Synthesis of the Selective Nuclear Receptor LXRa Agonist, Riccardins and Development of Anti-arteriosclerosis Drug

• Project/Area Number: 18590113
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Tokushima Bunri University
• Principal Investigator: FUKUYAMA Yoshiyasu Tokushima Bunri University, 薬学部, 教授 (70208990)
• Co-Investigator(Kenkyū-buntansha): ASAKAWA Yoshinori 徳島文理大学, 薬学部, 教授 (50033874)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,000,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥600,000); Fiscal Year 2008: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
• Keywords: リカルデイン / パラジウム触媒 / 核内受容体 / コレステロール代謝 / 天然物合成 / 大環状ビスビベンジル / LXRα アゴニスト / 鈴木・宮浦反応 / リカルデインC / 核内受容体LXR / パラジウム / Suzuki-Miyaura反応 / アゴニスト / 構造活性相関 / 動脈硬化改善薬 / コレステロール / Stille-Kelly反応

Research Abstract

研究成果の概要:大環状ビスビベンジル化合物リカルデイン C はコレステロールのセンサー蛋白である核内レセプター LXRα の特異的アゴニスト活性を有する天然物として知られ、新しい抗コレステロール薬への展開が期待されている。リカルデイン Cの効率的合成法の開発と、活性発現に必要な構造因子を明らかにする目的で合成研究を行い、その合成に成功した。さらに、7 種の誘導体を調製し、アゴニスト活性を検討した結果、リカルデイン C のみにLXRα特異的アゴニスト活性が発現したが、他の誘導体には全く活性が認められなかった。

Research Products

• [Journal Article] The First Synthesis of Neovibsanin B (2009)
  • Author(s): H. Imagawa, H. Saijo, T. Kurisaki, M. Kubo, Y. Fukuyama, M. Nishizawa
  • Journal Title: Org. Lett. 11 Pages: 1253-1255
  • Peer Reviewed
• [Journal Article] Sweet and Bitter Constituents of Wilbrandia species (2009)
  • Author(s): M. Ochi, K. Moriyama, K. Ohmae, Y. Fukuyama, K. Nihei, I. Kubo
  • Journal Title: Food Chemistry 115 Pages: 61-65
  • Peer Reviewed
• [Journal Article] Total Synthesis of Pseudodehydrothyrsiferol (2009)
  • Author(s): H. Hioki, M. Motosue, Y. Mizutani, A. Noda, K. Shnimoda, M. Kubo, K. Harada, Y. Fukuyama, M. Kodama
  • Journal Title: Org. Lett., 11 Pages: 579-582
  • Peer Reviewed
• [Journal Article] Synthesis of Riccardin C and Its Seven Analogues: the Role of Their Phenolic Hydroxy Groups as LXRα Receptor Agonists (2009)
  • Author(s): H. Hioki, N. Shima, K. Kawaguchi, K. Harada, M. Kubo, T. Esumi, T. Mogami, T. Hashimoto, Y. Asakawa, Y. Fukuyama
  • Journal Title: Bioorg. Med. Chem. Lett. 19 Pages: 746-749
  • Peer Reviewed
• [Journal Article] Novel NGF-Potentiating Diterpenoids from a Brazilian Medicinal Plant, Ptychopetalum olacoides (2009)
  • Author(s): W. Tang, H. Hioki, K. Harada, M. Kubo, Y. Fukuyama
  • Journal Title: Bioorg. Med. Chem. Lett. 19 Pages: 890-894
  • Peer Reviewed
• [Journal Article] Acetal-Bearing Rearranged Vibsane-type Diterpenoids from Viburnum awabuki (2009)
  • Author(s): M. Kubo, Y. Minoshima, A. Arimoto, H. Minami, K. Harada, H. Hioki, Y. Fukuyama
  • Journal Title: Heterocycles 77 Pages: 539-546
  • Peer Reviewed
• [Journal Article] Synthesis of Riccardin C and Its Seven Analogues : the Role of Their Phenolic Hydroxy Groups as LXRa Receptor Agonists. (2009)
  • Author(s): Y. Fukuyama, et al.
