shinsuke Inuki, Hiroaki Ohno and Nobutaka Fujii :
Pachastrissamine (jaspine B) and its stereoisomers inhibit sphingosine kinases and atypical protein kinase C.,
Bioorganic & Medicinal Chemistry, 19, 18, 5402-5408, 2011.

(要約): Sphingosine kinases (SphKs) are oncogenic enzymes that regulate the critical balance between ceramide and sphingosine-1-phosphate. Much effort has been dedicated to develop inhibitors against these enzymes. Naturally occurring pachastrissamine (jaspine B) and all its stereoisomers were prepared and evaluated for their inhibitory effects against SphKs. All eight stereoisomers exhibited moderate to potent inhibitory activity against SphK1 and SphK2. Inhibitory effects were profiled against protein kinase C (PKC) isoforms by in vitro experiments. Atypical PKCs (PKCζ and PKCι) were inhibited by several pachastrissamine stereoisomers. The improved activity over N,N-dimethylsphingosine suggests that the cyclic scaffold in pachastrissamines facilitates potential favorable interactions with SphKs and PKCs.
(キーワード): Dose-Response Relationship, Drug / Molecular Conformation / Phosphotransferases (Alcohol Group Acceptor) / Protein Kinase C / Protein Kinase Inhibitors / Sphingosine / Stereoisomerism / Structure-Activity Relationship
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.bmc.2011.07.061
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21868240; ● Search Scopus @ Elsevier (PMID): 21868240; ● Search Scopus @ Elsevier (DOI): 10.1016/j.bmc.2011.07.061

(DOI: 10.1016/j.bmc.2011.07.061, PubMed: 21868240) Akira Iwata, Shinsuke Inuki, Shinya Oishi, Nobutaka Fujii and Hiroaki Ohno :
Formal total synthesis of (+)-lysergic acid via zinc(II)-mediated regioselective ring-opening reduction of 2-alkynyl-3-indolyloxirane.,
The Journal of Organic Chemistry, 76, 13, 5506-5512, 2011.

(要約): Asymmetric formal synthesis of (+)-lysergic acid was achieved with a reductive ring-opening reaction of chiral 2-alkynyl-3-indolyloxirane with NaBH(3)CN as the key step. With Zn(OTf)(2) as an additive, the ring-opening reaction proceeded regioselectively at the 3-position to give the corresponding propargyl alcohol, which was a precursor of the allenic amide for palladium-catalyzed domino cyclization to construct the ergot alkaloid core structure.
(キーワード): Catalysis / Ethylene Oxide / Lysergic Acid / Molecular Conformation / Organometallic Compounds / Oxidation-Reduction / Stereoisomerism / Zinc
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/jo2008324
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21598967; ● Search Scopus @ Elsevier (PMID): 21598967; ● Search Scopus @ Elsevier (DOI): 10.1021/jo2008324

(DOI: 10.1021/jo2008324, PubMed: 21598967) Shinsuke Inuki, Akira Iwata, Shinya Oishi, Nobutaka Fujii and Hiroaki Ohno :
Enantioselective total synthesis of (+)-lysergic acid, (+)-lysergol, and (+)-isolysergol by palladium-catalyzed domino cyclization of allenes bearing amino and bromoindolyl groups.,
The Journal of Organic Chemistry, 76, 7, 2072-2083, 2011.

