Inhibition activities of iminosugars against glycoprotein processing

• Project/Area Number: 22590059
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: University of Toyama
• Principal Investigator: ADACHI Isao 富山大学, 大学病院, 教授 (30151070)
• Co-Investigator(Kenkyū-buntansha): TAKAHATA Hiroki 東北薬科大学, 薬学部, 教授 (00109109) ; KATO Atsushi 富山大学, 大学病院, 准教授 (60303236)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: イミノ糖 / グリコシダーゼ / 光学異性体 / リソソーム病 / シャペロン

Research Abstract

We studied the concise synthesis of DGJ and L-DGJ from L- and D-tagatose respectively in just four steps, and shows the value of the enantiomers of tagatose as chirons. As with other α-galactosidases L-DGJ was found to be an inhibitor of α-Gal A, about 1000-fold weaker than its enantiomer DGJ. L-DGJ was also found to be a chaperone for α-Gal A, again about 1000 times less active than DGJ. Non-competitive inhibition by L-DGJ is consistent with binding at a different site than DGJ which shows competitive inhibition and binds at the active site. While the inhibition of the same glycosidase by both enantiomers of an iminosugar is well-known, this is the first example of enantiomeric iminosugars acting as synergistic pharmacological chaperones for misfolded proteins; this result may indicate that binding at the active site of the enzyme is not necessary. There are many hundreds of pyrrolidine, piperidine and azepane sugar mimics but azetidines are only just beginning to be studied. There are few examples of carbohydratederived azetidines, although the properties of hydroxyazetidines are of current interest. N-Alkyl hydroxyazetidines are potent inhibitors of purine nucleoside phosphorylase with subnanomolar Ki. We studied the synthesis of an azetidine analogue of 6,7-diepicastanospermine and compares its glycosidase activity also with D-altronojirimycin.

