2023/10/11 更新

写真a

アマイケ カズマ
天池 一真
AMAIKE Kazuma
所属
物質科学国際研究センター 助教
大学院担当
大学院理学研究科
職名
助教
外部リンク

学位 1

  1. 博士(理学) ( 2016年3月   名古屋大学 ) 

 

論文 22

  1. Nickel/Photoredox-Catalyzed Decarboxylative Coupling of Aryl Bromides with N -Protected Glycine as an Aminomethyl Source

    Jung Jaehyun, Kinoshita Takumi, Makihara Yuta, Sakakibara Yota, Amaike Kazuma, Murakami Kei, Itami Kenichiro

    SYNLETT     2023年7月

  2. Development of a novel PET ligand, [<SUP>11</SUP>C]GO289 targeting CK2 expressed in the brain

    Ogata Aya, Yamada Takashi, Hattori Saori, Ikenuma Hiroshi, Abe Junichiro, Tada Mari, Ichise Masanori, Suzuki Masaaki, Ito Kengo, Kato Takashi, Amaike Kazuma, Hirota Tsuyoshi, Kakita Akiyoshi, Itami Kenichiro, Kimura Yasuyuki

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS   90 巻   頁: 129327   2023年6月

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    記述言語:英語   出版者・発行元:Bioorganic and Medicinal Chemistry Letters  

    Positron emission tomography (PET) is a powerful imaging tool that enables early in vivo detection of Alzheimer's disease (AD). For this purpose, various PET ligands have been developed to image β-amyloid and tau protein aggregates characteristically found in the brain of AD patients. In this study, we initiated to develop another type of PET ligand that targets protein kinase CK2 (formerly termed as casein kinase II), because its expression level is known to be altered in postmortem AD brains. CK2 is a serine/threonine protein kinase, an important component of cellular signaling pathways that control cellular degeneration. In AD, the CK2 level in the brain is thought to be elevated by its involvement in both phosphorylation of proteins such as tau and neuroinflammation. Decreased CK2 activity and expression levels lead to β-amyloid accumulation. In addition, since CK2 also contributes to the phosphorylation of tau protein, the expression level and activity of CK2 is expected to undergo significant changes during the progression of AD pathology. Furthermore, CK2 could act as a potential target for modulating the inflammatory response in AD. Therefore, PET imaging targeting CK2 expressed in the brain could be a useful another imaging biomarker for AD. We synthesized and radiolabeled a CK2 inhibitor, [11C]GO289, in high yields from its precursor and [11C]methyl iodide under basic conditions. On autoradiography, [11C]GO289 specifically bound to CK2 in both rat and human brain sections. On baseline PET imaging, this ligand entered and rapidly washed out of the rat brain with its peak activity rather being small (SUV < 1.0). However, on blocking, there was no detectable CK2 specific binding signal. Thus, [11C]GO289 may be useful in vitro but not so in vivo in its current formulation. The lack of detectable specific binding signal in the latter may be due to a relatively high component of nonspecific binding signal in the overall rather weak PET signal, or it may also be related to the known fact that ATP can competitively binds to subunits of CK2, reducing its availability for this ligand. In the future, it will be necessary for PET imaging of CK2 to try out different non-ATP competitive formulations of CK2 inhibitor that can also provide significantly higher in vivo brain penetration.

    DOI: 10.1016/j.bmcl.2023.129327

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  3. C-H arylation enables synthesis of imidazole-4-carboxamide (ICA) based fairy chemicals with plant growth-promoting activity

    Ueda Ayaka, Amaike Kazuma, Shirotani Yoko, Ito Hideto, Warstat Robin, Choi Jae-Hoon, Kawagishi Hirokazu, Itami Kenichiro

    CANADIAN JOURNAL OF CHEMISTRY   101 巻 ( 7 ) 頁: 449 - 452   2023年5月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Canadian Journal of Chemistry  

    Imidazole-4-carboxamide (ICA), which is one of the groups of “fairy chemicals” (FCs) that cause the fairy ring phenomena, has plant growth inhibitory activity. FCs have the potential as candidates for a new family of plant hormones as they have been found endogenously in all plant species tested and show growth-regulating activities against the plants. While basic research on FCs is progressing, they are also expected to be applied not only to agrochemicals but also as pharmaceuticals. Derivatization of one of the FCs, 2-azahypoxanthine, and the structure-activity relationship (SAR) studies have clarified its activity as a plant growth promoter. Yet, ICA has not been derivatized at all and SAR regarding its activity remains unknown. In this study, we synthesized the derivatives of ICA by direct C-H arylation of ICA precursors and evaluated its activity in rice. The 12 total compounds including the arylated ICAs and their precursors were evaluated for root and shoot elongation in rice, resulting in the discovery that a number of compounds unexpectedly have an elongation activity in the root and shoot.

