Creation of Suparmolecular Catalyts by Design of Functionalized Molecular Blocks and Reaction Field

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17K08225
• Research Institution: Tokyo University of Science
• Principal Investigator: 青木 伸 東京理科大学, 薬学部生命創薬科学科, 教授 (00222472)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 超分子 / 自己集積 / 酵素モデル / リン酸モノエステル / 加水分解 / 触媒 / 二相系

Outline of Annual Research Achievements

人工の分子集積体（超分子）の化学の発展は目覚しいが、触媒機能を有する超分子の例は非常に限られている。その主な理由として、i)酵素のように反応中心で酸と塩基を一定の距離間隔で配置する人工触媒の設計が困難である事、ii)反応の遷移状態を安定化する触媒設計が未開拓である事、iii)従来のモデル錯体は金属イオンの第一配位圏の再現だけにとどまり、アミノ酸などの触媒基を、活性中心周囲（外圏）に三次元的に配置できていない事、iv) 上記の条件を満たす構造を共有結合でつくるには長い合成ルートが必要であり、しかも極少量しか合成できず、詳細な解析ができない事、が挙げられる。これらを克服するためには、様々な官能基をもつ分子ブロックを短時間で多数合成し、溶液中で混合するだけで多様な三次元的活性中心を構築する必要がある。
そこで本研究は、分子間相互作用による自己集積的分子構築によって、三次元的に官能基を配置した酵素類似活性中心を構築した。官能基化された分子ブロックを合成し、その他の分子と混合するだけで、金属活性中心と触媒官能基が三次元的に配置された超分子を創製した。長鎖アルキル基を一つだけ導入した二核亜鉛錯体と化学修飾したバルビタール誘導体と銅イオンの組み合わせによる超分子を有機溶媒とpH緩衝水溶液の二相系溶媒で構築し、リン酸モノエステルのの加水分解を行ったところ、大きな反応加速と触媒回転を確認した。結果として、酵素モデルを様々な分子部品を組わ合わせて自己集積させて構築したこと、二相系溶媒（有機溶媒／水）によって反応を行ったこと、二相系の人工的反応であるにも関わらず、天然酵素と同様の速度論的法則（Michaelis-Menten速度論）に従うこと、反応が触媒回転することなどを明らかにした。天然酵素による触媒的反応機構の物理化学的理解の一端になるものと考えられる。

