Conformationally restricted polyamines: Solid-phase synthesis and biological evaluation

• Project/Area Number: 15K08027
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Nagoya City University
• Principal Investigator: Umezawa Naoki 名古屋市立大学, 大学院薬学研究科, 准教授 (40347422)
• Co-Investigator(Renkei-kenkyūsha): YOSHIKAWA Kenichi 同志社大学, 生命医科学部, 教授 (80110823) ; YOSHIKAWA Yuko 立命館大学, 生命科学部, 教授 (80291871) ; UMEHARA Takashi 独立行政法人理化学研究所, 生命機能科学研究センター・エピジェネティクス制御研究ユニット, ユニットリーダー (20415095) ; INOUE Katsuhisa 東京薬科大学, 薬学部, 教授 (50315892)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ポリアミン / 固相合成 / ペプチド

Outline of Final Research Achievements

Polyamines are organic cations containing multiple amino groups, and are found in all living organisms. In most cases, polyamines have flexible structure and show wide variety of biological functions. We have been developing solid-phase synthesis of polyamines based on peptide chemistry; the peptide on the solid support was exhaustively reduced and crude polyamine thus obtained was purified by reversed-phase HPLC.
In this research, we have improved our solid-phase synthesis for branched and cyclic polyamines. Also, we have evaluated following 4 functions of synthesized polyamines, 1) the effect on DNA duplex structure, 2) lysine-specific demethylases inhibition, 3) prevention of thermal inactivation of protein, and 4) effect on ribozyme activity.