  • Journal Title: Bioorg. Med. Chem. Lett. 19 Pages: 890-894
  • Peer Reviewed
• [Journal Article] Total Synthesis of Pseudodehydrothyrsierol. (2009)
  • Author(s): Y. Fukuyama, et al.
  • Journal Title: Org. Lett. 11 Pages: 579-582
  • Peer Reviewed
• [Journal Article] The First Synthesis of Neovibsanin B. (2009)
  • Author(s): Y. Fukuyama, et al.
  • Journal Title: Org. Lett. 11 Pages: 1253-1255
  • Peer Reviewed
• [Journal Article] Efficient Construction of a Chiral All-carbon Quaternary Center by Asymmetric 1,4-addittion and Its Application to Total Synthesis of (+)-Bakuchiol (2008)
  • Author(s): T. Esumi, H. Shimizu, A. Kashiyama, C. Sasaki, M. Toyota, Y. Fukuyama
  • Journal Title: Tetrahedron Lett. 49 Pages: 6846-6849
  • Peer Reviewed
• [Journal Article] Clerodane Diterpenoids with NGF-Potentiating Activity from Ptychopetalum olacoides (2008)
  • Author(s): W. Tang, H. Hioki, K. Harada, M. Kubo, Y. Fukuyama
  • Journal Title: J. Nat. Prod. 71 Pages: 1760-1763
  • Peer Reviewed
• [Journal Article] Solid-phase Combinatorial Synthesis of 2-Arylquinazolines and 2-Arylquinazolines by an 4-Alkoxyaniline Linker (2008)
  • Author(s): H, Hioki, K. Matsushita, M. Kubo, K. Harada, M. Kodama, Y. Fukuyama
  • Journal Title: J. Comb. Chem. 10, (5) Pages: 620-623
  • Peer Reviewed
• [Journal Article] Two New Sesquiterpenoids and Two New Prenylated Phenylpropanoids from Illicium fargesii, and Neuroprotective Activity of Macranthol (2008)
  • Author(s): M. Moriyama, J.-M. Huang, C.-S. Yang, M. Kubo, K. Harada, H. Hioki, Y. Fukuyama
  • Journal Title: Chem. Pharm. Bull. 56 Pages: 1201-1204
  • NAID: 110006838336
  • Peer Reviewed
• [Journal Article] Synthesis of (-)-Talaumidin, a Neurotrophic 2,5-Diaryl-3,4-dimethyl Tetrahydrofuran Lignan, and Its Stereosiomers (2008)
  • Author(s): Y. Fukuyama, K. Harada, T. Esumi, D. Hojyo, Y. Kujime, N. Kubo, M. Kubo, H. Hioki
  • Journal Title: Heterocycles 76, 1 Pages: 551-567
  • Peer Reviewed
• [Journal Article] Synthetic Studies toward Neovibsanins A and B: Construction of the Neovibsanin Core Utilizing Palladium(0)-catalyzed Carbonylative Cyclization with Carbon Monoxide (2008)
  • Author(s): T. Esumi, M. Zhao, T. Kawakami, M. Fukumoto, M. Toyota, Y. Fukuyama
  • Journal Title: Tetrahedron Lett. 49 Pages: 2692-2696
  • Peer Reviewed
• [Journal Article] Synthetic Studies toward Neovibsanins A and B:Construction of the Neovibsanin Core Utilizing Palladium(0)-catalyzed Carbollylative Cyclization with Carbon Monoxide (2008)
  • Author(s): Y.Fukuyarrla, et. al.
