Strategy for designing selective rhamnosidase inhibitors: Synthesis and biological evaluation of L-DMDP cyclic isothioureas

• Project/Area Number: 15K08021
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: University of Toyama
• Principal Investigator: ADACHI ISAO 富山大学, 附属病院, 教授 (30151070)
• Co-Investigator(Kenkyū-buntansha): 加藤 敦 富山大学, 附属病院, 准教授 (60303236) ; 名取 良浩 東北医科薬科大学, 薬学部, 助教 (50584455)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ラムノシダーゼ / イミノ糖 / 結核菌 / グリコシダーゼ阻害剤 / グリコシダーゼ

Outline of Final Research Achievements

This study shows that the cyclization of L-DMDP thioureas to bicyclic L-DMDP isothioureas improved α-L-rhamnosidase inhibition which was further enhanced by increasing the length of the alkyl chain. 3’, 4’-dichlorobenzyl-L-DMDP cyclic isothiourea (3r) was found to display the most potent and selective inhibition of α-L-rhamnosidase, with IC50 value of 0.22 μM,increased by about 46-fold compared to the positive control 5-epi-deoxyrhamnojirimycin (5-epi-DRJ ; IC50 = 10 μM) and occupied the active-site of this enzyme (Ki = 0.11 μM). Bicyclic isothioureas of ido-L-DMDP did not inhibit α-L-rhamnosidase. These new mimics of L-rhamnose may affect other enzymes associated with the biochemistry of rhamnose including enzymes involved in progression of tuberculosis.

Research Products

• [Int'l Joint Research] Chinese Academy of Sciences(中国)
• [Int'l Joint Research] University of Oxford(英国)
• [Int'l Joint Research] Chinese Academy of Sciences(中国)
• [Int'l Joint Research] University of Oxford(英国)
• [Int'l Joint Research] Chinese Academy of Sciences/Jiangxi Normal University(中国)
• [Int'l Joint Research]
• [Journal Article] Strategy for designing selective α-L-rhamnosidase inhibitors: Synthesis and biological evaluation of L-DMDP cyclic isothioureas. (2016)
  • Author(s): Miyawaki, S., Hirokami, Y., Kinami, K., Hoshino, M., Minehira, D., Miyamoto, D., Nash, R. J., Fleet, G. W. J., Adachi, I., Kato, A.
  • Journal Title: Bioorg. Med. Chem. Volume: 25 (1) Issue: 1 Pages: 107-115
  • DOI: 10.1016/j.bmc.2016.10.015
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 選択的α-L-rhamnosidase阻害剤のデザイン戦略：L-DMDP cyclic isothioureasの合成と構造最適化 (2017)
  • Author(s): 星野 雅子、加藤 敦、宮脇 章太、広上 由季、木南 今日子、友原 啓介、宮本 大樹、足立 伊佐雄、豊岡 尚樹
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター他
  • Year and Date: 2017-03-25
• [Presentation] Synthesis and interactions of rhamnose iminosugar mimics with the rhamnose operon, rhamnosidases, and rhamnose isomerase (2015)
  • Author(s): Liu, Z., Kelly, C., Yoshihara, A., Izumori, K., Wormald, M., Otero-Casas, J., Estevez-Reino, A., Heap, J., Kato, A., Adachi, I., Jenkinson, S., Fleet, G., Estevez, R.
  • Organizer: Pacifichem2015
  • Place of Presentation: Honolulu, Hawaii, USA
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Presentation] Catalytic asymmetric syntheses and biological evaluations of α-1-C-substituted L-iminofuranose derivatives as α-glucosidase inhibitor (2015)
  • Author(s): Natori, Y., Kato, A., Adachi, I., Yoshimura, Y.
  • Organizer: Pacifichem2015
  • Place of Presentation: Honolulu, Hawaii, USA
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Presentation] 1-C-n-ブチル-L-イミノフラノース誘導体の触媒的不斉合成と酵素阻害活性評価 (2015)
  • Author(s): 佐久間俊嘉、名取良浩、中川進平、加藤 敦、足立伊佐雄、吉村祐一
  • Organizer: 第33回メディシナルケミストリーシンポジウム
  • Place of Presentation: 幕張国際研修センター
  • Year and Date: 2015-11-25