Development of novel transcription modulators based on de novo design of scaffolds

• Project/Area Number: 25460146
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: Fujii Shinya 東京大学, 分子細胞生物学研究所, 講師 (60389179)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 生物活性化合物 / 転写因子 / ステロイドホルモン / アンドロゲン受容体 / プロゲステロン受容体 / グルココルチコイド受容体 / ケイ素 / 医薬化学 / 核内受容体 / アンドロゲン / プロゲステロン / グルココルチコイド / PPAR / ファーマコフォア / クルクミン / 前立腺癌

Outline of Final Research Achievements

In this research, development of novel biologically active compounds based on de novo design of scaffolds, with focusing on the pharmacophores of biologically active natural products, was investigated. Based on the structures of several natural products including curcumin, various modulators for nuclear receptors such as androgen receptor and progesterone receptor were developed. The developed compounds are versatile lead compounds for drug discovery, and the methodology developed here is also a promising approach for structural development.

Research Products

• [Journal Article] Altered activity profile of a tertiary silanol analog of multi-targeting nuclear receptor modulator T0901317 (2016)
  • Author(s): Toyama, H.; Sato, S.; Shirakawa, H.; Komai, M.; Hashimoto, Y.; Fujii, S.*
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 26 Pages: 1817-1820
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Design and synthesis of silicon-containing fatty acid amide derivatives as novel peroxisome proliferator-activated receptor (PPAR) agonists (2015)
  • Author(s): Daisuke Kajita, Masaharu Nakamura, Yotaro Matsumoto, Minoru Ishikawa, Yuichi Hashimoto and Shinya Fujii
  • Journal Title: Bioorganic & Medicinal Chemistry Letter Volume: 25 Issue: 16 Pages: 3350-3354
  • DOI: 10.1016/j.bmcl.2015.05.045
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Design and synthesis of novel ROR inverse agonists based on dibenzosilole scaffolds as a hydrophobic core structure (2015)
  • Author(s): Toyama, H.; Nakamura, M.; Hashimoto, Y.; Fujii, S.*
  • Journal Title: Bioorg. Med. Chem. Volume: 23 Issue: 13 Pages: 2982-2988
  • DOI: 10.1016/j.bmc.2015.05.004
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Carboxylic derivatives of vitamin K2 inhibit hepatocellular carcinoma cell growth through caspase/transglutaminase-related signaling pathways (2015)
  • Author(s): Qin, X.-Y.; Fujii, S.; Shimizu, A.; Kagechika, H.; Kojima, S.
  • Journal Title: J. Nutr. Sci. Vitaminol. Volume: 61 Pages: 285-290
  • NAID: 130005102615
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Systematic synthesis and anti-inflammatory activity of ω-carboxylated menaquinone derivatives -Investigation on identified and putative vitamin K metabolites- (2015)
  • Author(s): Fujii, S.; Shimizu, A.; Takeda, N.; Oguchi, K.; Katsurai, T.; Shirakawa, H.; Komai, M.; Kagechika, H.
  • Journal Title: Bioorg. Med. Chem. Volume: 23 Issue: 10 Pages: 2344-2352
  • DOI: 10.1016/j.bmc.2015.03.070
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Design and synthesis of 4-benzyl-1-(2H)-phthalazinone derivatives as novel androgen receptor antagonists (2015)
  • Author(s): Kazumi Inoue, Ko Urushibara, Misae Kanai, Kei Yura, Shinya Fujii, Mari Ishigami-Yuasa, Yuichi Hashimoto, Shuichi Mori, Emiko Kawachi, Mio Matsumura, Tomoya Hirano, Hiroyuki Kagechika, Aya Tanatani
  • Journal Title: European Journal of Medicinal Chemistry Volume: 102 Pages: 310-319
  • DOI: 10.1016/j.ejmech.2015.08.002
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 新規ファーマコフォアの構築に基づくアンドロゲン受容体パンアンタゴニストの創製 (2015)
  • Author(s): 藤井晋也，山田歩，森修一，影近弘之
  • Journal Title: ケミカルバイオロジー Volume: 18 Pages: 6-8
• [Journal Article] Development of 1,3-diphenyladamantane derivatives as nonsteroidal progesterone receptor antagonists. (2015)