Research Products

• [Journal Article] α-1-C-Butyl-LAB as a second-generation iminosugar-based oral α-glucosidase inhibitor for improving postprandial hyperglycemia (2012)
  • Author(s): Kato, A., Hayashi, E., Miyauchi, S., Adachi, I., Imahori, T., Natori, Y., Yoshimura, Y., Nash, R. J., Shimaoka, H., Nakagome, I., Koseki, J., Hirono, S., Takahata, H
  • Journal Title: J. Med. Chem Volume: 55(23) Pages: 10347-10362
  • Peer Reviewed
• [Journal Article] Synthesis from D-altrose of (5R,6R,7R,8S)-5,7-dihydroxy-8-hydroxymethylconidine and 2,4-dideoxy-2,4-imino-D-glucitol, azetidine analogues of swainsonine and 1,4-dideoxy-1,4-imino-D-mannitol (2012)
  • Author(s): Araujo, N., Jenkinson, S. F., Martinez, R. F., Glawar, A. F. G., Wormald, M. R., Butters, T. D., Nakagawa, S., Adachi, I., Kato, A.Yoshihara, A., Akimitsu, K., Izumori, K., Fleet, G. W. J
  • Journal Title: Org. Lett Volume: 14(16) Pages: 4174-4177
  • Peer Reviewed
• [Journal Article] Asymmetric synthesis of 1-alkyl-2-deoxyiminofuranoses via The iridium-catalyzed intramolecular cyclization of an allylic carbonate (2012)
  • Author(s): Natori, Y., Kikuchi, S., Yoshimura, Y., Kato, A., Adachi, I., Takahata, H
  • Journal Title: Heterocycles Volume: 86(2) Pages: 1401-1417
  • Peer Reviewed
• [Journal Article] Asymmetric synthesis of 2-propylisofagomine using allylic hydroxy group accelerated ring-closing enyne metathesis (2012)
  • Author(s): Taguchi, T., Imahori, T., Yoshimura, Y., Kato, A., Adachi, I., Kawahara, M., Yamaguchi, K., Takahata, H
  • Journal Title: Heterocycles Volume: 84(2) Pages: 929-944
  • Peer Reviewed
• [Journal Article] Asymmetric synthesis of 2-propylisofagomine using allylic hydroxy group accelerated ring-closing enyne metathesis. (2012)
  • Author(s): Taguchi, T., Imahori, T., Yoshimura, Y., Kato, A., Adachi, I., Kawahara, M., Yamaguchi, K., Takahata, H.
  • Journal Title: Heterocycles Volume: 84 (2) Issue: 2 Pages: 929-944
  • DOI: 10.3987/com-11-s(p)74
  • Peer Reviewed
• [Journal Article] Asymmetric synthesis of 1-alkyl-2-deoxyiminofuranoses via The iridium-catalyzed intramolecular cyclization of an allylic carbonate. (2012)
  • Author(s): Natori, Y., Kikuchi, S., Yoshimura, Y., Kato, A., Adachi, I., Takahata, H.
  • Journal Title: Heterocycles Volume: 86 (2) Issue: 2 Pages: 1401-1417
  • DOI: 10.3987/com-12-s(n)99
  • Peer Reviewed
• [Journal Article] Synthesis from D-altrose of (5R,6R,7R,8S)-5,7-dihydroxy-8-hydroxymethylconidine and 2,4-dideoxy-2,4-imino-D-glucitol, azetidine analogues of swainsonine and 1,4-dideoxy-1,4-imino-D-mannitol. (2012)
  • Author(s): Araujo, N., Jenkinson, S. F., Martinez, R. F., Glawar, A. F. G., Wormald, M. R., Butters, T. D., Nakagawa, S., Adachi, I., Kato, A. Yoshihara, A., Akimitsu, K., Izumori, K., Fleet, G. W. J.
  • Journal Title: Org. Lett. Volume: 14 (16) Issue: 16 Pages: 4174-4177
  • DOI: 10.1021/ol301844n
  • Peer Reviewed
• [Journal Article] α-1-C-Butyl-LAB as a second-generation iminosugar-based oral α-glucosidase inhibitor for improving postprandial hyperglycemia. (2012)
  • Author(s): Kato, A., Hayashi, E., Miyauchi, S., Adachi, I., Imahori, T., Natori, Y., Yoshimura, Y., Nash, R. J., Shimaoka, H., Nakagome, I., Koseki, J., Hirono, S., Takahata, H.