(要約): Enantioselective total synthesis of the biologically important indole alkaloids (+)-lysergol, (+)-isolysergol, and (+)-lysergic acid is described. Key features of these total synthesis include (1) a facile synthesis of a chiral 1,3-amino alcohol via the Pd(0)- and In(I)-mediated reductive coupling reaction between L-serine-derived 2-ethynylaziridine and formaldehyde; (2) the Cr(II)/Ni(0)-mediated Nozaki-Hiyama-Kishi (NHK) reaction of an indole-3-acetaldehyde with iodoalkyne; and (3) Pd(0)-catalyzed domino cyclization of an allene bearing amino and bromoindolyl groups. This domino cyclization enabled direct construction of the C/D ring system of the ergot alkaloids skeleton, as well as the creation of the C5 stereogenic center with transfer of the allenic axial chirality to the central chirality.
(キーワード): Catalysis / Cyclization / Ergolines / Ergot Alkaloids / Indoles / Lysergic Acid / Magnetic Resonance Spectroscopy / Molecular Structure / Palladium / Stereoisomerism
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/jo102388e
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21361331; ● Search Scopus @ Elsevier (PMID): 21361331; ● Search Scopus @ Elsevier (DOI): 10.1021/jo102388e

(DOI: 10.1021/jo102388e, PubMed: 21361331) Yuji Yoshimitsu, Shinsuke Inuki, Shinya Oishi, Nobutaka Fujii and Hiroaki Ohno :
Stereoselective divergent synthesis of four diastereomers of pachastrissamine (jaspine B).,
The Journal of Organic Chemistry, 75, 11, 3843-3846, 2010.

(要約): A divergent short synthesis of four diastereomers of pachastrissamine was achieved. Natural pachastrissamine was synthesized through bis-tosylation of the common intermediate and cyclization. 2-epi-Pachastrissamine was obtained by monotosylation and spontaneous cyclization of D-ribo-phytosphingosine derivative. By use of regio- and stereospecific ring-opening reaction of the orthoester assisted by a Boc group as a key step, 3-epi- and 2,3-epi-pachastrissamines were synthesized. The three stereogenic centers of all the diastereomers were constructed by using Garner's aldehyde as the sole chiral source.
(キーワード): Aldehydes / Cyclization / Sphingosine / Stereoisomerism / Tosyl Compounds
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/jo1005284
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20408556; ● Search Scopus @ Elsevier (PMID): 20408556; ● Search Scopus @ Elsevier (DOI): 10.1021/jo1005284

(DOI: 10.1021/jo1005284, PubMed: 20408556) Shinsuke Inuki, Yuji Yoshimitsu, Shinya Oishi, Nobutaka Fujii and Hiroaki Ohno :
Ring-construction/stereoselective functionalization cascade: total synthesis of pachastrissamine (jaspine B) through palladium-catalyzed bis-cyclization of propargyl chlorides and carbonates.,
The Journal of Organic Chemistry, 75, 11, 3831-3842, 2010.

(要約): Palladium(0)-catalyzed cyclization of bromoallenes, propargyl chlorides, and carbonates bearing hydroxy and benzamide groups as internal nucleophiles stereoselectively provides functionalized tetrahydrofuran. Cyclization reactivity is dependent on the relative configuration of the benzamide and leaving groups, and on the nature of the leaving groups. This bis-cyclization was used as the key step in a short total synthesis of pachastrissamine, which is a biologically active marine natural product.
(キーワード): Alkynes / Carbonates / Catalysis / Chlorides / Cyclization / Palladium / Sphingosine / Stereoisomerism
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/jo100544v
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20455522; ● Search Scopus @ Elsevier (PMID): 20455522; ● Search Scopus @ Elsevier (DOI): 10.1021/jo100544v

(DOI: 10.1021/jo100544v, PubMed: 20455522) Shinsuke Inuki, Yuji Yoshimitsu, Shinya Oishi, Nobutaka Fujii and Hiroaki Ohno :
Ring-construction/stereoselective functionalization cascade: total synthesis of pachastrissamine (jaspine B) through palladium-catalyzed bis-cyclization of bromoallenes.,
Organic Letters, 11, 19, 4478-4481, 2009.