    DOI: 10.1139/cjc-2022-0256

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  4. Revisiting PFA-mediated tissue fixation chemistry: FixEL enables trapping of small molecules in the brain to visualize their distribution changes

    Nonaka Hiroshi, Mino Takeharu, Sakamoto Seiji, Oh Jae Hoon, Watanabe Yu, Ishikawa Mamoru, Tsushima Akihiro, Amaike Kazuma, Kiyonaka Shigeki, Tamura Tomonori, Radu Aricescu A., Kakegawa Wataru, Miura Eriko, Yuzaki Michisuke, Hamachi Itaru

    Chem   9 巻 ( 2 ) 頁: 523 - 540   2023年2月

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    記述言語:英語  

    Various small molecules have been used as functional probes for tissue imaging in medical diagnosis and pharmaceutical drugs for disease treatment. The spatial distribution, target selectivity, and diffusion/excretion kinetics of small molecules in structurally complicated specimens are critical for function. However, robust methods for precisely evaluating these parameters in the brain have been limited. Herein, we report a new method termed “fixation-driven chemical cross-linking of exogenous ligands (FixEL), ” which traps and images exogenously administered molecules of interest (MOIs) in complex tissues. This method relies on protein-MOI interactions and chemical cross-linking of amine-tethered MOI with paraformaldehyde used for perfusion fixation. FixEL is used to obtain images of the distribution of the small molecules, which addresses selective/nonselective binding to proteins, time-dependent localization changes, and diffusion/retention kinetics of MOIs such as the scaffold of PET tracer derivatives or drug-like small molecules.

    CiNii Research

  5. Revisiting PFA-mediated tissue fixation chemistry:<i> FixEL</i> enables trapping of small molecules in the brain to visualize their distribution changes

    Nonaka Hiroshi, Mino Takeharu, Sakamoto Seiji, Oh Jae Hoon, Watanabe Yu, Ishikawa Mamoru, Tsushima Akihiro, Amaike Kazuma, Kiyonaka Shigeki, Tamura Tomonori, Aricescu A. Radu, Kakegawa Wataru, Miura Eriko, Yuzaki Michisuke, Hamachi Itaru

    CHEM   9 巻 ( 2 ) 頁: 523 - 540   2023年2月

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    出版者・発行元:Chem  

    Various small molecules have been used as functional probes for tissue imaging in medical diagnosis and pharmaceutical drugs for disease treatment. The spatial distribution, target selectivity, and diffusion/excretion kinetics of small molecules in structurally complicated specimens are critical for function. However, robust methods for precisely evaluating these parameters in the brain have been limited. Herein, we report a new method termed “fixation-driven chemical cross-linking of exogenous ligands (FixEL),” which traps and images exogenously administered molecules of interest (MOIs) in complex tissues. This method relies on protein-MOI interactions and chemical cross-linking of amine-tethered MOI with paraformaldehyde used for perfusion fixation. FixEL is used to obtain images of the distribution of the small molecules, which addresses selective/nonselective binding to proteins, time-dependent localization changes, and diffusion/retention kinetics of MOIs such as the scaffold of PET tracer derivatives or drug-like small molecules.

    DOI: 10.1016/j.chempr.2022.11.005

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  6. Discovery of 2,6-Dihalopurines as Stomata Opening Inhibitors: Implication of an LRX-Mediated H plus -ATPase Phosphorylation Pathway

    Ueda Ayaka, Aihara Yusuke, Sato Shinya, Kano Keiko, Mishiro-Sato Emi, Kitano Hiroyuki, Sato Ayato, Fujimoto Kazuhiro J., Yanai Takeshi, Amaike Kazuma, Kinoshita Toshinori, Itami Kenichiro

    ACS CHEMICAL BIOLOGY   18 巻 ( 2 ) 頁: 347 - 355   2023年1月

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    記述言語:英語   出版者・発行元:ACS Chemical Biology  

    Stomata are pores in the leaf epidermis of plants and their opening and closing regulate gas exchange and water transpiration. Stomatal movements play key roles in both plant growth and stress responses. In recent years, small molecules regulating stomatal movements have been used as a powerful tool in mechanistic studies, as well as key players for agricultural applications. Therefore, the development of new molecules regulating stomatal movement and the elucidation of their mechanisms have attracted much attention. We herein describe the discovery of 2,6-dihalopurines, AUs, as a new stomatal opening inhibitor, and their mechanistic study. Based on biological assays, AUs may involve in the pathway related with plasma membrane H+-ATPase phosphorylation. In addition, we identified leucine-rich repeat extensin proteins (LRXs), LRX3, LRX4 and LRX5 as well as RALF, as target protein candidates of AUs by affinity based pull down assay and molecular dynamics simulation. The mechanism of stomatal movement related with the LRXs-RALF is an unexplored pathway, and therefore further studies may lead to the discovery of new signaling pathways and regulatory factors in the stomatal movement.

