Design, synthesis, and biological evaluation of iminosugars as pharmacological chaperone for Gaucher disease

2013 Fiscal Year Final Research Report

• Project/Area Number: 23590127
• 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: KATO Atsushi 富山大学, 大学病院, 准教授 (60303236)
• Co-Investigator(Kenkyū-buntansha): TAKAHATA Hiroki 東北薬科大学, 薬学部, 教授 (00109109) ; HIRONO Shuichi 北里大学, 薬学部, 教授 (30146328) ; ISHII Satoshi 大分大学, 医学部, 客員研究員 (00222935) ; ADACHI Isao 富山大学, 大学病院, 教授 (30151070)
• Project Period (FY): 2011 – 2013
• Keywords: リソソーム病 / グリコシダーゼ / イミノ糖 / シャペロン / フォールディング

Research Abstract

We report on the identification of the required configuration and binding orientation of iminosugars against b-glucocerebrosidase. A molecular docking study revealed that strong-binding iminosugars had a favorable van der Waals interactions and the hydrogen bonding. Calystegines, which is one of the candidates for pharmacological chaperone, bound into the same active site as isofagomine and the essential hydrogen bonds formed to Asp127, Glu235 and Glu340 were maintained. However, their binding orientations were obviously different. It is noteworthy that Type 1 orientated calystegines effectively stabilized b-glucocerebrosidase, and consequently increased intracellular b-glucocerebrosidase activities in N370S fibroblasts, while Type 2 orientated calystegines could not keep the enzyme activity. These results clearly indicate that the binding orientations of iminosugars are changed by the configuration of the hydroxyl groups.