(要約): Palladium(0)-catalyzed cyclization of bromoallenes bearing hydroxyl and benzamide groups as internal nucleophiles stereoselectively provides functionalized tetrahydrofuran. With this bis-cyclization as the key step, a short total synthesis of pachastrissamine, a biologically active marine natural product, was achieved.
(キーワード): Alkadienes / Catalysis / Cyclization / Molecular Structure / Palladium / Sphingosine / Stereoisomerism
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/ol901904w
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19739618; ● Search Scopus @ Elsevier (PMID): 19739618; ● Search Scopus @ Elsevier (DOI): 10.1021/ol901904w

(DOI: 10.1021/ol901904w, PubMed: 19739618) Tsukasa Mizuhara, Shinsuke Inuki, Shinya Oishi, Nobutaka Fujii and Hiroaki Ohno :
Cu(II)-mediated oxidative intermolecular ortho C-H functionalisation using tetrahydropyrimidine as the directing group.,
Chemical Communications, 23, 3413-3415, 2009.

(要約): Tetrahydropyrimidine works efficiently as a directing group in Cu(ii)-mediated oxidative aromatic C-H functionalisation for the selective introduction of oxygen or nitrogen to the ortho-position.
(キーワード): Aniline Compounds / Carbon / Catalysis / Copper / Hydrogen / Hydroxylation / Oxidation-Reduction / Pyrimidines
(出版サイトへのリンク): ● Publication site (DOI): 10.1039/b905586j
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19503888; ● Search Scopus @ Elsevier (PMID): 19503888; ● Search Scopus @ Elsevier (DOI): 10.1039/b905586j

(DOI: 10.1039/b905586j, PubMed: 19503888) Shinsuke Inuki, Shinya Oishi, Nobutaka Fujii and Hiroaki Ohno :
Total synthesis of (+/-)-lysergic acid, lysergol, and isolysergol by palladium-catalyzed domino cyclization of amino allenes bearing a bromoindolyl group.,
Organic Letters, 10, 22, 5239-5242, 2008.

(要約): Ergot alkaloids and their synthetic analogs have been reported to exhibit broad biological activity. We investigated direct construction of the C/D ring system of ergot alkaloids based on palladium-catalyzed domino cyclization of amino allenes. With this biscyclization as the key step, total synthesis of (+/-)-lysergic acid, (+/-)-lysergol, and (+/-)-isolysergol was achieved.
(キーワード): Alkadienes / Bromine / Catalysis / Cyclization / Ergolines / Indoles / Lysergic Acid / Palladium / Stereoisomerism
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/ol8022648
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18956869; ● Search Scopus @ Elsevier (PMID): 18956869; ● Search Scopus @ Elsevier (DOI): 10.1021/ol8022648

(DOI: 10.1021/ol8022648, PubMed: 18956869) Satoshi Ueda, Manabu Kato, Shinsuke Inuki, Hiroaki Ohno, Barry Evans, Zi-xuan Wang, C Stephen Peiper, Kazuki Izumi, Eiichi Kodama, Masao Matsuoka, Hideko Nagasawa, Shinya Oishi and Nobutaka Fujii :
Identification of novel non-peptide CXCR4 antagonists by ligand-based design approach.,
Bioorganic & Medicinal Chemistry Letters, 18, 14, 4124-4129, 2008.

(要約): The design and synthesis of novel non-peptide CXCR4 antagonists is described. The peptide backbone of highly potent cyclic peptide-based CXCR4 antagonists was entirely replaced by an indole framework, which was expected to reproduce the disposition of the key pharmacophores consistent with those of potential bioactive conformations of the original peptides. A structure-activity relationship study on a series of modified indoles identified novel small-molecule antagonists having three pharmacophore functional groups through the appropriate linkers.
(キーワード): Chemistry, Pharmaceutical / Chemokines / Chemotaxis / Drug Design / Humans / Inhibitory Concentration 50 / Ligands / Models, Chemical / Molecular Conformation / Peptides / Peptides, Cyclic / Receptors, CXCR4 / Structure-Activity Relationship / T-Lymphocytes
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.bmcl.2008.05.092
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18539453; ● Search Scopus @ Elsevier (PMID): 18539453; ● Search Scopus @ Elsevier (DOI): 10.1016/j.bmcl.2008.05.092

(DOI: 10.1016/j.bmcl.2008.05.092, PubMed: 18539453) Toshiaki Watanabe, Satoshi Ueda, Shinsuke Inuki, Shinya Oishi, Nobutaka Fujii and Hiroaki Ohno :
One-pot synthesis of carbazoles by palladium-catalyzed N-arylation and oxidative coupling.,
Chemical Communications, 43, 4516-4518, 2007.