    DOI: 10.1021/acschembio.2c00771

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  7. Synthesis, properties, and material hybridization of bare aromatic polymers enabled by dendrimer support

    Fujiki Shusei, Amaike Kazuma, Yagi Akiko, Itami Kenichiro

    NATURE COMMUNICATIONS   13 巻 ( 1 ) 頁: 5358   2022年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nature Communications  

    Aromatic polymers are the first-choice platform for current organic materials due to their distinct optical, electronic, and mechanical properties as well as their biocompatibility. However, bare aromatic polymer backbones tend to strongly aggregate, rendering them essentially insoluble in organic solvent. While the typical solution is to install many solubilizing substituents on the backbones, this often provokes undesired property changes. Herein, we report the synthesis of bare aromatic polymers enabled by a dendrimer support. An initiator arene containing a diterpenoid-based dendrimer undergoes Pd-catalyzed polymerization with monomers bearing no solubilizing substituents to furnish bare aromatic polymers such as polythiophenes and poly(para-phenylene)s. The high solubility of dendrimer-ligated polymers allows not only the unveiling of the properties of unsubstituted π-conjugated backbone, but also mild release of dendrimer-free aromatic polymers and even transfer of aromatic polymers to other materials, such as silica gel and protein, which may accelerate the creation of hybrid materials nowadays challenging to access.

    DOI: 10.1038/s41467-022-33100-7

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    その他リンク: https://www.nature.com/articles/s41467-022-33100-7

  8. Photopharmacological Manipulation of Mammalian CRY1 for Regulation of the Circadian Clock

    Kolarski Dusan, Miller Simon, Oshima Tsuyoshi, Nagai Yoshiko, Aoki Yugo, Kobauri Piermichele, Srivastava Ashutosh, Sugiyama Akiko, Amaike Kazuma, Sato Ayato, Tama Florence, Szymanski Wiktor, Feringa Ben L., Itami Kenichiro, Hirota Tsuyoshi

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   143 巻 ( 4 ) 頁: 2078 - 2087   2021年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of the American Chemical Society  

    CRY1 and CRY2 proteins are highly conserved components of the circadian clock that controls daily physiological rhythms. Disruption of CRY functions are related to many diseases, including circadian sleep phase disorder. Development of isoform-selective and spatiotemporally controllable tools will facilitate the understanding of shared and distinct functions of CRY1 and CRY2. Here, we developed CRY1-selective compounds that enable light-dependent manipulation of the circadian clock. From phenotypic chemical screening in human cells, we identified benzophenone derivatives that lengthened the circadian period. These compounds selectively interacted with the CRY1 photolyase homology region, resulting in activation of CRY1 but not CRY2. The benzophenone moiety rearranged a CRY1 region called the "lid loop"located outside of the compound-binding pocket and formed a unique interaction with Phe409 in the lid loop. Manipulation of this key interaction was achieved by rationally designed replacement of the benzophenone with a switchable azobenzene moiety whose cis-trans isomerization can be controlled by light. The metastable cis form exhibited sufficiently high half-life in aqueous solutions and structurally mimicked the benzophenone unit, enabling reversible period regulation over days by cellular irradiation with visible light. This study revealed an unprecedented role of the lid loop in CRY-compound interaction and paves the way for spatiotemporal regulation of CRY1 activity by photopharmacology for molecular understanding of CRY1-dependent functions in health and disease.

