論文 - 松丸　尊紀

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.

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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.

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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.

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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.

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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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Structure, solubility, and permeability relationships in a diverse middle molecule library

Miyachi H., Kanamitsu K., Ishii M., Watanabe E., Katsuyama A., Otsuguro S., Yakushiji F., Watanabe M., Matsui K., Sato Y., Shuto S., Tadokoro T., Kita S., Matsumaru T., Matsuda A., Hirose T., Iwatsuki M., Shigeta Y., Nagano T., Kojima H., Ichikawa S., Sunazuka T., Maenaka K.

Bioorganic and Medicinal Chemistry Letters 37 2021年04月

ISSN  0960894X

　概要を見る

To develop methodology to predict the potential druggability of middle molecules, we examined the structure, solubility, and permeability relationships of a diverse library (HKDL ver.1) consisting of 510 molecules (359 natural product derivatives, 76 non-natural products, 46 natural products, and 29 non-natural product derivatives). The library included peptides, depsipeptides, macrolides, and lignans, and 476 of the 510 compounds had a molecular weight in the range of 500–2000 Da. The solubility and passive diffusion velocity of the middle molecules were assessed using the parallel artificial membrane permeability assay (PAMPA). Quantitative values of solubility of 471 molecules and passive diffusion velocity of 287 molecules were obtained, and their correlations with the structural features of the molecules were examined. Based on the results, we propose a method to predict the passive diffusion characteristics of middle molecules from their three-dimensional structural features.

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Pd-catalyzed Regio- A nd Stereoselective Hydrostannylation of an Alkyl Ethynyl Ether/One-Pot Stille Coupling Enables the Synthesis of 14-Membered Macrolactone of Luminamicin

Sugawara A., Takada H., Hirose T., Kimishima A., Yamada T., Toda M., Kojima T., Matsumaru T., Sunazuka T.

Organic Letters 23 （ 5 ） 1758 - 1763 2021年03月

ISSN  15237060

　概要を見る

Regio- A nd stereoselective hydrostannylation of alkyl ethynyl ethers generates alkenyl ethers, which are useful building blocks in organic synthesis. This efficient synthetic method, however, is limited. Here, we report not only an efficient method for a highly regio- A nd stereoselective Pd-catalyzed hydrostannylation of alkyl ethynyl ethers but also a scalable synthesis and construction of the core framework of luminamicin possessing all functional groups and stereocenters.

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Toward the total synthesis of luminamicin; an anaerobic antibiotic: construction of highly functionalized cis-decalin containing a bridged ether moiety

松丸 尊紀

JOURNAL OF ANTIBIOTICS 71 （ 2 ） 268 - 272 2018年02月

研究論文（学術雑誌）,  ISSN  0021-8820

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Solid-Phase Modular Synthesis of Park Nucleotide and Lipids I and II Analogues

松丸 尊紀

CHEMICAL & PHARMACEUTICAL BULLETIN 66 （ 1 ） 84 - 95 2018年01月

研究論文（学術雑誌）,  ISSN  0009-2363

Total Synthesis of Tunicamycin V

松丸 尊紀

ORGANIC LETTERS 20 （ 1 ） 256 - 259 2018年01月

研究論文（学術雑誌）,  ISSN  1523-7060

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Divergent synthesis of kinase inhibitor derivatives, leading to discovery of selective Gck inhibitors

松丸 尊紀

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 27 （ 10 ） 2144 - 2147 2017年05月

研究論文（学術雑誌）,  ISSN  0960-894X

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Synthetic studies toward citrinadin A: construction of the pentacyclic core

松丸 尊紀

JOURNAL OF ANTIBIOTICS 69 （ 4 ） 331 - 336 2016年04月

研究論文（学術雑誌）,  ISSN  0021-8820

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Drug Discovery Assisted by Kinetic Target Guided Synthesis

松丸 尊紀

JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN 73 （ 12 ） 1245 - 1246 2015年12月

研究論文（学術雑誌）,  ISSN  0037-9980

The cell competition-based high-throughput screening identifies small compounds that promote the elimination of RasV12-transformed cells from epithelia

松丸 尊紀

SCIENTIFIC REPORTS 5   4089 - 4093 2015年10月

研究論文（学術雑誌）,  ISSN  2045-2322

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Synthetic studies toward the citrinadins: enantioselective preparation of an advanced spirooxindole intermediate

松丸 尊紀

TETRAHEDRON 70 （ 27-28 ） 4089 - 4093 2014年07月

研究論文（学術雑誌）,  ISSN  0040-4020

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An Enantioselective Total Synthesis and Stereochennical Revision of (+)-Citrinadin B

松丸 尊紀

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 135 （ 30 ） 10890 - 10893 2013年07月

研究論文（学術雑誌）,  ISSN  0002-7863

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Toward the total synthesis of Luminamicin: construction of 14-membered lactone framework possessing versatile enol ether moiety

松丸 尊紀

TETRAHEDRON LETTERS 53 （ 23 ） 2813 - 2816 2012年06月

研究論文（学術雑誌）,  ISSN  0040-4039

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Synthesis and biological properties of tensyuic acids B, C, and E, and investigation of the optical purity of natural tensyuic acid B

松丸 尊紀

TETRAHEDRON 64 （ 30-31 ） 7369 - 7377 2008年07月

研究論文（学術雑誌）,  ISSN  0040-4020

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Synthesis of the oxa-bridged octalin system of two anti-anaerobe antibiotics, luminamicin and lustromycin

Sunazuka Toshiaki, Handa Masaki, Hirose Tomoyasu, Matsumaru Takanori, Togashi Yuko, Nakamura Kaoru, Iwai Yuzuru, Omura Satoshi

Tetrahedron Letters 48 （ 30 ） 5297 - 5300 2007年07月

ISSN  0040-4039

　概要を見る

<p>An efficient, stereocontrolled entry to the 11-oxatricyclo[5.3.1.^1,70^3,8]undecane nucleus of luminamicin and lustromycin was afforded via intramolecular hetero-Michael addition of enone 7 followed by intramolecular aldol condensation of aldehyde 5 by way of the epimerization at the stereocenter attached by the aldehyde group.</p>

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Studies toward the total synthesis of irumamycin: stereoselective preparation of the C(15)-C(27) segment via two-directional chain synthesis

松丸 尊紀

TETRAHEDRON LETTERS 48 （ 3 ） 413 - 416 2007年01月

研究論文（学術雑誌）,  ISSN  0040-4039

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