(要約): One-pot N-arylation and oxidative coupling can be promoted by a common palladium catalyst in the presence of appropriate additives: palladium-catalyzed N-arylation of anilines with aryl triflates under the standard conditions followed by addition of acetic acid under oxygen or air atmosphere afforded various types of functionalized carbazoles in good to excellent yields.
(キーワード): Aniline Compounds / Carbazoles / Catalysis / Mesylates / Oxidation-Reduction / Palladium
(出版サイトへのリンク): ● Publication site (DOI): 10.1039/b707899d
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 17971974; ● Search Scopus @ Elsevier (PMID): 17971974; ● Search Scopus @ Elsevier (DOI): 10.1039/b707899d

(DOI: 10.1039/b707899d, PubMed: 17971974)

MISC

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総説・解説

藤本ゆかり, 塩川善右, 井貫晋輔, 相羽俊彦, 荒井洋平 :
天然化合物を基盤とした免疫調節性分子の合成と展開,
有合化, 81, 9, 867-876, 2023年9月.

(出版サイトへのリンク): ● Publication site (DOI): 10.5059/yukigoseikyokaishi.81.867
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390860332469078144; ● Search Scopus @ Elsevier (DOI): 10.5059/yukigoseikyokaishi.81.867

(DOI: 10.5059/yukigoseikyokaishi.81.867, CiNii: 1390860332469078144) Kazunari Ueki, Kodai Sueyoshi, Shinsuke Inuki and Yukari Fujimoto :
Chemical Synthesis and Molecular Interaction Analysis of α-Galactosyl Ceramide Derivatives as CD1d Ligands.,
Methods in Molecular Biology, 2613, 13-22, 2023.

(要約): CD1d is a non-classical major histocompatibility complex (MHC) protein, responsible for lipid antigen presentation, which presents lipids to natural killer T (NKT) cells. Various CD1d lipid ligands have been reported, including microbial and endogenous glycolipids/phospholipids. Among them, an α-galactosylceramide (α-GalCer), a representative CD1d ligand, is one of the most potent ligands and its derivatives have been developed. In this chapter, the chemistry of α-GalCer and its derivatives are described with an emphasis on their chemical syntheses and molecular interaction analysis with CD1d are described.
(キーワード): Galactosylceramides / Ligands / Antigens, CD1d / Glycolipids / Antigen Presentation
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/978-1-0716-2910-9_2
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 36587067; ● Search Scopus @ Elsevier (PMID): 36587067; ● Search Scopus @ Elsevier (DOI): 10.1007/978-1-0716-2910-9_2

(DOI: 10.1007/978-1-0716-2910-9_2, PubMed: 36587067) 井貫晋輔, 藤本ゆかり :
脂質改変型CD1dリガンドの創製,
月刊ファインケミカル, 51, 12-17, 2022年.

(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1010580143262146944

(CiNii: 1010580143262146944) C Luca Greiner, Junpei Matsuoka, Shinsuke Inuki and Hiroaki Ohno :
Azido-Alkynes in Gold(I)-Catalyzed Indole Syntheses.,
Chemical Record, 21, 12, 3897-3910, Sep. 2021.