    DOI: 10.1021/jacs.0c12280

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  9. An Isoform-Selective Modulator of Cryptochrome 1 Regulates Circadian Rhythms in Mammals 国際誌

    Miller Simon, Aikawa Yoshiki, Sugiyama Akiko, Nagai Yoshiko, Hara Aya, Oshima Tsuyoshi, Amaike Kazuma, Kay Steve A., Itami Kenichiro, Hirota Tsuyoshi

    CELL CHEMICAL BIOLOGY   27 巻 ( 9 ) 頁: 1192 - +   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cell Chemical Biology  

    Cryptochrome 1 (CRY1) and CRY2 are core regulators of the circadian clock, and the development of isoform-selective modulators is important for the elucidation of their redundant and distinct functions. Here, we report the identification and functional characterization of a small-molecule modulator of the mammalian circadian clock that selectively controls CRY1. Cell-based circadian chemical screening identified a thienopyrimidine derivative KL201 that lengthened the period of circadian rhythms in cells and tissues. Functional assays revealed stabilization of CRY1 but not CRY2 by KL201. A structure-activity relationship study of KL201 derivatives in combination with X-ray crystallography of the CRY1-KL201 complex uncovered critical sites and interactions required for CRY1 regulation. KL201 bound to CRY1 in overlap with FBXL3, a subunit of ubiquitin ligase complex, and the effect of KL201 was blunted by knockdown of FBXL3. KL201 will facilitate isoform-selective regulation of CRY1 to accelerate chronobiology research and therapeutics against clock-related diseases.

    DOI: 10.1016/j.chembiol.2020.05.008

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  10. Small Molecules Modulating Mammalian Biological Clocks: Exciting New Opportunities for Synthetic Chemistry

    Amaike Kazuma, Oshima Tsuyoshi, Skoulding Nicola Stephanie, Toyama Yoshifumi, Hirota Tsuyoshi, Itami Kenichiro

    CHEM   6 巻 ( 9 ) 頁: 2186 - 2198   2020年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Chem  

    Challenges and opportunities: • Increasing opportunities for the discovery of new circadian clock modulators, which are attractive drug candidates for clock-related diseases in pharmaceutical industry, and to enhance crop yield in agriculture. • Development of new reactions for rapid access to hit compound derivatives, accelerating structure-activity relationship studies, which are generally time consuming. • New approaches for target identification of clock-modulating small molecules, which is still challenging, enable molecular-level understanding and new structural designs.

    DOI: 10.1016/j.chempr.2020.08.011

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  11. Construction of a Fluorescent Screening System of Allosteric Modulators for the GABA<sub>A</sub> Receptor Using a Turn-On Probe 査読有り

    Sakamoto Seiji, Yamaura Kei, Numata Tomohiro, Harada Fumio, Amaike Kazuma, Inoue Ryuji, Kiyonaka Shigeki, Hamachi Itaru

    ACS CENTRAL SCIENCE   5 巻 ( 9 ) 頁: 1541 - 1553   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACS Central Science  

    γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. The fast inhibitory actions of GABA are mainly mediated by GABAA receptors (GABAARs), which are widely recognized as clinically relevant drug targets. However, it remains difficult to create screening systems for drug candidates that act on GABAARs because of the existence of multiple ligand-binding sites and the delicate pentameric structures of GABAARs. We here developed the first turn-on fluorescent imaging probe for GABAARs, which can be used to quantitatively evaluate ligand-receptor interactions under live cell conditions. Using noncovalent labeling of GABAARs with this turn-on probe, a new imaging-based ligand assay system, which allows discovery of positive allosteric modulators (PAMs) for the GABAAR, was successfully constructed. Our system is applicable to high-throughput ligand screening, and we discovered new small molecules that function as PAMs for GABAARs. These results highlight the power of the use of a turn-on fluorescent probe to screen drugs for complicated membrane proteins that cannot be addressed by conventional methods.

    DOI: 10.1021/acscentsci.9b00539

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  12. Synthesis of multiply arylated pyridines 査読有り

    Asako Takashi, Hayashi Wakana, Amaike Kazuma, Suzuki Shin, Itami Kenichiro, Muto Kei, Yamaguchi Junichiro

    TETRAHEDRON   73 巻 ( 26 ) 頁: 3669 - 3676   2017年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Tetrahedron  

    We have achieved a synthesis of multiply arylated pyridines by using a [4 + 2] cycloaddition of 2,4-diaryl-5-chloroxazoles and cinnamic acids as a key reaction. The resulting hydroxytriarylpyridines can be derivatized into triarylpyridines, tetraarylpyridines and pentaarylpyridines by sequential cross-couplings. This synthetic method allows for facile and rapid access to highly arylated pyridines with different aryl substituents.