  • Journal Title: Tetrahedron Lett 49 Pages: 2692-2696
  • Peer Reviewed
• [Journal Article] Antioxidative Phenylpropanoidsubstituted Epicatechins from Trichilia catigua (2007)
  • Author(s): W. Tang, H. Hioki, K. Harada, M. Kubo, Y. Fukuyama
  • Journal Title: J. Nat. Prod. 70 Pages: 2010-2013
  • Peer Reviewed
• [Journal Article] Solid-phase Combinatorial Synthesis of Benzothiazoles, Benzimidazoles and Benzoxazoles Using a Traceless Linker (2007)
  • Author(s): H, Hioki, K. Matsushita, M. Kubo, K. Harada, M. Kodama, Y. Fukuyama
  • Journal Title: Tetrahedron 63 Pages: 11315-11324
  • Peer Reviewed
• [Journal Article] An Efficient Synthesis of the CD rings Model for Merrilactone A (2007)
  • Author(s): K. Harada, H. Ito, H. Hioki, Y. Fukuyama
  • Journal Title: Tetrahedron Lett. 48 Pages: 6105-6108
  • Peer Reviewed
• [Journal Article] Total Synthesis and Bioactivity of an Unnatural Enantiomer of Merrilactone A: Development of an Enantioselective Desymmerization Strategy (2007)
  • Author(s): M. Inoue, N. Lee, T. Sato, M. Hirama, M. Moriyama, Y. Fukuyama
  • Journal Title: J. Org. Chem. 72 Pages: 3065-3075
  • Peer Reviewed
• [Journal Article] Structure and Neurotrophic Activity of Novel Sesqui-neolignans from the Pericarps of Illicium fargesii (2007)
  • Author(s): M. Moriyama, Jian-Mei Huang, Chun-Shu Yang, H. Hioki, K. Harada, M. Kubo, Y. Fukuyama
  • Journal Title: Tetrahedron 63 Pages: 4243-4249
  • Peer Reviewed
• [Journal Article] An Efficient Synthesis of the CD Rings Model for Merrilactone A (2007)
  • Author(s): Y.Fukuyama, et. al.
  • Journal Title: Tetrahedron Lett 48 Pages: 6105-6108
  • Peer Reviewed
• [Journal Article] ビブサン型ジテルペンの化学と生理活性 (2007)
  • Author(s): 福山 愛保
  • Journal Title: 有機合成化学協会誌 65 Pages: 585-597
  • Peer Reviewed
• [Journal Article] Structure and Neurotrophic Activity of Novel Sesqui-neolignans from the Pericarps of Illicium fargesii. (2007)
  • Author(s): Y.Fukuyama et al.
  • Journal Title: Tetrahedron (In press)
• [Journal Article] Total Synthesis and Bioactivity of an Unnatural Enantiomer of Merrilactone A : Development of an Enantioselective Desymmerization Stratgey. (2007)
  • Author(s): Y.Fukuyama et al.
  • Journal Title: J.Org.Chem. (In press)
• [Journal Article] Two Diterpene Rhamnosides, Mimosasides B and C, from Mimosa hostilis (2006)
  • Author(s): A. Ohsaki, R. Yokoyama, H. Miyatake, Y. Fukuyama
  • Journal Title: Chem. Pharm. Bull. 54, Pages: 1728-1729
  • NAID: 110004863649
  • Peer Reviewed
• [Journal Article] Neovibsanin F and its Congeners, Rearranged Vibsane-type Diterpenes from Viburnum suspesnsiom (2006)
  • Author(s): Y. Fukuyama, H. Fujii, M. Kubo, H. Minami, H. Takahashi
  • Journal Title: J. Nat. Prod. 69 Pages: 1098-1100
  • Peer Reviewed
• [Journal Article] Degraded and Oxetane-bearing Limonoids from Melia azedarach (2006)
  • Author(s): Y. Fukuyama, M. Nakaoka, T. Yamamoto, H. Takahashi, H. Minami
  • Journal Title: Chem. Pharm. Bull. 54 Pages: 1219-1222
  • Peer Reviewed
• [Journal Article] A Norbergenin Derivatives Inhibits Neuronal Cell Damage Induced by Tunicamycin (2006)
  • Author(s): S. Suzuki, Y. Okuse, M. Kawase, M. Takiguchi, Y. Fukuyama, H. Takahashi, M. Sato
  • Journal Title: Biol. Pharm. Bull. 29 Pages: 1335-1338
  • NAID: 110005602297
  • Peer Reviewed
• [Journal Article] First Enantioselective Synthesis of (-)-Talaumidin, a Neutrotrophic Diaryltetrahydrofuran-type Lignan (2006)
  • Author(s): T. Esumi, D. Houjyou, H. Zhai, Y. Fukuyama
  • Journal Title: Tetrahedron Lett. 47 Pages: 3979-3983
  • Peer Reviewed
• [Journal Article] First Enantioselective Synthesis of (-)-Talaumidin, a Neutrotrophic Diarylteyrahedrofuran-type Lignan (2006)
  • Author(s): Y.Fukuyama et al.