(要約): The exploitation of nitrogen-functionalized reactive intermediates plays an important role in the synthesis of biologically relevant scaffolds in the field of pharmaceutical sciences. Those based on gold carbenes carry a strong potential for the design of highly efficient cascade processes toward the synthesis of compounds containing a fused indole core structure. This personal account gives a detailed explanation of our contribution to this sector, and embraces the reaction development of efficient gold-catalyzed cascade processes based on diversely functionalized azido-alkynes. Challenging cyclizations and their subsequent application in the synthesis of pharmaceutically relevant scaffolds and natural products conducted in an intra- or intermolecular fashion are key features of our research.
(キーワード): Alkynes / Catalysis / Cyclization / Gold / Indoles
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/tcr.202100202
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34498385; ● Search Scopus @ Elsevier (PMID): 34498385; ● Search Scopus @ Elsevier (DOI): 10.1002/tcr.202100202

(DOI: 10.1002/tcr.202100202, PubMed: 34498385) Hiroaki Ohno and Shinsuke Inuki :
Nonbiomimetic total synthesis of indole alkaloids using alkyne-based strategies.,
Organic & Biomolecular Chemistry, 19, 16, 3551-3568, Apr. 2021.

(要約): Biomimetic natural product synthesis is generally straightforward and efficient because of its established feasibility in nature and utility in comprehensive synthesis, and the cost-effectiveness of naturally derived starting materials. On the other hand, nonbiomimetic strategies can be an important option in natural product synthesis since (1) nonbiomimetic synthesis offers more flexibility and can demonstrate the originality of chemists, and (2) the structures of derivatives accessible by nonbiomimetic synthesis can be considerably different from those that are synthesised in nature. This review summarises nonbiomimetic total syntheses of indole alkaloids using alkyne chemistry for constructing core structures, including ergot alkaloids, monoterpene indole alkaloids (mainly corynanthe, aspidosperma, strychnos, and akuammiline), and pyrroloindole and related alkaloids. To clarify the differences between alkyne-based strategies and biosynthesis, the alkynes in nature and the biosyntheses of indole alkaloids are also outlined.
(キーワード): Alkynes / Indole Alkaloids / Molecular Structure / Stereoisomerism
(出版サイトへのリンク): ● Publication site (DOI): 10.1039/d0ob02577a
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33908430; ● Search Scopus @ Elsevier (PMID): 33908430; ● Search Scopus @ Elsevier (DOI): 10.1039/d0ob02577a

(DOI: 10.1039/d0ob02577a, PubMed: 33908430) Shinsuke Inuki and Hiroaki Ohno :
Total Syntheses of Myriocin, Mycestericins and Sphingofungin E: Sphingosine Analogues Containing a β, β¤-Dihydroxy α-Amino Acid Framework,
Chemistry Letters, 50, 6, 1313-1324, Apr. 2021.

(出版サイトへのリンク): ● Publication site (DOI): 10.1246/cl.210133
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1360288448374715264; ● Summary page in Scopus @ Elsevier: 2-s2.0-85108250066

(DOI: 10.1246/cl.210133, CiNii: 1360288448374715264, Elsevier: Scopus) Shinsuke Inuki and Yukari Fujimoto :
Total synthesis of naturally occurring chiral cyclopropane fatty acids and related compounds,
Tetrahedron Letters, 60, 16, 1083-1090, Mar. 2019.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.tetlet.2019.03.043
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1360004232528155904; ● Summary page in Scopus @ Elsevier: 2-s2.0-85063267352

(DOI: 10.1016/j.tetlet.2019.03.043, CiNii: 1360004232528155904, Elsevier: Scopus) 竝河悦子, 柏原瑛美, 平田菜摘, 井貫晋輔, 藤本ゆかり :
Th2バイアス型脂質改変CD1dリガンド開発と機能解析,
エンドトキシン・自然免疫研究, 22, 0, 43-48, 2019年.

(出版サイトへのリンク): ● Publication site (DOI): 10.24753/jeiis.22.0_43
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390001277381854848; ● Search Scopus @ Elsevier (DOI): 10.24753/jeiis.22.0_43

(DOI: 10.24753/jeiis.22.0_43, CiNii: 1390001277381854848) Hiroaki Ohno and Shinsuke Inuki :
Recent Progress in Palladium-Catalyzed Cascade Cyclizations for Natural Product Synthesis,
Synthesis, 50, 700-710, Jan. 2018.