  • Author(s): Mori, S.; Takeuchi, Y.; Tanatani, A.; Kagechika, H.; Fujii, S.
  • Journal Title: Bioorg. Med. Chem Volume: 23 Issue: 4 Pages: 803-809
  • DOI: 10.1016/j.bmc.2014.12.047
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Discovery of Novel SPAK Inhibitors That Block WNK Kinase Signaling to Cation Chloride Transporters (2014)
  • Author(s): Kikuchi E, Mori T, Zeniya M, Isobe K, Ishigami-Yuasa M, Fujii S, Kagechika H, Ishihara T, Mizushima T, Sasaki S, Sohara E, Rai T, Uchida S
  • Journal Title: J Am Soc Nephrol Volume: 26 Issue: 7 Pages: 1525-1536
  • DOI: 10.1681/asn.2014060560
  • Peer Reviewed
• [Journal Article] Lipase-catalyzed asymmetric acylation of boron cluster-containing secondary alcohols. (2014)
  • Author(s): Mori, S.; Takagaki, R.; Fujii, S.; Matsumura, M.; Tanatani, A.; Kagechika, H.
  • Journal Title: Tetrahedron Asymm. Volume: 25 Issue: 23 Pages: 1505-1512
  • DOI: 10.1016/j.tetasy.2014.10.009
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Structural development of p-carborane-based potent non-secosteroidal vitamin D analogs. (2014)
  • Author(s): Fujii, S.; Sekine, R.; Kano, A.; Masuno, H.; Songkram, C.; Kawachi, E.; Hirano, T.; Tanatani, A.; Kagechika, H.
  • Journal Title: Bioorg. Med. Chem Volume: 22 Issue: 21 Pages: 5891-5901
  • DOI: 10.1016/j.bmc.2014.09.020
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Development of p-carborane-based nonsteroidal progesterone receptor antagonists. (2014)
  • Author(s): Fujii, S.; Nakano, E.; Yanagida, N.; Mori, S.; Masuno, H.; Kagechika, H.
  • Journal Title: Bioorg. Med. Chem. Volume: 22 Issue: 19 Pages: 5329-5337
  • DOI: 10.1016/j.bmc.2014.07.049
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Design and synthesis of tetraol derivatives of 1,12-dicarba-closo-dodecaborane as non-secosteroidal vitamin D analogs. (2014)
  • Author(s): Fujii, S.; Kano, A.; Masuno, H.; Songkram, C.; Kawachi, E.; Hirano, T.; Tanatani, A.; Kagechika, H
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 24 Issue: 18 Pages: 4515-4519
  • DOI: 10.1016/j.bmcl.2014.07.075
  • Peer Reviewed
• [Journal Article] Design and synthesis of nonsteroidal progesterone receptor antagonists based on C,C’-diphenylcarborane scaffold as a hydrophobic pharmacophore. (2014)
  • Author(s): Fujii, S.; Yamada, A.; Nakano, E.; Takeuchi, Y.; Mori, S.; Masuno, H.; Kagechika, H.
  • Journal Title: Eur. J. Med. Chem. Volume: 84 Pages: 264-277
  • DOI: 10.1016/j.ejmech.2014.07.034
  • Peer Reviewed
• [Journal Article] Development of 2-Thioxoquinazoline-4-one Derivatives as Dual and Selective Inhibitors of Dynamin-Related Protein 1 (Drp1) and Puromycin-Sensitive Aminopeptidase (PSA) (2014)
  • Author(s): Numadate, A.; Mita, Y.; Matsumoto, Y.; Fujii, S.; Hashimoto, Y.
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 62 Issue: 10 Pages: 979-988
  • DOI: 10.1248/cpb.c14-00333
  • NAID: 130004693775
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed
• [Journal Article] Synthesis and Structure–Activity Relationship Study of Triazine-Based Inhibitors of the DNA Binding of NF-κB (2014)
  • Author(s): Fujii, S.; Kobayashi, T.; Nakatsu, A.; Miyazawa, H.; Kagechika, H.
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 62 Issue: 7 Pages: 700-708
  • DOI: 10.1248/cpb.c14-00218
  • NAID: 130004053804
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed
• [Journal Article] 球状疎水性ファーマコフォアを有する非セコステロイド型ＶＤＲリガンドの創製研究 (2014)
  • Author(s): 藤井晋也，棚谷綾，平野智也，影近弘之
  • Journal Title: ビタミン Volume: 88 Pages: 389-395
  • NAID: 110009843773
  • Peer Reviewed
• [Journal Article] Synthesis and structure-activity relationship of p-carborane-based non-secosteroidal vitamin D analogs. (2014)
