松丸　尊紀 （マツマル　タカノリ）

Matsumaru, Takanori

写真a

所属（所属キャンパス）

理工学部 化学科 （矢上）

職名

助教
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  • Identification of BAY61-3606 Derivatives With Improved Activity in Splicing Modulation That Induces Inclusion of Cassette Exons Similar to the Splicing Factor 3B Subunit 1 Mutation

    Matsumaru T., Iwamatsu T., Ishigami K., Inai M., Kanto W., Ishigaki A., Toyoda A., Shuto S., Maenaka K., Nakagawa S., Maita H.

    Chemical Biology and Drug Design 104 （ 4 ）  2024年10月

    ISSN  17470277

    　概要を見る

    Splicing modulation by a small compound offers therapeutic potential for diseases caused by splicing abnormality. However, only a few classes of compounds that can modulate splicing have been identified. We previously identified BAY61-3606, a multiple kinase inhibitor, as a compound that relaxes the splicing fidelity at the 3′ splice site recognition. We have also reported the synthesis of derivatives of BAY61-3606. In this study, we tested those compounds for their splicing modulation capabilities and identified two contrasting compounds. These compounds were further investigated for their effects on the whole transcriptome, and analysis of changes in transcription and splicing revealed that the highly active derivative in the splicing reporter assay also showed significantly higher activity in modulating the splicing of endogenously expressed genes. Particularly, cassette exon inclusion was highly upregulated by this compound, and clustering analysis revealed that these effects resembled those in splicing factor 3b subunit 1 (SF3B1) K700E mutant cells but contrasted with those of the splicing inhibitor H3B-8800. Additionally, a group of serine/arginine-rich (SR) protein genes was identified as representatively affected, likely via modulation of poison exon inclusion. This finding could guide further analysis of the mode of action of these compounds on splicing, which could be valuable for developing drugs for diseases associated with splicing abnormalities.

  • Structural basis for plastic glycolipid recognition of the C-type lectin Mincle

    Furukawa A., Shuchi Y., Wang J., Guillen-Poza P.A., Ishizuka S., Kagoshima M., Ikeno R., Kumeta H., Yamasaki S., Matsumaru T., Saitoh T., Maenaka K.

    Structure 31 （ 9 ） 1077 - 1085.e5 2023年09月

    ISSN  09692126

    　概要を見る

    Mincle (macrophage-inducible C-type lectin, CLEC4E) is a C-type lectin immune-stimulatory receptor for cord factor, trehalose dimycolate (TDM), which serves as a potent component of adjuvants. The recognition of glycolipids by Mincle, especially their lipid parts, is poorly understood. Here, we performed nuclear magnetic resonance analysis, revealing that titration of trehalose harboring a linear short acyl chain showed a chemical shift perturbation of hydrophobic residues next to the Ca-binding site. Notably, there were split signals for Tyr201 upon complex formation, indicating two binding modes for the acyl chain. In addition, most Mincle residues close to the Ca-binding site showed no observable signals, suggesting their mobility on an ∼ ms scale even after complex formation. Mutagenesis study supported two putative lipid-binding modes for branched acyl-chain TDM binding. These results provide novel insights into the plastic-binding modes of Mincle toward a wide range of glycol- and glycerol-lipids, important for rational adjuvant development.

  • Chemical Degradation-Inspired Total Synthesis of the Antibiotic Macrodiolide, Luminamicin

    Kimishima A., Ando H., Sennari G., Noguchi Y., Sekikawa S., Kojima T., Ohara M., Watanabe Y., Inahashi Y., Takada H., Sugawara A., Matsumaru T., Iwatsuki M., Hirose T., Sunazuka T.

