Development of synthetic receptors for heme based on a supramolecular chemistry approach and applications toward chemical biology

• Project/Area Number: 18K06551
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Nagoya City University
• Principal Investigator: Yosuke Hisamatsu 名古屋市立大学, 医薬学総合研究院(薬学), 講師 (80587270)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ヘム / 蛍光 / 人工レセプター / ホスト・ゲスト化学 / 超分子化学 / ホストゲスト化学 / 超分子 / 自己集合 / プロトポルフィリンIX / 光増感剤 / 光線力学療法 / 蛍光プローブ / ピンセット分子

Outline of Final Research Achievements

Heme plays important roles in a variety of biological systems and the development of tools for the detection of heme in living cells is important for understanding of physiological roles of heme. In this research project, new tweezer-type synthetic receptors that form stable complexes with heme were developed. Moreover, the fluorescent synthetic receptor exhibits a heme-concentration dependent fluorescence response in aqueous solution at neutral pH.

Academic Significance and Societal Importance of the Research Achievements

生体分子を水中で精密に認識する人工レセプターの開発と応用は、ホスト・ゲスト化学の分野において重要な研究課題の一つである。本研究期間において、生体内で重要な役割を持つヘムに対して高い結合親和性と蛍光応答性をもつ新規人工レセプターを開発した。今後、本研究で得られた知見を活用し改善を加えることで、ヘムの研究に貢献できる実用的なツールへと発展させたい。