  • Journal Title: J. Med. Chem. Volume: 55 (23) Issue: 23 Pages: 10347-10362
  • DOI: 10.1021/jm301304e
  • Peer Reviewed
• [Journal Article] Synthesis, conformational analysis, and evaluation as glycosidase inhibitors of two ether-bridged iminosugars (2011)
  • Author(s): Luo, B., Marcelo, F., Desire, J., Zhang, Y., Sollogoub, M., Kato, A., Adachi, I., Canada, F. Jimenez-Barbero, J., Bleriot, Y
  • Journal Title: J. Carb. Chem Volume: 30(7-9) Pages: 641-654
  • Peer Reviewed
• [Journal Article] Looking-glass synergistic pharmacological chaperones: DGJ and L-DGJ from the enantiomers of tagatose (2011)
  • Author(s): Jenkinson, S. F., Fleet, G. W. J., Nash, R. J., Koike, Y., Adachi, I., Yoshihara, A., Morimoto, K., Izumori, K., Kato, A
  • Journal Title: Org. Lett Volume: 13(15) Pages: 4064-4067
  • Peer Reviewed
• [Presentation] α-1-C-アルキル-D-アラビノイミノ糖誘導体の触媒的不斉合成とその生物活性 (2013)
  • Author(s): 渡邊靖香、佐久間俊嘉、名取良浩、吉村祐一、佐藤香純、加藤 敦、足立伊佐雄、高畑廣紀
  • Organizer: 日本薬学会第133 年会
  • Place of Presentation: 横浜
• [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 (2013)
  • Author(s): 佐久間俊嘉、渡邊はるか、名取良浩、吉村祐一、中川進平、加藤 敦、足立伊佐雄、高畑廣紀
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
• [Presentation] C1位に4-アリールブチル基を導入したL-アラビノイミノ糖誘導体の不斉合成と生物活性評価 (2013)
  • Author(s): 名取良浩、今堀龍志、吉村祐一、嶋田陽介、加藤 敦、足立伊佐雄、高畑廣紀
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
• [Presentation] 次世代型イミノ糖であるα-1-C-alkyl-LABの特性と生物活性について(第1報) (2013)
  • Author(s): 足立伊佐雄、加藤 敦、林 恵利奈、中川進平、名取良浩、吉村祐一、高畑廣紀
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
• [Presentation] 次世代型イミノ糖であるα-1-C-alkyl-LABの特性と生物活性について(第2報) (2013)
  • Author(s): 加藤 敦、林 恵利奈、足立伊佐雄、今堀龍志、名取良浩、吉村祐一、島岡秀行、中込 泉、小関 準、広野修一、高畑廣紀
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
• [Presentation] 次世代型イミノ糖であるα-1-C-alkyl-LABの特性と生物活性について（第1報） (2013)
  • Author(s): 足立伊佐雄、加藤 敦、林 恵利奈、中川進平、名取良浩、吉村祐一、高畑廣紀
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] 次世代型イミノ糖であるα-1-C-alkyl-LABの特性と生物活性について（第2報） (2013)
  • Author(s): 加藤 敦、林 恵利奈、足立伊佐雄、今堀龍志、名取良浩、吉村祐一、島岡秀行、中込 泉、小関 準、広野修一、高畑廣紀
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] α-1-C-アルキル-D-アラビノイミノ糖誘導体の触媒的不斉合成とその生物活性 (2013)
  • Author(s): 渡邊靖香、佐久間俊嘉、名取良浩、吉村祐一、佐藤香純、加藤 敦、足立伊佐雄、高畑廣紀
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] C1位に4-アリールブチル基を組み込んだL-アラビノイミノフラノースの触媒的不斉合成と生物活性評価 (2012)
  • Author(s): 名取良浩、吉村祐一、 高畑廣紀、嶋田陽介、加藤 敦、足立伊佐雄
  • Organizer: 第38回反応と合成の進歩シンポジウム
  • Place of Presentation: 東京
• [Presentation] C1位に4-アリールブチル基を導入したL-アラビノイミノ糖誘導体の触媒的不斉合成 (2012)
  • Author(s): 名取良浩、今堀龍志、吉村祐一、中川進平、加藤 敦、足立伊佐雄、高畑廣紀
  • Organizer: 日本薬学会第132 年会
  • Place of Presentation: 札幌
• [Presentation] C1位アルキルL-アラビノイミノフラノース誘導体の触媒的不斉合成とその生物活性 (2011)
  • Author(s): 名取良浩、今堀龍志、吉村祐一、中川進平、加藤 敦、足立伊佐雄、高畑廣紀
  • Organizer: 第53回天然有機化合物討論会
  • Place of Presentation: 大阪
• [Presentation] フコシダーゼ阻害活性が期待されるイミノ糖誘導体の合成研究 (2011)
  • Author(s): 坂 知樹、杉本健士、松谷裕二、中川進平、山下侑子、加藤 敦、足立伊佐雄、豊岡尚樹
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
• [Presentation] C1置換L-アラビノイミノ糖誘導体の触媒的不斉合成 (2011)
  • Author(s): 名取良浩、今堀龍志、吉村祐一、中川進平、加藤 敦、足立伊佐雄、高畑廣紀
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
• [Presentation] Pharmacological chaperone活性を有するL型イミノ糖の可能性について (2010)
  • Author(s): 小池有理子、加藤 敦、足立伊佐雄、石井 達
  • Organizer: 第83回日本生化学会大会
  • Place of Presentation: 神戸