    DOI: 10.1016/j.tet.2017.03.095

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  13. Affinity-Guided Oxime Chemistry for Selective Protein Acylation in Live Tissue Systems. 査読有り

    Tamura T, Song Z, Amaike K, Lee S, Yin S, Kiyonaka S, Hamachi I

    Journal of the American Chemical Society   139 巻 ( 40 ) 頁: 14181 - 14191   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1021/JACS.7B07339

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  14. Recognition-driven chemical labeling of endogenous proteins in multi-molecular crowding in live cells. 査読有り

    Amaike K, Tamura T, Hamachi I

    Chemical communications (Cambridge, England)   53 巻 ( 88 ) 頁: 11972 - 11983   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1039/C7CC07177A

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  15. Synthesis of Triarylpyridines in Thiopeptide Antibiotics by Using a C-H Arylation/Ring-Transformation Strategy 査読有り

    Amaike Kazuma, Itami Kenichiro, Yamaguchi Junichiro

    CHEMISTRY-A EUROPEAN JOURNAL   22 巻 ( 13 ) 頁: 4384 - 4388   2016年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Chemistry - A European Journal  

    We have described a C-H arylation/ring-transformation strategy for the synthesis of triarylpyridines, which form the core structure of thiopeptide antibiotics. This synthetic method readily gave 2,3,6-triarylpyridines in a regioselective manner by a two-phase approach: C-H arylation (a nickel-catalyzed decarbonylative Suzuki-Miyaura cross-coupling and decarbonylative C-H coupling for the synthesis of 2,4-diaryloxazoles) and ring transformation ([4+2] cycloaddition of 2,4-diaryloxazoles with (hetero)arylacrylic acids). To showcase these methods, we have accomplished the formal synthesis of thiopeptide antibiotics GE2270 s and amythiamicins.

    DOI: 10.1002/chem.201600351

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  16. Direct C7 Functionalization of Tryptophan. Synthesis of Methyl (<i>S</i>)-2-((<i>tert</i>-Butoxycarbonyl)amino)-3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1<i>H</i>-indol-3-yl)propanoate. 査読有り

    Amaike K, Loach RP, Movassaghi M

    Organic syntheses; an annual publication of satisfactory methods for the preparation of organic chemicals   92 巻   頁: 373 - +   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.15227/ORGSYN.092.0373

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  17. β-Selective C-H Arylation of Pyrroles Leading to Concise Syntheses of Lamellarins C and I 査読有り

    Ueda Kirika, Amaike Kazuma, Maceiczyk Richard M., Itami Kenichiro, Yamaguchi Junichiro

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   136 巻 ( 38 ) 頁: 13226 - 13232   2014年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of the American Chemical Society  

    The first general β-selective C-H arylation of pyrroles has been developed by using a rhodium catalyst. This C-H arylation reaction, which is retrosynthetically straightforward but results in unusual regioselectivity, could result in de novo syntheses of pyrrole-derived natural products and pharmaceuticals. As such, we have successfully synthesized polycyclic marine pyrrole alkaloids, lamellarins C and I, by using this β-selective arylation of pyrroles with aryl iodides (C-H/C-I coupling) and a new double C-H/C-H coupling as key steps.

    DOI: 10.1021/ja508449y

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  18. Late-Stage C-H Coupling Enables Rapid Identification of HDAC Inhibitors: Synthesis and Evaluation of NCH-31 Analogues 査読有り

    Sekizawa Hiromi, Amaike Kazuma, Itoh Yukihiro, Suzuki Takayoshi, Itami Kenichiro, Yamaguchi Junichiro

    ACS MEDICINAL CHEMISTRY LETTERS   5 巻 ( 5 ) 頁: 582 - 586   2014年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACS Medicinal Chemistry Letters  

    We previously reported the discovery of NCH-31, a potent histone deacetylase (HDAC) inhibitor. By utilizing our C-H coupling reaction, we rapidly synthesized 16 analogues (IYS-1 through IYS-15 and IYS-Me) of NCH-31 with different aryl groups at the C4-position of 2-aminothiazole core of NCH-31. Subsequent biological testing of these derivatives revealed that 3-fluorophenyl (IYS-10) and 4-fluorophenyl (IYS-15) derivatives act as potent pan-HDAC inhibitor. Additionally, 4-methylphenyl (IYS-1) and 3-fluoro-4-methylphenyl (IYS-14) derivatives acted as HDAC6-insensitive inhibitors. The present work clearly shows the power of the late-stage C-H coupling approach to rapidly identify novel and highly active/selective biofunctional molecules. © 2014 American Chemical Society.