Research Products

• [Journal Article] Docking and SAR studies of calystegines : binding orientation and influence on pharmacological chaperone effects for Gaucher's disease (2014)
  • Author(s): Kato, A., Nakagome, I., Nakagawa, S., Koike, Y., Nash, R. J., Adachi, I., Hirono, S
  • Journal Title: Bioorg. Med. Chem Volume: 22 (8) Pages: 2435-2441
  • DOI: 10.1016/j.bmc.2014.02.057
  • Peer Reviewed
• [Journal Article] Synthesis of eight stereoisomers of pochonicine : Nanomolar inhibition ofβ-N-acetylhexosaminidases (2013)
  • Author(s): Zhu, J. -S., Nakagawa, S., Chen, W., Adachi, I., Jia, Y.-M., Hu, X. -G., Fleet, G. W. J., Wilson,F.X., Nitoda, T., Horne, G., van Well,R., Kato, A., Yu, C.-Y
  • Journal Title: J. Org. Chem Volume: 78 (20) Pages: 10298–10309
  • DOI: 10.1021/jo401694e
  • Peer Reviewed
• [Journal Article] C-Branched iminosugars :α-glucosidase inhibition by enantiomers of isoDMDP, isoDGDP and isoDAB–L-isoDMDP compared to miglitol and miglustat (2013)
  • Author(s): Jenkinson, S. F., Best, D., Saville, A. W., Mui, J., Martínez, R. F., Nakagawa, S., Kunimatsu, T., Alonzi, D. S., Butters, T. D., Norez, C., Becq, F., Blériot, Y. Wilson, F. X., Weymouth-Wilson, A. C., Kato, A., Fleet, G. J
  • Journal Title: J. Org. Chem Volume: 78 (15) Pages: 7373-7776
  • DOI: 10.1021/jo4005487
  • Peer Reviewed
• [Journal Article] (3R,4S,5R,6R,7S)-3,4,5,7-Tetrahydroxyconid ine, anazetidine analogue of 6,7-diepicastanospermine and aconformationally constrained D-deoxyaltronojirimycin, from L-arabinose (2013)
  • Author(s): Martínez, R. F., Araújo, N., Jenkinson, S. F., Nakagawa, S., Kato, A., Fleet, G. W. J
  • Journal Title: Bioorg. Med. Chem Volume: 21 (16) Pages: 4813-4819
  • DOI: 10.1016/j.bmc.2013.03.004
  • Peer Reviewed
• [Journal Article] General synthesis of sugar-derived azepane nitrones : precursors of azepane iminosugars (2013)
  • Author(s): Zhao, W. -B., Nakagawa, S., Kato, A., Adachi, I., Jia, Y. -M., Hu, X. -G., Fleet, G. J., Wilson, F. X., Horne, G., Yoshihara, A., Izumori, K., Yu, C. -Y
  • Journal Title: J. Org. Chem Volume: 78 (7) Pages: 3208-3221
  • DOI: 10.1021/jo400130p
  • Peer Reviewed
• [Journal Article] 3-Hydroxyazetidine carboxylic acids : non-proteinogenic amino acids for medicinal chemists (2013)
  • Author(s): Jenkinson, S. F., Thompson, A. L., Nakagawa, S., Kato, A., Butters, T. D., Fleet, G. W. J
  • Journal Title: ChemMedChem Volume: 8 (4) Pages: 658-666
  • DOI: 10.1002/cmdc.201200541
  • Peer Reviewed
• [Journal Article] α-1-C-Butyl-LAB as a second-generation iminosugar-based oralα-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
  • DOI: 10.1021/jm301304e
  • Peer Reviewed
• [Journal Article] Glycosidase inhibition by all 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols prepared from the enantiomers of glucuronolactone (2012)
  • Author(s): Ayers, B., Ngo, M., Jenkinson, S. F Martínez, R. F., Shimada, Y., Adachi, I., Weymouth-Wilson, A. C., Kato, A., Fleet, G. W. J
  • Journal Title: J. Org. Chem Volume: 77 (18) Pages: 7777-7792
  • DOI: 10.1021/jo301243s
  • Peer Reviewed
• [Journal Article] Synthesis from D-altrose of (5R,6R,7R,8S)-5,7-dihydroxy-8-hydroxymet hylconidine 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): Araújo, N., Jenkinson, S. F., Martínez, 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
  • DOI: 10.1021/ol301844n
  • Peer Reviewed
• [Journal Article] Scalable syntheses of both enantiomers of DNJNAc and DGJNAc from glucuronolactone : The effect of N-alkylation on hexosaminidase inhinition (2012)
  • Author(s): Glawar, A. F. G., Best, D., Ayers, B., Miyauchi, S., Nakagawa, S., Agulilar-Moncayo, M., Fernandez, J. M. G., Mellet, C. O., Crabtree, E. V., Butters, T. D., Wilson, F. X., Kato, A., Fleet, G. W. J
  • Journal Title: Chem. Eur. J Volume: 18 (30) Pages: 9341-9359
  • DOI: 10.1002/chem.201200110
  • Peer Reviewed
• [Journal Article] Azetidine iminosugars from the cyclization of 3,5-di-O-triflates ofα-furanosides and of 2,4-di-O-triflates ofβ-pyranosides derived from glucose (2012)
  • Author(s): Lenagh-Snow, G. M. J., Araujo, N., Jenkinson, S. F., Martinez, R. F., Shimada, Y, Yu, C.-Y., Kato, A., Fleet, G. W. J
  • Journal Title: Org. Lett Volume: 14 (8) Pages: 2142-2145
  • DOI: 10.1021/ol300669v
  • Peer Reviewed
• [Journal Article] Eight stereoisomers of homonojirimycin from D-mannose (2012)
  • Author(s): Lenagh-Snow, G. M. J., Jenkinson, S. F., Newberry, S. J., Kato, A., Nakagawa, S., Adachi, I., Wormald, M. R., Yoshihara, A., Morimoto, K., Akimitsu, K., Izumori, K., Fleet, G. W. J
  • Journal Title: Org. Lett Volume: 14 (8) Pages: 2050-2053
  • DOI: 10.1021/ol3005744
  • Peer Reviewed
• [Journal Article] Inhibition of non-mammalian glycosidases by azetidine iminosugars derived from stable 3,5-di-O-triflates of pentoses (2011)
  • Author(s): Lenagh-Snow, G. M. J., Araujo, N., Jenkinson, S. F., Rutherford, C., Nakagawa, S., Kato, A., Yu, C.-Y., Weymouth-Wilson, A. C., Fleet, G. W. J
