Development of SIRT6 activators targeting for Warburg effect

• Project/Area Number: 15K18899
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Nagoya City University
• Principal Investigator: Kawaguchi Mitsuyasu 名古屋市立大学, 大学院薬学研究科, 助教 (10735682)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: Sirtuin / 蛍光プローブ / ワールブルグ効果

Outline of Final Research Achievements

In general, sirtuin activity is detectable by a protease (eg. trypsin) coupled two-steps method. However, such method has several problems, cumbersome procedure, false-positive compounds on chemical screening.
In this study, focusing on interesting reports showing that sirtuin recognize and hydrolize long-chain fatty acyl groups, we hypothesized that sirtuin can hydrolize acyl groups of large quencher dyes. We exhibited that sirtuin activity is detectable by a FRET based novel fluorescence probe, SFP3, and applied this methodology for chemical screening. We identified novel scaffolds of SIRT6 inhibitor and activiator.

Research Products

• [Journal Article] A yellowish-green-light-controllable nitric oxide donor based on N-nitrosoaminophenol applicable for photocontrolled vasolidation (2017)
  • Author(s): Okuno H, Ieda N, Hotta Y, Kawaguchi M, Kimura K, Nakagawa H.
  • Journal Title: Org. Biomol. Chem. Volume: 15 Issue: 13 Pages: 2791-2796
  • DOI: 10.1039/c7ob00245a
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Visible Light-Controlled Nitric Oxide Release from Hindered Nitrobenzene Derivatives for Specific Modulation of Mitochondrial Dynamics (2016)
  • Author(s): Kai Kitamura, Mitsuyasu Kawaguchi, Naoya Ieda, Naoki Miyata, and Hidehiko Nakagawa
  • Journal Title: ACS Chem. Biol. Volume: 11 Issue: 5 Pages: 1271-1278
  • DOI: 10.1021/acschembio.5b00962
  • Peer Reviewed / Open Access
• [Journal Article] (7-Diethylaminocomarin-4-yl)methyl Ester of Suberoylanilide Hydroxamic Acid as a Caged Inhibitor for Photocontrol of Histone Deacetylase Activity (2016)
  • Author(s): Naoya Ieda, Sota Yamada, Mitsuyasu Kawaguchi, Naoki Miyata, and Hidehiko Nakagawa
  • Journal Title: Bioorg. Med. Chem. Volume: 24 Issue: 12 Pages: 2789-2793
  • DOI: 10.1016/j.bmc.2016.04.042
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fluorescence Probe for Imaging Sirtuin Activity in Living Cells, Based on One-Step Cleavage of Dabcyl Quencher (2016)
  • Author(s): Kawaguchi M, Ikegawa S, Ieda N, Nakagawa H.
  • Journal Title: ChemBioChem Volume: 17 Issue: 20 Pages: 1961-1967
  • DOI: 10.1002/cbic.201600374
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A double bond-conjugated dimethylnitrobenzene-type photolabile nitric oxide donor with improved two-photon cross section (2015)
  • Author(s): 1.N. Ieda, K. Hishikawa, K. Eto, K. Kitamura, M. Kawaguchi, T. Suzuki, K. Fukuhara, N. Miyata, T. Furuta, J. Nabekura, H. Nakagawa
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 25 Issue: 16 Pages: 3172-3175
  • DOI: 10.1016/j.bmcl.2015.05.095
  • Peer Reviewed / Open Access
• [Journal Article] Identification of tissue-restricted bio-reaction suitable for in vivo targeting by fluorescent substrate library-based enzyme discovery (2015)