    DOI: 10.1021/ml500024s

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  19. C7-derivatization of C3-alkylindoles including tryptophans and tryptamines. 査読有り

    Loach RP, Fenton OS, Amaike K, Siegel DS, Ozkal E, Movassaghi M

    The Journal of organic chemistry   79 巻 ( 22 ) 頁: 11254 - 11263   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1021/JO502062Z

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  20. Nickel-Catalyzed Direct Coupling of Heteroarenes

    Yamaguchi Junichiro, Muto Kei, Amaike Kazuma, Yamamoto Takuya, Itami Kenichiro

    JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN   71 巻 ( 6 ) 頁: 576 - 587   2013年6月

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    記述言語:日本語  

    Web of Science

  21. Nickel-catalyzed direct coupling of heteroarenes 査読有り

    Yamaguchi J., Muto K., Amaike K., Yamamoto T., Itami K.

    Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry   71 巻 ( 6 ) 頁: 576 - 587   2013年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry  

    Nickel-catalyzed cross-coupling reactions have recently been receiving significant attention from the synthetic community as a way to construct carbon-carbon or carbon-heteroatom bonds, because nickel catalysts are less expensive and less toxic than palladium catalysts. We herein describe our recent developments in nickel-catalyzed biaryl coupling methodology, along with mechanistic studies and applications to the synthesis of natural products and pharmaceuticals. In particular, we focus on nickel-catalyzed direct coupling reactions in which "unreactive" bonds such as C-H, C-O, and C-C bonds are converted into biaryl moieties.

    DOI: 10.5059/YUKIGOSEIKYOKAISHI.71.576

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  22. Decarbonylative C-H Coupling of Azoles and Aryl Esters: Unprecedented Nickel Catalysis and Application to the Synthesis of Muscoride A 査読有り

    Amaike Kazuma, Muto Kei, Yamaguchi Junichiro, Itami Kenichiro

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   134 巻 ( 33 ) 頁: 13573 - 13576   2012年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of the American Chemical Society  

    A nickel-catalyzed decarbonylative C-H biaryl coupling of azoles and aryl esters is described. The newly developed catalytic system does not require the use of expensive metal catalysts or silver- or copper-based stoichiometric oxidants. We have successfully applied this new C-H arylation reaction to a convergent formal synthesis of muscoride A. © 2012 American Chemical Society.

    DOI: 10.1021/ja306062c

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▼全件表示

MISC 1

  1. Synthesis of Natural Products and Pharmaceuticals via Catalytic C-H Functionalization

    Yamaguchi J., Amaike K., Itami K.  

    Transition Metal-Catalyzed Heterocycle Synthesis via C-H Activation   頁: 505 - 550   2016年1月

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    記述言語:英語   出版者・発行元:Transition Metal-Catalyzed Heterocycle Synthesis via C-H Activation  

    The synthesis of natural products and pharmaceuticals, particularly those containing heterocyclic frameworks, can be dramatically simplified by using catalytic C-H functionalization. C-H functionalization has gathered significant interest from the organic synthesis community because it provides a new strategy to construct carbon-carbon and carbon-heteroatom bonds in highly functionalized, complex molecules without prefunctionalization. In this book chapter, methods in heterocycle substitution and synthesis using catalytic C-H functionalization are classified by heterocycle, with specific focus on the cutting-edge synthesis of natural products and pharmaceuticals.

    DOI: 10.1002/9783527691920.ch16

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科研費 3

  1. 核酸輸送を加速させる一次元伸張ナノカーボン分子の創製

    研究課題/研究課題番号:22K14797  2022年4月 - 2024年3月

    科学研究費助成事業  若手研究

    天池 一真

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    担当区分:研究代表者 

    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    核酸輸送はDNAやRNAを外部から宿主細胞に導入することであり、創薬や育種の現場から基礎生物学に至るまで生命科学研究に絶対的に不可欠な技術である。生命現象の理解と制御のさらなる高度化が必要な今、効率や選択性はもちろんのこと生体直交性などの多様な機能が核酸輸送に求められている。核酸輸送の分野に全く新しい方法、キャリア分子群の登場がまたれる所以である。本研究では、哺乳・植物・昆虫を対象とした核酸輸送を加速させるテーラーメイドな核酸輸送ナノカーボン分子を創製することで基礎と応用の両面からこの分野に非線形のブレークスルーをもたらす。

  2. シナジー効果を有する化合物群のAI による探索と設計

    研究課題/研究課題番号:20H05797  2020年10月 - 2023年3月

    科学研究費助成事業  学術変革領域研究(B)