Research Products

• [Journal Article] The Design and Green Synthesis of Novel Benzotriazoloquinolinyl Spirooxindolopyrrolizidines: Antimycobacterial and Antiproliferative Studies (2020)
  • Author(s): V. Pogaku, V. S. Krishna, C. Balachandran, K. Rangan, D. Sriram, S. Aoki, S. Basavoju,
  • Journal Title: Carbohydrate Res. Volume: 487 Pages: 107888(12pages)
  • DOI: 10.1039/c9nj03802g
  • Peer Reviewed
• [Journal Article] One-Pot Synthesis of Cyclic Oligosaccharides by the Polyglycosylation of Monothioglycosides (2020)
  • Author(s): H. Someya, G. Ishigami, T. Itoh, Y. Saga, Y. Yamada, and S. Aoki,
  • Journal Title: Carbohydrate Research Volume: 487 Pages: 107888(12pages)
  • DOI: org/10.1016/j.carres.2019.107888
  • Peer Reviewed
• [Journal Article] Unprecedented Formation of Palladium(II)-Pyrazole Based Thiourea from Chromone Thiosemicarbazone and [PdCl2(PPh3)2]: Interaction with Biomolecules and Apoptosis through Mitochondrial Signaling Pathway (2020)
  • Author(s): H. Jebiti, C. Balachandran, M. Muthu T. Y. Arun, N. S. P. Bhuvanesh, S. Aoki, and R. Karvembu,
  • Journal Title: J. Inorg. Biochem. Volume: 205 Pages: 110988(11pages)
  • DOI: org/10.1016/j.jinorgbio.2019.110988
  • Peer Reviewed
• [Journal Article] Iron Oxide Nanoparticle Core-Sell Magnetic Microspheres: Applications toward Targeted Drug Delivery (2020)
  • Author(s): S. Ayyanaar, M. P. Kesavan, C. Balachandran, S. Rasala, S. Aoki, J. Rajesh, T. Webster, G. Rajagopal
  • Journal Title: Nanomed. Nanotech. Biol. Med., Volume: 24 Pages: 102134(11pages)
  • DOI: org/10.1016/j.nano.2019.192134
  • Peer Reviewed / Open Access
• [Journal Article] Simple and Convenient Method for the Isolation, Culture, and Re-collection of Cancer Cells from Blood by Using Glass-Bead Filters (2019)
  • Author(s): B. Shashni, H. Matsuura, R. Saito, T. Hirata, S. Ariyasu, K. Nomura, H. Takemura, K. Akimoto, N.Aikawa, A. Yasumori and S. Aoki,
  • Journal Title: ACS Biomater. Sci. Eng Volume: 5 Pages: 438-452
  • DOI: 10.1021/acsbiomaterials.8b01335
  • Peer Reviewed
• [Journal Article] Stereoselective Aldol Reactions of Dihydroxyacetone Derivatives Catalyzed by Chiral Zn2+ Complexes (2019)
  • Author(s): M. Yasuda, Y. Saga, T. Tokunaga, S. Itoh, and S. Aoki
  • Journal Title: Tetrahedron Volume: 75 Pages: 5603-5616
  • DOI: org/10.1016/j.tet.2018.12.060
  • Peer Reviewed
• [Journal Article] Catalytic Hydrolysis of Phosphate Monoester by Supramolecular Phosphatases Formed from a Monoalkylated Dizinc(II) Complex, Cyclic Diimide Units & Copper(II) in Two-Phase Solvent System (2019)
  • Author(s): A. B. Rahman, H. Imafuku, Y. Miyazawa, A. Kafle, H. Sakai, Y. Saga, and S. Aoki
  • Journal Title: Inorg. Chem. Volume: 58 Pages: 5603-5616
  • DOI: 10.1021/acs.inorgchem.8b03586
  • Peer Reviewed
• [Journal Article] Design, Synthesis, DNA/HSA Binding and Cytotoxic Activity of Half-Sandwich Ru(II)-Arene Complexes Containing Tiarylamines-Thiosemicarbazone Hybrids (2019)
  • Author(s): K. Jeyalakshmi, J. Haribabu, C. Balachandran, E. Narmatha, N. S. P. Bhuvanesh, S. Aoki, and Ramasamy Karvembu
  • Journal Title: ACS Omega Volume: 4 Pages: 11712-11723
  • DOI: org/10.1039/C8NJ04246B
  • Peer Reviewed / Open Access
• [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): Y. Miyazawa, A. B. Rahman, Y. Saga, H. Imafuku, Y. Hisamatsu, and S. Aoki
  • Journal Title: Micromachines Volume: 10 Pages: 452 (24 pages)
  • DOI: org/10.3390/mi10070452
  • Peer Reviewed / Open Access
• [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): K. Naito, K. Yokoi, C. Balachandran, Y. Hisamatsu, and S. Aoki,
  • Journal Title: J. Inorg. Biochem. Volume: 199 Pages: 110785(17pges)
  • DOI: org/10.1016/j.jinorgbio.2019.110785
  • Peer Reviewed