Research Products

• [Journal Article] Fluorescence Response and Self‐Assembly of a Tweezer‐Type Synthetic Receptor Triggered by Complexation with Heme and Its Catabolites (2021)
  • Author(s): Hisamatsu Yosuke、Otani Koki、Takase Hiroshi、Umezawa Naoki、Higuchi Tsunehiko
  • Journal Title: Chemistry - A European Journal Volume: 27 Issue: 21 Pages: 6489-6499
  • DOI: 10.1002/chem.202003872
  • Peer Reviewed
• [Journal Article] Structure-Based Identification of Potent Lysine-Specific Demethylase 1 Inhibitor Peptides and Temporary Cyclization to Enhance Proteolytic Stability and Cell Growth-Inhibitory Activity (2021)
  • Author(s): Kitagawa Hiroki、Kikuchi Masaki、Sato Shin、Watanabe Hisami、Umezawa Naoki、Kato Maiko、Hisamatsu Yosuke、Umehara Takashi、Higuchi Tsunehiko
  • Journal Title: Journal of Medicinal Chemistry Volume: 64 Issue: 7 Pages: 3707-3719
  • DOI: 10.1021/acs.jmedchem.0c01371
  • Peer Reviewed
• [Journal Article] Catalytic Hydrolysis of Phosphate Monoester by Supramolecular Complexes Formed by the Self-Assembly of a Hydrophobic Bis(Zn2+-cyclen) Complex, Copper, and Barbital Units That Are Functionalized with Amino Acids in a Two-Phase Solvent System (2019)
  • Author(s): Yuya Miyazawa, Akib Bin Rahaman, Yutaka Saga, Hiroki Imafuku, Yosuke Hisamatsu, Shin Aoki
  • Journal Title: Micromachines Volume: 10 Issue: 7 Pages: 452-452
  • DOI: 10.3390/mi10070452
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Methylene chain ruler for evaluating the regioselectivity of a substrate-recognising oxidation catalyst (2019)
  • Author(s): Teramae Shota、Kito Akane、Shingaki Tomoteru、Hamaguchi Yu、Yano Yuuki、Nakayama Takamori、Kobayashi Yuko、Kato Nobuki、Umezawa Naoki、Hisamatsu Yosuke、Nagano Tetsuo、Higuchi Tsunehiko
  • Journal Title: Chemical Communications Volume: 55 Issue: 58 Pages: 8378-8381
  • DOI: 10.1039/c9cc03041g
  • Peer Reviewed
• [Journal Article] Design, synthesis, and anticancer activity of iridium(III) complex-peptide hybrids that contain hydrophobic acyl groups at the N-terminus of the peptide units (2019)
  • Author(s): Naito Kana、Yokoi Kenta、Balachandran Chandrasekar、Hisamatsu Yosuke、Aoki Shin
  • Journal Title: Journal of Inorganic Biochemistry Volume: 199 Pages: 110785-110785
  • DOI: 10.1016/j.jinorgbio.2019.110785
  • Peer Reviewed
• [Journal Article] Stable Iron Porphyrin Intramolecularly Coordinated by Alcoholate Anion: Synthesis and Evaluation of Axial Ligand Effect of Alcoholate on Spectroscopy and Catalytic Activity (2019)
  • Author(s): Yoshinori Shirakawa, Yuuki Yano, Yuki Niwa, Kanako Inabe, Naoki Umezawa, Nobuki Kato, Yosuke Hisamatsu and Tsunehiko Higuchi
  • Journal Title: Inorganic Chemistry Volume: 58 Issue: 7 Pages: 4268-4274
  • DOI: 10.1021/acs.inorgchem.8b03384
  • Peer Reviewed
• [Journal Article] Effect of the o-Acetamido Group on pH-Dependent Light Emission of a 3-Hydroxyphenyl-Substituted Dioxetane Luminophore (2019)
  • Author(s): Yosuke Hisamatsu, Takehiro Fukiage, Kojiro Honma, Andrii G. Balia, Naoki Umezawa, Nobuki Kato and Tsunehiko Higuchi
  • Journal Title: Organic Letters Volume: 21 Issue: 5 Pages: 1258-1262
  • DOI: 10.1021/acs.orglett.8b03913
  • Peer Reviewed
• [Journal Article] Inhibition of FAD-dependent lysine-specific demethylases by chiral polyamine analogues (2018)
  • Author(s): Naoki Umezawa, Kasumi Tsuji, Shin Sato, Masaaki Kikuchi, Hisami Watanabe, Yuhei Horai, Masashi Yamaguchi, Yosuke Hisamatsu, Takeshi Umehara and Tsunehiko Higuchi
  • Journal Title: RSC Advances Volume: 8 Issue: 64 Pages: 36895-36902
  • DOI: 10.1039/c8ra07879c
  • Peer Reviewed / Open Access
• [Journal Article] Design and Synthesis of a 4-Aminoquinoline-Based Molecular Tweezer That Recognizes Protoporphyrin IX and Iron(III) Protoporphyrin IX and Its Application as a Supramolecular Photosensitizer (2018)
  • Author(s): Yosuke Hisamatsu, Naoki Umezawa, Hirokazu Yagi, Koichi Kato and Tsunehiko Higuchi
  • Journal Title: Chemical Science Volume: 9 Issue: 38 Pages: 7455-7467
  • DOI: 10.1039/c8sc02133c
  • Peer Reviewed / Open Access
• [Journal Article] Potent Antimalarial Activity of Two Arenes Linked with Triamine Designed To Have Multiple Interactions with Heme (2018)
  • Author(s): Yosuke Sakata, Kosuke Yabunaka, Yuko Kobayashi, Hirohisa Omiya, Naoki Umezawa, Hye- Sook Kim, Yusuke Wataya, Yoshimi Tomita, Yosuke Hisamatsu, Nobuki Kato, Hirokazu Yagi, Tadashi Satoh, Koichi Kato, Haruto Ishikawa and Tsunehiko Higuchi
  • Journal Title: ACS Medicinal Chemistry Letters Volume: 9 Issue: 10 Pages: 980-985
  • DOI: 10.1021/acsmedchemlett.8b00222
  • Peer Reviewed / Open Access
• [Journal Article] Luminescent Iridium Complex-Peptide Hybrids (IPHs) for Therapeutics of Cancer: Design and Synthesis of IPHs for Detection of Cancer Cells and Induction of Their Necrosis-type Cell Death (2018)
  • Author(s): Abdullah-Al Masum, Yosuke Hisamatsu, Kenta Yokoi, and Shin Aoki
  • Journal Title: Bioinorganic Chemistry and Applications Volume: 2018 Pages: 1-18
  • DOI: 10.1155/2018/7578965
  • Peer Reviewed / Open Access
• [Journal Article] Design and Synthesis of a Luminescent Iridium Complex-Peptide (IPH) that Detects Cancer Cells and Induces Their Apoptosis (2018)
  • Author(s): Abdullah-Al Masum, Kenta Yokoi, Yosuke Hisamatsu, Kana Naito, Babita Shashni, and Shin Aoki,
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 26 Issue: 17 Pages: 4804-4816
  • DOI: 10.1016/j.bmc.2018.08.016
  • Peer Reviewed
• [Journal Article] Stereospecific Synthesis of Tris-heteroleptic Tris-cyclometalated Iridium(III) Complexes via Different Heteroleptic Halogen-Bridged Iridium(III) Dimers and Their Photophysical Properties (2018)
  • Author(s): Yuichi Tamura, Yosuke Hisamatsu, Ayami Kazama, Kenji Yoza, Kyouhei, Sato, Reiko Kuroda, Shin Aok
  • Journal Title: Inorganic Chemistry Volume: 57 Issue: 8 Pages: 4571-4589
  • DOI: 10.1021/acs.inorgchem.8b00323
  • Peer Reviewed
• [Presentation] Design, Synthesis and Biological Applications of 4-Aminoquinoline-Based Molecular Tweezers That Recognize Protoporphyrin IX and Heme (2020)
  • Author(s): Hisamatsu Yosuke
  • Organizer: 7th International Postgraduate Conference on Pharmaceutical Sciences (iPoPS2020)
  • Int'l Joint Research / Invited
• [Presentation] ヘム認識能を有する蛍光性分子ピンセットの設計・合成 (2019)
  • Author(s): 大谷紘生、久松洋介、梅澤直樹、樋口恒彦
  • Organizer: 日本ケミカルバイオロジー学会第１４回年会
• [Presentation] 水中でヘムを認識する蛍光性人工レセプターの開発 (2019)
  • Author(s): 久松洋介、大谷紘生、梅澤直樹、樋口恒彦
  • Organizer: 第１３回バイオ関連化学シンポジウム２０１９
• [Presentation] プロトポルフィリンIXと分子ピンセットからなる超分子型光増感剤の光線力学療法への応用 (2019)
  • Author(s): 久松洋介、梅澤直樹、矢木宏和、加藤晃一、樋口恒彦
  • Organizer: 日本酸化ストレス学会東海支部 第7回学術集会
• [Presentation] 光線力学療法への応用を指向した超分子型光増感剤の開発 (2018)
  • Author(s): 久松洋介、大谷紘生、梅澤直樹、矢木宏和、加藤晃一、樋口恒彦
  • Organizer: 第12回バイオ関連化学シンポジウム
• [Presentation] プロトポルフィリンIX及びその鉄(III)錯体を認識する分子ピンセットの設計・合成と超分子型光増感剤への応用 (2018)
  • Author(s): 久松洋介、大谷紘生、梅澤直樹、矢木宏和、加藤晃一、樋口恒彦
  • Organizer: 第16回ホスト-ゲスト・超分子化学シンポジウム