    山西 芳裕, 天池 一真, 竹下 潤一, 味八木 茂

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    担当区分:研究分担者 

    複数の薬剤の組み合わせによる相乗効果(薬剤シナジー)を活用した化学療法が、がんや神経変性疾患など多因子疾患に対する有効な治療法として注目されている。本研究では、疾患状態の生体情報を入力とし、シナジー効果を有する薬剤群を予測するAIを開発する。さらに、より高いシナジー効果を有する新しい化合物群を設計するAIを開発する。有機化合物の組み合わせ数は膨大であり、実験的に全ての可能性を検証することは不可能である。生体情報から複数の薬剤群(または化合物群)を最適化できないか?という問いに対し、物質・生命科学のビッグデータと情報科学のAI技術を融合し、新たな方法論を創生する。
    複数の薬剤の組み合わせによる相乗効果(薬剤シナジー)を活用した化学療法が、がんや神経変性疾患など多因子疾患に対する有効な治療法として注目されている。有機化合物の組み合わせ数は膨大であり、実験的に全ての可能性を検証することは不可能である。本研究では、疾患状態の生体情報を入力とし、シナジー効果を有する薬剤群を予測するAIを開発する。
    慢性骨髄性白血病など様々な疾患患者の遺伝子発現プロファイルデータやヒト由来細胞における化合物応答遺伝子発現データをGEO(Gene Expression Obmnibus)から収集して、情報解析できる形に整備した。ネットワーク生物学の技術を駆使し、シグナル伝達、タンパク質間相互作用、遺伝子制御などの生体分子ネットワークのトポロジーを基に、異なる薬剤が影響を及ぼす遺伝子群とシナジー効果の関係を解析した。遺伝子発現プロファイルの視点から、疾患特有の遺伝子発現プロファイルと相関する薬剤の組み合わせを、最適な薬剤の組み合わせの候補として予測する手法のプロトタイプを開発し、その性能を数値的に検証した。その結果、先行研究の手法を大幅に上回る精度を達成することができた。
    組合せ最適化などの数理科学を活用し、薬剤や生体分子の組合せ問題の数理モデル化とその理論的解法の開発を行った。薬剤や医薬品以外の化合物データに関しても、ChEMBL, PubChemなどの化学物質データベースのデータを整備した。化合物の化学構造や遺伝子発現プロファイルを基に、新しい化合物の組み合わせを検出する最適化アルゴリズムを実装した。
    有機合成に関する知識に基づく分子設計をAIに組み込む方法を開発した。合成のしやすさなども考慮する方法を検討した。さらに設計した分子を迅速に供給するため、周辺化合物を一挙に合成する方法の開発に取り組んだ。
    慢性骨髄性白血病など様々な疾患患者の遺伝子発現プロファイルデータ、ヒト由来細胞における化合物応答遺伝子発現データ、遺伝子制御などの生体分子ネットワークのトポロジーを基に、最適な薬剤の組み合わせの候補を予測する手法のプロトタイプを開発し、その性能を数値的に検証した。その結果、先行研究の手法を大幅に上回る精度を達成することができた。また、組合せ最適化などの数理科学を活用し、薬剤の組合せを検出する最適化アルゴリズムを実装した。医療の問題における化合物の組み合わせを再現できるかで評価し、良好な結果を得ることができた。AIで予測した化合物の構造を実際に合成したところ、期待する活性を持つことが確認できた。
    現在の開発した手法のプロトタイプは、承認薬で性能を確認している。これを承認薬以外の化合物にも応用し、大規模なデータにおいても高い性能を示すか検証する。薬理班と連携して、予測した化合物の組み合わせ効果の数を増やして実験検証をより進める。組み合わせ効果に関連すると思われる遺伝子群の発現変動の考察を行う。