  • Journal Title: Org. Lett Volume: 13 (21) Pages: 5834-5837
  • DOI: 10.1021/ol2024482
  • 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
  • DOI: 10.1021/ol201552q
  • Peer Reviewed
• [Presentation] Calystegine類のβ-glucocerebrosidaseに対する結合親和性とファーマコロジカルシャペロン効果について (2014)
  • Author(s): 加藤敦、中込泉、中川進平、広野修一、足立伊佐雄
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
  • Year and Date: 20140328-31
• [Presentation] 新規β-glucocerebrosidase高親和性リガンドcalystegine B_2の結合様式に対するin silico解析 (2014)
  • Author(s): 中込泉、加藤敦、山乙教之、足立伊佐雄、広野修一
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
  • Year and Date: 20140328-31
• [Presentation] DGJNAc誘導体の結合親和性とpharmacological chaperone活性について (2014)
  • Author(s): 中川進平、加藤敦、足立伊佐雄
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
  • Year and Date: 20140328-31
• [Presentation] トリアゾール環を側鎖に持つD-イミノフラノース誘導体の合成と生物活性評価 (2014)
  • Author(s): 名取良浩、盛友莉恵、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134年会
  • Place of Presentation: 熊本
  • Year and Date: 20140328-31
• [Presentation] β-1-C-n-ブチル-L-イミノ糖誘導体の触媒的不斉合成とα-グルコシダーゼ阻害作用に対する構造活性相関 (2014)
  • Author(s): 佐久間俊嘉、名取良浩、吉村祐一、加藤敦、足立伊佐雄、中川進平、高畑廣紀
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
  • Year and Date: 20140328-31
• [Presentation] 新規β-glucocerebrosidase阻害剤calystegine B_2のインシリコ結合様式解析 (2013)
  • Author(s): 中込泉、加藤敦、山乙教之、足立伊佐雄、広野修一
  • Organizer: 第41回構造活性相関シンポジウム
  • Place of Presentation: 西宮
  • Year and Date: 20131107-08
• [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
  • Year and Date: 20130328-30
• [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
  • Year and Date: 20130328-30
• [Presentation] ピロリジン型イミノ糖の構造活性相関に基づいたシャペロン様化合物のデザイン研究 (2013)
  • Author(s): 中川進平、加藤敦、足立伊佐雄
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
  • Year and Date: 20130328-30
• [Presentation] 七員環型イミノ糖の誘導体化とグリコシダーゼ阻害活性 (2013)
  • Author(s): 岩城蓮、加藤敦、中川進平、足立伊佐雄
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
  • Year and Date: 20130328-30
• [Presentation] コンピュータリガンドドッキングによるα-glucosidase阻害剤α-1-C-Butyl-LABのmaltase及びβ-glucosidaseに対する結合様式解析 (2013)
  • Author(s): 中込泉、小関準、山乙教之、合田浩明、広野修一、加藤敦、林恵利奈、足立伊佐雄、今堀龍志、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
  • Year and Date: 20130328-30
• [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
  • Year and Date: 20130328-30
• [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
  • Year and Date: 20130328-30
• [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
  • Year and Date: 20130328-30
• [Presentation] Sucrase及びIsomaltaseへのLAB化合物の結合様式に関する理論的研究 (2012)
  • Author(s): 小関準、中込泉、足立伊佐雄、加藤敦、広野修一
  • Organizer: 第40回構造活性相関シンポジウム
  • Place of Presentation: 岡崎
  • Year and Date: 20121129-30
• [Presentation] Docking and SAR studies of D- and L-isofagomine isomers as humanβ-glucocerebrosidase inhibitors (2012)
  • Author(s): Kato, A., Miyauchi, S., Nakagome, I., Yoshimura, Y., Hirono, S., Takahata, H., Adachi, I
  • Organizer: 8th AFMC International Medicinal Chemistry Symposium (AIMECS11)
  • Place of Presentation: Keio, Japan
  • Year and Date: 20121129-1202
• [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
  • Year and Date: 20121105-06
• [Presentation] L-アラビノイミノフラノースをベースとした食後過血糖改善薬のデザイン合成研究 (2012)
  • Author(s): 加藤敦、林恵利奈、中川進平、足立伊佐雄、中込泉、小関準、広野修一、名取良浩、今堀龍志、吉村祐一、高畑廣紀
  • Organizer: 第31回糖質学会年会
  • Place of Presentation: 鹿児島
  • Year and Date: 20120917-20
• [Presentation] Synthesis amd biological evaluation of azetidines derivatives from carbohydrates (2012)
  • Author(s): Araújo, N., Martínez, R. F., Lenagh-Snow, G. M. J., Glawar, A. F. G., Jenkinson, S. F., Kato, A., Fleet, G.W.J
  • Organizer: 26^<th> International Carbohydrate Symposium (ICS2012)
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 20120722-27
• [Presentation] Synthesis of glycosidase inhibitors based on bicyclic azetidines for the treatment of cancer (2012)
  • Author(s): Martínez, R. F., Araújo, N., Jenkinson, S. F., Kato, A., and Fleet, G. W. J
  • Organizer: 26^<th> International Carbohydrate Symposium (ICS2012)
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 20120722-27
• [Presentation] Isofagomine類のβ-glucocerebrosidaseに対する結合親和性と構造活性相関について (2012)
  • Author(s): 加藤敦、中川進平、足立伊佐雄、中込泉、広野修一、吉村祐一、高畑廣紀
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
  • Year and Date: 20120329-31
• [Presentation] LABNAcを中心としたβ-N-acetyl-hexosaminidaseに対する構造活性相関とPC活性について (2012)
  • Author(s): 中川進平、加藤敦、嶋田陽介、足立伊
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
  • Year and Date: 20120329-31
• [Presentation] N-アセチルヘキソサミニダーゼを標的とした1-N型イミノ糖のデザイン研究 (2012)
  • Author(s): 嶋田陽介、加藤敦、佐藤香純、中川進平、足立伊佐雄
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
  • Year and Date: 20120329-31
• [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
  • Year and Date: 20110927-29
• [Presentation] D-およびL-isofagomine類の合成とグリコシダーゼ阻害活性 (2011)
  • Author(s): 加藤敦、宮内沙織、中川進平、足立伊佐雄、中込泉、広野修一、吉村祐一、高畑廣紀
  • Organizer: 第30回日本糖質学会年会
  • Place of Presentation: 長岡
  • Year and Date: 20110711-13