• [Journal Article] Evaluation of Zn2+ Coordination Structures in Chiral Zn2+ Complexes Based on Shape Measurement Factors: Relationships between Activity and the Coordination Structure (2019)
  • Author(s): S. Aoki, C. Kikuchi, Y. Kitagawa, Y. Hasegawa, S. Sonoike, Y. Saga, and M. Hatanaka,
  • Journal Title: Eur. J. Inorg. Chem. Volume: - Pages: 4740-4751
  • DOI: 10.1002/ejic.201900934
  • Peer Reviewed
• [Journal Article] NHC Catalyzed Green Synthesis of Functionalized Chromones: DFT Mechanistic Insights and in vitro Activities in Cancer Cells (2019)
  • Author(s): N. Murugesh, J. Haribabu, K. Arumugam, C. Balachandran, R.Swaathy, S. Aoki, A. Sreekanth, R. Karvembu, and S. Vedachalam
  • Journal Title: New J. Chem. Volume: - Pages: 13509-13525
  • DOI: 10.1039/c9nj02650a
  • Peer Reviewed
• [Journal Article] A New Class of&Pyrrolidino-1,2,3-triazole Derivatives as β-Adrenergic Receptor Inhibitors: Synthesis, Pharmacological and Docking Studies (2019)
  • Author(s): K. Easwaramoorthi, J. A. Rajendran, K. C. Rao, C. Balachandran, Y. Arun, S. M. Mahalingam, N. Arumugam, A. I. Almansour, R. S. Kumar, D. M. Al-thamili, S. Aoki,
  • Journal Title: Molecules Volume: 24 Pages: 3501 (19 pages)
  • DOI: org/10.3390/molecules24193501
  • Peer Reviewed
• [Presentation] 672.Design and Synthesis of Artificial Phosphatases Formed by the Self-Assembly of Monoalkylated Dizinc(II) Complex, Copper, and Diimide Units Functionalized with Lewis Acid or Crown Ether Moities (2020)
  • Author(s): Akib Bin Rahman, Yuya Miyazawa, and Shin Aoki
  • Organizer: 7th International Postgraduate Conference on Pharmaceutical Sciences 2020 (iPoPS2020)、2/27~2/28、2020, Noda, Japan
  • Invited
• [Presentation] Design and Synthesis of Supramolecular Complexes Formed by the Self-Assembly of Monoalkylated Dizinc(II) Complex, Copper, and Diimide Units with Lewis Acid or Crown Ether Moieties (2020)
  • Author(s): Akib Bin Rahman, Yuya Miyazawa, and Shin Aoki
  • Organizer: Akib Bin Rahman, Yuya Miyazawa, and Shin Aoki
  • Invited
• [Presentation] 2.モノアルキル化された二核亜鉛錯体と有機分子ブロックの自己集積による超分子ホスファターゼの設計・合成とリン酸モノエステル加水分解活性 (2019)
  • Author(s): 青木 伸、Akib Bin Rahman、宮澤 有哉、嵯峨 裕
  • Organizer: 第17回ホストゲスト・超分子化学シンポジウム
• [Presentation] Design and Synthesis of Cyclometalated Iridium(III) Complex-Peptide Hybrids for the Induction of Cancer Cell Death (2019)
  • Author(s): Shin Aoki
  • Organizer: The 9th World Congress on Chemistry and Medicinal Chemistry (WCC2019)
  • Int'l Joint Research / Invited
• [Presentation] 23.Design, Synthesis, and Phosphatase Activities of Supramolecular Complexes Inspired by an Active Center of Alkaline Phosphatase (2019)
  • Author(s): Yuya Miyazawa, Yutaka Saga, Akib Bin Rahman, Hiroki Imafuku, Shin Aoki
  • Organizer: 錯体化学会第69回討論会
• [Presentation] 25.Design and Synthesis of Metallosupramoelcular Catalysts in Two-Phase Solvent Systems that Mimic Natural Enzymes (2019)
  • Author(s): Shin Aoki
  • Organizer: 7th Asian Congress on Coordination Chemistry (ACCC7)
  • Int'l Joint Research / Invited
• [Presentation] 646.Design and Synthesis of Tetrakis(Zn2+-cyclen) Complex Bridged with an Alkyl Chain for the Contruction of Supramolecular Phosphatase by Self-Assembly with Barbital and Copper(II) (2019)
  • Author(s): Yuka Kobayashi, Akib Bin Rahman, Yuya Miyazawa, Yutaka Saga, and Shin Aoki
  • Organizer: 7th Asian Congress on Coordination Chemistry (ACCC7)
  • Int'l Joint Research
• [Presentation] 659.Design & Synthesis of Supramolecular Phosphatases Based on Self-Assembly of Molecular Building Blocks & Mechanistic Study by Means of Imaging of Reaction Mixtures (2019)
  • Author(s): Akib Bin Rahman, Yuya Miyazawa, Ananda Kafle, Hideki Sakai, Yutaka Saga, and Shin Aoki
  • Organizer: 東京理科大学総合研究院イメージングフロンティアセンターシンポジウム
• [Remarks] 東京理科大学薬学部ホームページ
  • URL: https://www.rs.noda.tus.ac.jp/aokilab/