  3. フェアリー化合物の科学とその応用展開

    研究課題/研究課題番号:20H05620  2020年7月 - 2025年3月

    科学研究費助成事業  特別推進研究

    河岸 洋和, 天池 一真, 鈴木 智大, 室井 誠, 高橋 公咲, 謝 肖男, 野村 崇人, 大内 仁志, 一家 崇志, 菅 敏幸, 伊藤 英人

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    担当区分:研究分担者 

    芝が輪状に周囲より繁茂あるいは枯死した後にキノコが発生する現象を「フェアリーリング」という。研究代表者はこの現象の原因物質(AHX,ICA,AOH)を発見した。その後,これら3物質(フェアリー化合物,fairy chemicalsと総称,FCsと略称)の植物における内生が判明し,さらに圃場試験において農作物の増収効果を示した。本研究では,植物と菌類中で新規な経路でこれらの物質が生合成されることを明らかにし,活性発現分子機構を解明する。また,農業への実用化を目指しFCsの作物の栽培実験での効果と作用機構を検討する。最終的にはFCsが新しい植物ホルモンであることを証明する。
    1. FCsの生合成経路・代謝経路・活性発現機構の解明:得られているFCs代謝産物のLC-MS/MSのよる定量法を開発し,イネにおける内生量の定量に成功した。FCsのシグナル因子・受容体の探索を行うため,シロイヌナズナの自然系統200以上からAHXに感受性が高い系統を選抜後,EMSによる変異原処理をした変異種子集団の作成を行った。AHXの受容体候補タンパク質であるイネのV-ATPase Bサブユニットの組換えタンパク質を作製し,AHXと本タンパク質の相互作用について解析中である。骨格起源の候補であるArgを含めた数種の同位体ラベルアミノ酸の取り込み実験を行い,骨格の起源がほぼ判明した。イネから得られたS-ICAr-Hを,ICAを処理したシロイヌナズナ,出芽酵母でも生成することを明らかにした。
    2. FCsによる作物増産効果の分子機構の解明:イネコアコレクション107品種を対象にFCs内生量を定量した。コムギ2品種を対象に,FCs処理による低窒素施肥条件下での収量増加効果をフィールド栽培試験により検討した。
    3. FCsの多彩な研究を支援する合成化学的アプローチ:プロセス合成の最適条件はほぼ確立した。FCsの窒素・炭素骨格の起源を明らかにするために必要となるグアニジノ基のみが15Nと13Cで完全にラベル化されたアルギニンは,グアニジン-13C, 15N3を原料に用い合成を達成した。AHX誘導体の気孔開口阻害活性を評価し,数種のAHX誘導体は気孔開口阻害活性をもつことを明らかにした。
    4. 新たな展開:AHXが低酸素因子(HIF)の産生を阻害し,酸素誘導網膜症モデルマウスに対して網膜血管新生を抑制することを見出した。AOHがヒト表皮細胞の賦活化し,DNAマイクロアレイによって,賦活化関連遺伝子の発現が促進されることが判明した。
    FCsの骨格起源の候補であるArgを含めた数種の同位体ラベルアミノ酸の取り込み実験を行い,骨格の起源がほぼ判明し,イネから得られたS-ICAr-Hを,ICAを処理したシロイヌナズナ,出芽酵母でも生成することを明らかにした。また,コムギ2品種を対象に,FCs処理による低窒素施肥条件下での収量増加効果をフィールド栽培試験により検討した。さらに,AHXが低酸素因子(HIF)の産生を阻害し,酸素誘導網膜症モデルマウスに対して網膜血管新生を抑制することを見出し,AOHがヒト表皮細胞の賦活化し,DNAマイクロアレイによって,賦活化関連遺伝子の発現が促進されることが明らかにした。以上のように,計画通りあるいは計画以上に進んでいる。
    1. FCsの生合成経路・代謝経路・活性発現機構の解明:FCsのさらなる代謝産物を単離,構造を行い,植物中での内生の有無を確認し生物活性を明らかにする。イネ,シロイヌナズナ,コムラサキシメジにおけるFCsの生合成に関わると考えられる酵素を大腸菌等で異種発現し,FCsとの関係を検討する。生命情報学的手法を用いてAHXに関わる受容体およびシグナル因子の探索を行う。FCs化合物の超高感度質量分析法を用いて,化合物ライブラリーを使用し,FCsの内生量を減少または増加させる化合物のスクリーニングを行う。生体分子間相互作用解析システムを用い,各FCsをリガンドとして固定,特異的結合物質を探索し,受容体・シグナル因子の発見を目指す。FCsの動物細胞など,他の種類の細胞についても相互作用するタンパク質を探索する。同位体ラベルした各種生合成前駆体の取り込み実験を行い,FCsや他の塩基も同時に分析し,その窒素・炭素骨格の起源を明らかにする。
    2. FCsによる作物増産効果の分子機構の解明:イネコアコレクションを対象にFCs内生量を質量分析により定量し,生合成に関わる遺伝要因をGWASにより明らかにする。メタボローム解析によりFCsに対する代謝応答を明らかにし,FCsの作用機序を解明する。FCsの温室またはフィールド環境下での栽培試験における検討する。
    3. FCsの多彩な研究を支援する合成化学的アプローチ:FCsの生合成中間体として予想されるFCsリボシドの5'-triphosphate や5'-diphosphateの合成的供給を行い,植物における内生の有無を検証する。FCsの各種誘導体による構造と活性の情報蓄積を目的として各種誘導体合成を行う。
    4. FCsの薬理効果をin vitro,in vivoでさらに検討する。