Research Products

• [Journal Article] Biogenic triamine and tetraamine activate core catalytic ability of Tetrahymena group I ribozyme in the absence of its large activator module (2018)
  • Author(s): Gulshan Mst Ara、Rahman Md Motiar、Matsumura Shigeyoshi、Higuchi Tsunehiko、Umezawa Naoki、Ikawa Yoshiya
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 496 Issue: 2 Pages: 594-600
  • DOI: 10.1016/j.bbrc.2018.01.085
  • Peer Reviewed
• [Journal Article] Active site geometry of a novel aminopropyltransferase for biosynthesis of hyperthermophile-specific branched-chain polyamine (2017)
  • Author(s): R. Hidese, K. M. Tse, S. Kimura, E. Mizohata, J. Fujita, Y. Horai, N. Umezawa, T. Higuchi, M. Niitsu, T. Oshima, T. Imanaka, T. Inoue, and S. Fujiwara
  • Journal Title: The FEBS Journal Volume: 284 Issue: 21 Pages: 3684-3701
  • DOI: 10.1111/febs.14262
  • Peer Reviewed / Open Access
• [Journal Article] Activation of lysine-specific demethylase 1 inhibitor peptide by redox-controlled cleavage of a traceless linker (2017)
  • Author(s): Yuichi Amano, Naoki Umezawa, Shin Sato, Hisami Watanabe, Takashi Umehara, Tsunehiko Higuchi
  • Journal Title: Bioorg. Med. Chem. Volume: 25 Issue: 3 Pages: 1227-1234
  • DOI: 10.1016/j.bmc.2016.12.033
  • Peer Reviewed
• [Journal Article] Polyoxygenated seco-cyclohexenes and other constituents from Uvaria valderramensis (2017)
  • Author(s): Allan Patrick G. Macabeo, Peter Yuosef M. Rubio, Tsunehiko Higuchi, Naoki Umezawa, Christian Faderl, Simon Budde, Porferio S. Bangcaya
  • Journal Title: Biochemical Systematics and Ecology Volume: 71 Pages: 200-204
  • DOI: 10.1016/j.bse.2017.02.013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Development and crystallographic evaluation of histone H3 peptide with N-terminal serine substitution as a potent inhibitor of lysine-specific demethylase 1 (2017)
  • Author(s): Yuichi Amano, Masaki Kikuchi, Shin Sato, Shigeyuki Yokoyama, Takashi Umehara, Naoki Umezawa, Tsunehiko Higuchi
  • Journal Title: Bioorg. Med. Chem. Volume: 25 Issue: 9 Pages: 2617-2624
  • DOI: 10.1016/j.bmc.2017.03.016
  • Peer Reviewed
• [Journal Article] Role of Thiolate Ligand in Spin State and Redox Switching in the Cytochrome P450 Catalytic Cycle (2017)
  • Author(s): Hiroshi Suzuki, Kanako Inabe, Yoshinori Shirakawa, Naoki Umezawa, Nobuki Kato, Tsunehiko Higuchi
  • Journal Title: Inorg. Chem. Volume: 56 Issue: 8 Pages: 4245-4248
  • DOI: 10.1021/acs.inorgchem.6b02499
  • Peer Reviewed
• [Journal Article] Naturally occurring branched-chain polyamines induce a crosslinked meshwork structure in a giant DNA. (2016)
  • Author(s): Muramatsu,A., Shimizu,Y., Yoshikawa, Y., Fukuda,W., Umezawa,N., Horai,Y., Higuchi,T., Fujiwara,S., Imanaka,T.,Yoshikawa,K.
  • Journal Title: J.Chem. Phys. J. Chem. Phys. Volume: 145 Issue: 23 Pages: 235103-235103
  • DOI: 10.1063/1.4972066
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Design of New Extraction Surfactants for Membrane Proteins from Peptide-Gemini Surfactants (PG-surfactants) (2016)
  • Author(s): M. Shibata, S. Koeda, T. Noji, K. Kawakami, Y. Ido, Y. Amano, N. Umezawa, T. Higuchi, T. Dewa, S. Itoh, N. Kamiya, T. Mizuno
  • Journal Title: Bioconjugate Chemistry Volume: 27 Issue: 10 Pages: 2469-2479
  • DOI: 10.1021/acs.bioconjchem.6b00417
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Structurally Diverse Polyamines: Solid-Phase Synthesis and Interaction with DNA (2015)
  • Author(s): Naoki Umezawa1, Yuhei Horai,. Yuki Imamura, Makoto Kawakubo, Mariko Nakahira, Nobuki Kato, Akira Muramatsu, Yuko Yoshikawa, Kenichi Yoshikawa, Tsunehiko Higuchi
  • Journal Title: ChemBioChem Volume: 16 Issue: 12 Pages: 1811-1819
  • DOI: 10.1002/cbic.201500121
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Efficient oxidation of ethers with pyridine N-oxide catalyzed by ruthenium porphyrins (2015)
  • Author(s): Nobuki Kato, Yu Hamaguchi, Naoki Umezawa and Tsunehiko Higuchi
  • Journal Title: J. Porphyrins Phthalocyanines Volume: 19 Issue: 01-03 Pages: 411-416
  • DOI: 10.1142/s1088424615500297
  • Peer Reviewed
• [Journal Article] 環状化を用いたペプチド機能の光制御 (2015)
  • Author(s): 梅澤直樹、樋口恒彦
  • Journal Title: 生体の科学 Volume: 66 Pages: 102-107
• [Presentation] Solid-phase synthesis of structurally diverse polyamines and specificity on their interaction with DNA duplex (2016)
  • Author(s): Naoki Umezawa, Yuhei Horai, Yuki Imamura, Akira Muramatsu, Kenichi Yoshikawa, Yuko Yoshikawa, Tsunehiko Higuchi
  • Organizer: The 8th Takeda Science Foundation Symposium on PharmaSciences, Biomolecule-Based Medicinal Science: Featuring Mid-Size Drugs
  • Place of Presentation: Center for Learning and Innovation Takeda Pharmaceutical Company Ltd.
  • Year and Date: 2016-01-21
  • Int'l Joint Research
• [Presentation] 多様なポリアミンの固相合成とDNA二重鎖に及ぼす影響 (2015)
  • Author(s): 梅澤 直樹、寳来 侑平、今村 優希、辻 佳寿美、村松 晃、吉川 研一、吉川 祐子、加藤 信樹、樋口 恒彦
  • Organizer: 第9回バイオ関連化学シンポジウム
  • Place of Presentation: 熊本大学工学部 黒髪南キャンパス
  • Year and Date: 2015-09-10
• [Presentation] 多様な骨格構造をもつポリアミンの固相合成とDNA二重鎖に及ぼす影響 (2015)
  • Author(s): 辻佳寿美、寳来侑平、梅澤直樹、加藤信樹、樋口恒彦
  • Organizer: 第61回日本薬学会東海支部大会
  • Place of Presentation: 名古屋市立大学大学院薬学研究科
  • Year and Date: 2015-07-04