  • Author(s): Kentaro Yoshioka, Toru Komatsu, Akihiro Nakada, Jun Onagi, Yugo Kuriki, Mitsuyasu Kawaguchi, Takuya Terai, Tasuku Ueno, Kenjiro Hanaoka, Tetsuo Nagano, and Yasuteru Urano
  • Journal Title: J. Am. Chem. Soc. Volume: 137 Issue: 38 Pages: 12187-12190
  • DOI: 10.1021/jacs.5b05884
  • Peer Reviewed
• [Journal Article] Peptidyl prolyl isomerase Pin1-inhibitory activity of D-glutamic and D-aspartic acid derivatives bearing a cyclic aliphatic amine moiety (2015)
  • Author(s): Nakagawa H, Seike S, Sugimoto M, Ieda N, Kawaguchi M, Suzuki T, Miyata N.
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 25 Issue: 23 Pages: 5619-5624
  • DOI: 10.1016/j.bmcl.2015.10.033
  • Peer Reviewed / Open Access
• [Presentation] SIRT6活性検出蛍光プローブの開発とケミカルスクリーニング (2017)
  • Author(s): 川口充康、池川祥平、家田直弥、中川秀彦
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-24
• [Presentation] Sirtuin蛍光プローブの開発と生細胞イメージング (2017)
  • Author(s): 川口充康、池川祥平、家田直弥、中川秀彦
  • Organizer: 日本酸化ストレス学会東海支部 第５回学術集会,
  • Place of Presentation: 名古屋
  • Year and Date: 2017-02-18
• [Presentation] Sirtuin蛍光プローブの開発と生細胞イメージングへの応用 (2016)
  • Author(s): 川口充康, 池川祥平、家田直弥, 中川秀彦
  • Organizer: 第14回 がんとハイポキシア研究会
  • Place of Presentation: 岐阜
  • Year and Date: 2016-11-04
• [Presentation] SIRT6活性検出プローブの開発とmodulatorの探索 (2016)
  • Author(s): 池川祥平, 川口充康, 家田直弥, 中川秀彦
  • Organizer: 日本薬学会東海支部 合同学術大会2016
  • Place of Presentation: 岐阜
  • Year and Date: 2016-10-30
• [Presentation] Development of one-step sirtuin activity fluorescence probe and living cell imaging (2016)
  • Author(s): Mitsuyasu Kawaguchi, Shohei Ikegawa, Naoya Ieda, Hidehiko Nakagawa
  • Organizer: ACS National Meeting
  • Place of Presentation: Philadelphia
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] Sirtuin活性検出蛍光プローブの開発と生細胞応用 (2016)
  • Author(s): 川口充康, 池川祥平, 家田直弥, 中川秀彦
  • Organizer: 日本ケミカルバイオロジー学会第11回年会
  • Place of Presentation: 京都
  • Year and Date: 2016-06-15
• [Presentation] Sirtuin活性検出蛍光プローブの開発と生細胞応用 (2016)
  • Author(s): 川口充康、池川祥平、家田直弥、中川秀彦
  • Organizer: ケミカルバイオロジー学会第１１回年会
  • Place of Presentation: 京都
  • Year and Date: 2016-06-15
• [Presentation] Sirtuin活性検出蛍光プローブの開発と細胞イメージング (2016)
  • Author(s): 川口充康, 池川祥平, 家田直弥, 中川秀彦
  • Organizer: 第14回次世代を担う有機化学シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2016-05-27
• [Presentation] Sirtuin活性検出蛍光プローブの開発と細胞イメージング (2016)
  • Author(s): 川口充康、池川祥平、家田直弥、中川秀彦
  • Organizer: 第１４回次世代シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2016-05-27
• [Presentation] MITOCHONDRIA-TARGETING NITRIC OXIDE RELEASERS CONTROLLABLE WITH VISIBLE LIGHT AND MODULATION OF MITOCHONDRIAL DYNAMICS (2016)
  • Author(s): Kai Kitamura, Mitsuyasu Kawaguchi, Naoya Ieda, Kazuhiro Hishikawa, Takayoshi Suzuki, Naoki Miyata, Hidehiko Nakagawa
  • Organizer: 26th IUPAC International symposium on photochemistry
  • Place of Presentation: Osaka
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] 簡便かつ高感度なSirtuin活性蛍光検出系の構築 (2016)
  • Author(s): 川口充康、池川祥平、家田直弥、中川秀彦
  • Organizer: 日本薬学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-26