  • Journal Title: Tetrahedron Lett 29・7 Pages: 1335-1338
• [Journal Article] Degraded and Oxetane-bearing Limonoids from Melia azedarach. (2006)
  • Author(s): Y.Fukuyama et al.
  • Journal Title: Chem.Pharm.Bull. 54・8 Pages: 1219-1222
• [Journal Article] A Norbergenin Derivatives Inhibits Neuronal Cell Damage Induced by Tunicamycin. (2006)
  • Author(s): Y.Fukuyama et al.
  • Journal Title: Biol.Pharm.Bull. 29・7 Pages: 1335-1338
  • NAID: 110005602297
• [Presentation] Cavicularin の合成研究 (2009)
  • Author(s): 島尚喜、原田研一、久保美和、日置英彰、福山愛保
  • Organizer: 日本薬学会第129 年会
  • Place of Presentation: 京都
• [Presentation] 核内受容体LXRαアゴニストRiccardin C とその誘導体の合成研究 (2008)
  • Author(s): ○島尚樹, 川口幸太, 原田研一, 久保美和, 日置英彰, 福山愛保
  • Organizer: 第34回反応と合成の進歩シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2008-11-04
• [Presentation] 核内受容体LXRαアゴニストRiccardin C の合成研究 (2008)
  • Author(s): 島 尚樹, 川口 幸太, 原田 研一, 久保 美和, 日置 英彰, 福山 愛保
  • Organizer: 日本薬学会第128年会
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-28
• [Presentation] 核内受容体 LXRαアゴニスト Riccardin C とその誘導体の合成研究 (2008)
  • Author(s): 島尚喜、川口幸太、原田研一、久保美和、日置英彰、福山愛保
  • Organizer: 第34 回反応と合成の進歩シンポジウム
  • Place of Presentation: 京都
• [Presentation] 核内受容体 LXRαアゴニスト Riccardin C の合成研究 (2008)
  • Author(s): 島尚喜、川口幸太、原田研一、久保美和、日置英彰、福山愛保
  • Organizer: 日本薬学会第128 年会
  • Place of Presentation: 横浜
• [Book] 神経毒と神経突起、栄養因子活性物質. 天然物化学-植物編-(山村庄亮、長谷川宏司 編) (2007)
  • Author(s): 福山愛保
  • Publisher: アイピーシー
• [Book] 天然物化学-植物編- (2007)
  • Author(s): 福山愛保
  • Total Pages: 428
  • Publisher: アイピーシー
• [Remarks]
  • URL: http://p.bunri-u.ac.jp/~fukuyama/fukuyama/index.htm
• [Patent(Industrial Property Rights)] 神経細胞賦活剤 (2008)
  • Inventor(s): 橋本麻美子、井ノ瀬利明、木村隆、橋本敏弘、吉川和子、福山愛保
  • Industrial Property Rights Holder: ユニチカ(株)
  • Filing Date: 2008-10-30
• [Patent(Industrial Property Rights)] 神経細胞突起伸展作用を有する置換シクロヘキセンを有効成分として含有する植物を利用することを特徴とする健康組成物 (2008)
  • Inventor(s): 福山愛保、日置英彰、堂上美和、原田研一、加藤榮信
  • Industrial Property Rights Holder: 細田真也
  • Filing Date: 2008-10-07
• [Patent(Industrial Property Rights)] ビステトラヒドロフラン化合物、その製造方法及び該化合物の用途 (2007)
  • Inventor(s): 西沢麦夫、福山愛保、今川洋
  • Industrial Property Rights Holder: 大塚化学(株)
  • Filing Date: 2007-03-01