(出版サイトへのリンク): ● Publication site (DOI): 10.1055/s-0036-1589165
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1873679867742669568; ● Search Scopus @ Elsevier (DOI): 10.1055/s-0036-1589165

(DOI: 10.1055/s-0036-1589165, CiNii: 1873679867742669568) 井貫晋輔 :
糖脂質 α-GalCer を基盤とした脂質改変型 CD1d リガンドの創製研究,
エンドトキシン・自然免疫研究20, -, 64-67, 2017年.

(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1010000781923228164

(CiNii: 1010000781923228164) 井貫晋輔 :
Au触媒によるアルキンの活性化を鍵としたグリコシル化反応,
有機合成化学協会誌, 74, 1, 69-70, 2016年1月.

(要約): Glycosylation reaction is an important class of reactions in organic chemistry, and the development of the method contributes to the synthesis of many biologically active compounds containing various glycoside bonds. Recently, several groups have developed novel glycosylation reactions using gold catalysis, which has unique reactivities, such as high`alkynophilicity'. In this short review, recent reports about gold-catalyzed glycosylation reactions through the activation of alkyne moieties are described.
(キーワード): Organic Chemistry
(出版サイトへのリンク): ● Publication site (DOI): 10.5059/yukigoseikyokaishi.74.69
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390001205340724480; ● Search Scopus @ Elsevier (DOI): 10.5059/yukigoseikyokaishi.74.69

(DOI: 10.5059/yukigoseikyokaishi.74.69, CiNii: 1390001205340724480) Hiroaki Ohno, Hiroaki Chiba, Shinsuke Inuki, Shinya Oishi and Nobutaka Fujii :
The Synthesis of Alkaloids Using Transition-Metal-Catalyzed Intramolecular Amination Reactions,
Synlett, 25, 02, 179-192, Jan. 2014.

(出版サイトへのリンク): ● Publication site (DOI): 10.1055/s-0033-1340165
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1050001335810686464; ● Summary page in Scopus @ Elsevier: 2-s2.0-84892440904

(DOI: 10.1055/s-0033-1340165, CiNii: 1050001335810686464, Elsevier: Scopus)

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補助金・競争的資金: T細胞応答に関わる免疫制御リガンドの網羅的探索と潜在空間構築 (研究課題/領域番号: 24H01769 )
自然免疫型T細胞の機能を利用した新たな創薬モダリティの創出 (研究課題/領域番号: 24K02147 )
常在アーキアと宿主間における化学コミュニケーション分子の実態解明 (研究課題/領域番号: 23K17975 )
連続環化反応を基盤とする天然物合成研究と中分子モダリティへの展開 (研究課題/領域番号: 23K27294 )
免疫センサーが認識する自己成分の戦略的同定と定量法の確立 (研究課題/領域番号: 22H05183 )
軟骨細胞内Ca2+を通じた新規骨伸長促進法と骨系統疾患治療法の探索 (研究課題/領域番号: 21K19565 )
粘膜免疫における細胞間化学コミュニケーションの理解に向けた機能性分子の創製 (研究課題/領域番号: 20H04773 )
T細胞応答に関わる分子基盤の解明を目指したケミカルツールの創製研究 (研究課題/領域番号: 20K06938 )
腸管免疫に関わる化学シグナルの理解と制御を目指したケミカルツールの創製と機能解析 (研究課題/領域番号: 18H04615 )
多環式骨格構築反応を基軸とする生物活性インドールアルカロイドの全合成と創薬展開 (研究課題/領域番号: 17H03971 )
免疫におけるサイトカインバランスの制御を指向した脂質抗原受容体リガンドの創製研究 (研究課題/領域番号: 16K16638 )
脂質抗原受容体CD1dの機能解明を目指した共有結合形成型リガンドの開発とその展開 (研究課題/領域番号: 26882036 )
自然免疫-獲得免疫を制御する外因性・内因性分子の合成と機能解析、新規制御分子創製 (研究課題/領域番号: 26282211 )
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専門分野・研究分野: ライフサイエンス (Life sciences) [薬系化学、創薬科学 (Pharmaceuticals - chemistry and drug development)]
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Jグローバル最終確認日: 2025/6/7 01:17
氏名（漢字）: 井貫晋輔
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氏名（英字）: Inuki Shinsuke
所属機関: 徳島大学教授