    Journal of the American Chemical Society 144 （ 50 ） 23148 - 23157 2022年12月

    ISSN  00027863

    　概要を見る

    This article describes the first total synthesis of luminamicin using a strategy combining chemical degradation with synthesis. Chemical degradation studies provided a sense of the inherent reactivity of the natural product, and deconstruction of the molecule gave rise to a key intermediate, which became the target for chemical synthesis. The core structure of the southern part of luminamicin was constructed by a 1,6-oxa-Michael reaction to form an oxa-bridged ring, followed by coupling with a functionalized organolithium species. Modified Shiina macrolactonization conditions forged the strained 10-membered lactone containing a tri-substituted olefin. Diastereoselective α-oxidation of the 10-membered lactone completed the center part to provide the key intermediate. Inspired by the degradation study, an unprecedented enol ether/maleic anhydride moiety was constructed with a one-pot chlorosulfide coupling and thiol β-elimination sequence. Finally, macrolactonization to the 14-membered ring in the presence of the highly electrophilic maleic anhydride moiety was accomplished using modified Mukaiyama reagents to complete the synthesis of luminamicin.

  • Trehalose diesters containing a polar functional group-modified lipid moiety: Synthesis and evaluation of Mincle-mediated signaling activity

    Matsumaru T., Sueyoshi K., Okubo K., Fujii S., Sakuratani K., Saito R., Ueki K., Yamasaki S., Fujimoto Y.

    Bioorganic and Medicinal Chemistry 75 2022年12月

    ISSN  09680896

    　概要を見る

    Mincle, a C-type lectin receptor (CLR), activates the innate immune system by recognizing certain complex lipid compounds. In this study, we designed and synthesized trehalose disteate (TDS) and dibehenate (TDB), containing a polar-functional group in the middle of fatty acid moieties, based on a model of the Mincle–glycolipids interaction. The modified fatty acids were prepared using hydroxy fatty acids as common intermediates, and conjugated with an appropriate trehalose moiety to synthesize the desired trehalose diesters. TDE derivatives containing the modified fatty acid have different Mincle-mediated signaling activities depending on the position of the functional group and the length of the lipids. The newly developed TDE derivatives exhibit signaling activity comparable or superior to that of TDS or TDB, and the results suggest that Mincle tolerates polar functional groups at a certain position of the lipid chain of TDE. The introduction of the polar functional groups into the lipid moiety of the glycolipids also resulted in improved solubility in polar solvents, which would be advantageous for various analyses and applications.

  • Fungal β-Mannosyloxymannitol Glycolipids and Their Analogues: Synthesis and Mincle-Mediated Signaling Activity

    Matsumaru T., Sakuratani K., Yanaka S., Kato K., Yamasaki S., Fujimoto Y.

    European Journal of Organic Chemistry 2022 （ 20 ）  2022年05月

    ISSN  1434193X

    　概要を見る

    Mincle, a C-type lectin receptor (CLR), senses certain lipid conjugates, leading to the activation of the innate immune system. The lipid conjugate ligands include glyco-, glycero-, and mannitol lipids. Recently, a fungal β-mannosyloxymannitol glycolipid demonstrating a novel architecture, “44-2,” was isolated from the fungus Malassezia and displayed potent Mincle-mediated signaling activity. For this study, we synthesized the diastereomeric pair of mannosyloxymannitol glycolipids and their analogues and analyzed the structure-activity relationships of Mincle-mediated signaling. The results suggest that the dimannosyl-fatty acid moiety in the mannosyloxymannitol glycolipid-type structure plays a major role in the molecular recognition of Mincle.

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  • 細菌由来リポタイコ酸および関連分子の合成と自然免疫受容体の機能解析

    2023年04月
    -
    2026年03月

    松丸 尊紀, 基盤研究(C), 補助金,  研究代表者

  • 自然免疫受容体Mincleのリガンド合成を基盤とした分子認識および細胞内挙動解析

    2020年04月
    -
    2023年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 松丸 尊紀, 基盤研究(C), 補助金,  研究代表者

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担当授業科目 【 表示 ／ 非表示 】

  • 理工学基礎実験

    2025年度

  • 化学実験第２

    2025年度

  • 理工学基礎実験

    2024年度

  • 化学実験第２

    2024年度

  • 理工学基礎実験

    2023年度

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所属学協会 【 表示 ／ 非表示 】

  • 日本化学会

    　

  • 日本薬学会

    　

  • 有機合成化学協会

    　

  • 日本ケミカルバイオロジー学会

    　
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