Design and synthesis of novel vitamin D receptor ligands having a functional group that reinforces the interaction with the receptor

• Project/Area Number: 23590142
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Tokushima Bunri University
• Principal Investigator: FUJISHIMA Toshie 徳島文理大学, 薬学部, 准教授 (90286980)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ビタミン / ホルモン / 核内受容体 / ステロイド / 化学合成

Research Abstract

Novel vitamin D receptor (VDR) ligands having a functional group designed to reinforce the interaction to the VDR through a certain amino acid residue were synthesized. The ligands having a carboxy group in the A-ring of vitamin D instead of the important 1alpha-hydroxy group were synthesized by a convergent method using palladium catalyst. In addition, vitamin D analogues having a spiro-oxetane fused at the C2 position in the A-ring were also synthesized. The VDR binding of the synthesized compounds revealed that the introduction of a carboxy group or an oxetane into the C2 position of the A-ring would compensate the loss of the 1alpha-hydroxy group to a certain extent to generate unique vitamin D analogues.

Research Products

• [Journal Article] Concise synthesis and characterization of novel seco-steroids bearing a spiro-oxetane instead of a metabolically labile C3-hydroxy group (2014)
  • Author(s): Toshie Fujishima, Tsutomu Suenaga, Takato Nozaki
  • Journal Title: Tetrahedron Lett Volume: 55 Issue: 28 Pages: 3805
  • DOI: 10.1016/j.tetlet.2014.05.060
• [Journal Article] Concise synthesis and characterization of novel seco-steroids bearing a spiro-oxetane instead of a metabolically labile C3-hydroxy group (2014)
  • Author(s): Toshie Fujishima, Tsutomu Suenaga, Takato Nozaki
  • Journal Title: Tetrahedron Lett. Volume: **
  • Peer Reviewed
• [Journal Article] Design and synthesis of novel 1,25-dihydroxyvitamin D₃ analogues having a spiro-oxetane fused at the C2 position in the A-ring (2013)
  • Author(s): Toshie Fujishima, Takato Nozaki, Tsutomu Suenaga
  • Journal Title: Bioorg. Med. Chem. Volume: 21 Issue: 17 Pages: 5209
  • DOI: 10.1016/j.bmc.2013.06.032
  • Peer Reviewed
• [Presentation] A環にスピロオキセタン構造を有する活性型ビタミンD3誘導体の合成 (2014)
  • Author(s): 末長努,藤島利江
  • Organizer: 日本薬学会第134年会
• [Presentation] A環にスピロオキセタン構造を有する活性型ビタミンD3誘導体の合成 (2014)
  • Author(s): 末長努，藤島利江
  • Organizer: 日本薬学会 第134年会
  • Place of Presentation: 熊本
• [Presentation] 20-ヒドロキシビタミンD3誘導体の合成研究 (2013)
  • Author(s): 藤島利江,末長努,山菅真基,大西翔太,川幡正俊,山口健太郎
  • Organizer: 日本ビタミン学会第65回大会
• [Presentation] 2位にオキセタンを有する活性型ビタミンD3誘導体の合成と生物活性 (2013)
  • Author(s): 藤島利江,野崎孝徒
  • Organizer: 日本薬学会第133年会
• [Presentation] 20-ヒドロキシビタミンD3誘導体の合成研究 (2013)
  • Author(s): 藤島利江，末長努，山菅真基，大西翔太，川幡正俊，山口健太郎
  • Organizer: 日本ビタミン学会 第65回大会
  • Place of Presentation: 東京
• [Presentation] 側鎖切断型20位ヒドロキシビタミンDの合成研究 (2013)
  • Author(s): 末長努，山菅真基，大西翔太，川幡正俊，山口健太郎，藤島利江
  • Organizer: 日本農芸化学関西・中四国・西日本支部および日本ビタミン学会近畿・中国四国・九州沖縄地区合同大会 2013年度 合同広島大会
  • Place of Presentation: 広島
• [Presentation] Incorporation of a spiro-oxetane into the A-ring of vitamin D: Design and syntheses of 1,25-dihydroxyvitamin D3 analogues bearing an additional ring fused in the A-ring (2013)
  • Author(s): Toshie Fujishima, Tsutomu Suenaga, Takato Nozaki
  • Organizer: The 9th AFMC international medicinal chemistry symposium
  • Place of Presentation: 台北
• [Presentation] A環2位にオキセタンを有する活性型ビタミンD3誘導体の合成と生物活性 (2013)
  • Author(s): 藤島利江，野崎孝徒
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
• [Presentation] 25-ヒドロキシビタミンD誘導体のデザインと合成 (2012)
  • Author(s): 藤島利江,白石敏幸,末長努
  • Organizer: 第30回メディシナルケミストリーシンポジウム
• [Presentation] 20位水酸化ビタミンD3誘導体の合成研究 (2012)
  • Author(s): 末長 努，大西 翔太，藤島 利江，川幡 正俊，山口 健太郎
  • Organizer: 日本ビタミン学会 第64回大会
  • Place of Presentation: 広島
• [Presentation] 25-ヒドロキシビタミンD誘導体のデザインと合成 (2012)
  • Author(s): 藤島 利江，白石 敏幸，末長 努
  • Organizer: 第30回メディシナルケミストリーシンポジウム
  • Place of Presentation: 東京
• [Presentation] A環部にオキセタンを有する活性型ビタミンD3誘導体の合成 (2012)
  • Author(s): 野崎孝徒，藤島利江
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
• [Presentation] 20位水酸化ビタミンD3誘導体の合成と生理活性 (2012)
  • Author(s): 末長努，藤島利江
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
• [Presentation] Novel vitamin D receptor ligands having a carboxyl group as a possible anchor to the crucial arginine residue in the ligand-binding domain (2011)
  • Author(s): Toshie Fujishima, Toshiyuki Shiraishi, Tsutomu Suenaga
  • Organizer: The 8^<th> AFMC international medicinal chemistry symposium
• [Presentation] Novel vitamin D receptor ligands having a carboxyl group as a possible anchor to the crucial arginine residue in the ligand-binding domain. (2011)
  • Author(s): Fujishima, T., Shiraishi, T., Suenaga, T., Nozaki, T., Kitamura, A.
  • Organizer: The 4th symposium vitamin D and analogs in cancer prevention and therapy
  • Place of Presentation: Homburg/Saar
• [Presentation] 20位水酸化ビタミンD3誘導体の合成研究 (2011)
  • Author(s): 末長努，藤島利江
  • Organizer: 日本ビタミン学会第63回大会
  • Place of Presentation: 広島
• [Presentation] Novel vitamin D receptor ligands having a carboxyl group as a possible anchor to the crucial arginine residue in the ligand-binding domain (2011)
  • Author(s): Fujishima, T., Shiraishi, T., Suenaga, T.
  • Organizer: The 8th AFMC medicinal chemistry symposium
  • Place of Presentation: Tokyo