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researchmap最終確認日: 2025/6/1 01:50
氏名（漢字）: 井貫晋輔
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氏名（英字）: Inuki Shinsuke
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所属: 徳島大学
部署: 大学院医歯薬学研究部
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研究者番号: 70736272

所属（現在）: 2025/4/1 : 徳島大学, 大学院医歯薬学研究部(薬学域), 教授

所属（過去の研究課題 情報に基づく）*注記: 2020/4/1 – 2024/4/1 : 京都大学, 薬学研究科, 准教授
2017/4/1 – 2019/4/1 : 京都大学, 薬学研究科, 助教
2016/4/1 – 2017/4/1 : 慶應義塾大学, 理工学部(矢上), 助教
2014/4/1 – 2016/4/1 : 慶應義塾大学, 理工学部, 助教

審査区分/研究分野

研究代表者

総合系 / 複合領域 / 生体分子科学 / 生物分子化学
小区分47010:薬系化学および創薬科学関連
理工系
小区分47050:環境および天然医薬資源学関連
合同審査対象区分:小区分47010:薬系化学および創薬科学関連、小区分47050:環境および天然医薬資源学関連
学術変革領域研究区分(Ⅱ)
中区分37:生体分子化学およびその関連分野

研究代表者以外

総合系 / 複合領域 / 生体分子科学 / 生物分子化学
生物系 / 医歯薬学 / 薬学 / 化学系薬学
中区分56:生体機能および感覚に関する外科学およびその関連分野
学術変革領域研究区分(Ⅲ)
小区分47010:薬系化学および創薬科学関連
小区分47050:環境および天然医薬資源学関連
合同審査対象区分:小区分47010:薬系化学および創薬科学関連、小区分47050:環境および天然医薬資源学関連

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研究代表者

免疫機能解析 / 生物有機化学 / ケミカルバイオロジー / 相互作用解析 / 分子動力学計算 / 免疫調節 / 脂質抗原受容体 / 共有結合 / 有機合成化学 / サイトカインバランス / 糖脂質 / NKT細胞 / CD1d / 糖脂質リガンド / 天然有機化合物 / 微生物代謝物 / 腸管免疫 / 化学コミュニケーション / 医薬品探索 / 天然物 / 粘膜免疫 / 構造展開 / ケミカルツール / 免疫応答 / T細胞 / 自然免疫型T細胞 / 低分子リガンド / コンジュゲート化 / ワクチンアジュバント / がん治療モダリティ / MHC分子 / ペプチド / 潜在空間 / アーキア / 常在微生物 / 自然免疫

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複合脂質 / 複合糖質 / 免疫調節 / 有機合成 / 自然免疫 / 獲得免疫 / 国際研究者交流 / アメリカ:イタリア:イギリス:ドイツ / 天然物合成 / 連続反応 / アルカロイド / 金触媒 / 創薬 / 多環式芳香族化合物 / インドール / 有機化学 / 軟骨内骨化 / 細胞内Ca2+ / C型ナトリウム利尿ペプチド / 軟骨無形成症 / 細胞内カルシウム / 軟骨細胞 / イオンチャネル / 骨伸長 / スクリーニング / 免疫センサー / 自己分子 / 免疫学 / 自己認識 / 自然免疫受容体 / Dectin-1 / 自然免疫型T細胞 / T細胞受容体 / C型レクチン受容体 / 中分子 / ケミカルスペース

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井貫 晋輔

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