  • Author(s): Fujii, S.; Kano, A.; Songkram, C.; Masuno, H.; Tao da, Y.; Kawachi, E.; Hirano, T.; Tanatani, A.; Kagechika, H.
  • Journal Title: Bioorg. Med. Chem. Volume: 22 Issue: 4 Pages: 1227-1235
  • DOI: 10.1016/j.bmc.2014.01.015
  • Peer Reviewed
• [Journal Article] Design and synthesis of 4-(4-benzoylaminophenoxy)phenol derivatives as androgen receptor antagonists. (2013)
  • Author(s): Yamada, A.; Fujii, S.; Mori, S.; Kagechika, H.
  • Journal Title: ACS Med. Chem. Lett. Volume: 4 Issue: 10 Pages: 937-941
  • DOI: 10.1021/ml4001744
  • Peer Reviewed
• [Journal Article] Copper-mediated C-C Cross-Coupling Reaction of Monocarba-closo-dodecaborate Anion for Construction of Functional Molecules (2013)
  • Author(s): Junichiro Kanazawa, Ryo Takita, Aleksandra Jankowiak, Shinya Fujii, Hiroyuki Kagechika, Daisuke Hashizume, Koichi Shudo, Piotr Kaszynski, and Masanobu Uchiyama
  • Journal Title: Angew. Chem. Int. Ed. Volume: 52 Issue: 31 Pages: 8017-8021
  • DOI: 10.1002/anie.201302448
  • Peer Reviewed
• [Journal Article] Chemical library screening for WNK signalling inhibitors using fluorescence correlation spectroscopy. (2013)
  • Author(s): Mori, T.; Kikuchi, E.; Watanabe, Y.; Fujii, S.; Ishigami-Yuasa, M.; Kagechika, H.; Sohara, E.; Rai, T.; Sasaki, S.; Uchida, S.
  • Journal Title: Biochem. J. Volume: 455 Issue: 3 Pages: 339-345
  • DOI: 10.1042/bj20130597
  • Peer Reviewed
• [Presentation] AF-1領域による機能制御を指向した新規アンドロゲン受容体モジュレーターの創製 (2016)
  • Author(s): 沼館慧剛，谷内出友美，梅田香織，槇島誠，橋本祐一，藤井晋也
  • Organizer: 日本薬学会第１３６回年会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-03-26
• [Presentation] 核内受容体リガンドを指向した1,3,5-トリアジン誘導体の設計と構造展開 (2016)
  • Author(s): 海東和麻，谷内出友美，中津亜紀，森修一，橋本祐一，影近弘之，藤井晋也
  • Organizer: 日本薬学会第１３６回年会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-03-26
• [Presentation] Development of nuclear receptor ligands based on the novel hydrophobic pharmacophore (2016)
  • Author(s): Shinya Fujii
  • Organizer: Advances in Retinoids research.
  • Place of Presentation: Strasbourg, France
  • Year and Date: 2016-01-29
  • Int'l Joint Research
• [Presentation] Development of novel nuclear receptor modulators based on silyl functionality as hydrophobic core structure (2015)
  • Author(s): Fujii, S.; Miyajima, Y.; Toyama, H.; Kajita, D.; Nakamura, M.; Kagechika, H.; Hashimoto, Y.
  • Organizer: ASMC2015
  • Place of Presentation: Rehovot, Israel
  • Year and Date: 2015-11-15
  • Int'l Joint Research
• [Presentation] Development of androgen receptor (AR) activation function-1 (AF-1) modulators (2015)
  • Author(s): Fujii, S.; Numadate, A.; Noguchi-Yachide, T.; Endo-Umeda, K.; Makishima, M.; Hashimoto, Y.
  • Organizer: 3rd International Conference on Retinoids.
  • Place of Presentation: 岐阜グランドホテル（岐阜県・岐阜市）
  • Year and Date: 2015-10-23
  • Int'l Joint Research
• [Presentation] 三次元分子構築と元素化学的アプローチを基盤とした疎水性ファーマコフォアの開発 (2015)
  • Author(s): 藤井晋也
  • Organizer: 第５９回日本薬学会関東支部大会
  • Place of Presentation: 日本大学薬学部（千葉県・船橋市）
  • Year and Date: 2015-09-12
• [Presentation] 新規疎水性ファーマコフォアを有するビタミンD受容体リガンドの創製 (2015)
  • Author(s): 藤井晋也，平野智也，棚谷綾，影近弘之
  • Organizer: 第１回Neo Vitamin D Workshop学術集会
  • Place of Presentation: 大津プリンスホテル（滋賀県・大津市）
  • Year and Date: 2015-08-28
• [Presentation] アンドロゲン受容体AF-1モジュレーターの創製 (2015)
  • Author(s): 沼館慧剛，谷内出友美，梅田香織，槇島誠，橋本祐一，藤井晋也
  • Organizer: 日本ケミカルバイオロジー学会第１０回年会
  • Place of Presentation: 東北大学（宮城県・仙台市）
  • Year and Date: 2015-06-10
• [Presentation] 含ケイ素複素環を骨格構造とする新規ROR転写抑制リガンドの創製 (2015)
  • Author(s): 外山大純，中村雅陽，橋本祐一，藤井晋也
  • Organizer: 日本ケミカルバイオロジー学会第１０回年会
  • Place of Presentation: 東北大学（宮城県・仙台市）
  • Year and Date: 2015-06-10
• [Presentation] メナキノン酸化誘導体の系統的合成と抗炎症作用 (2015)
  • Author(s): 藤井晋也，清水章貴，小口一起，桂井朋子，白川仁，駒井三千夫，影近弘之
  • Organizer: 日本ビタミン学会第６７回大会
  • Place of Presentation: 奈良県新公会堂（奈良県・奈良市）
  • Year and Date: 2015-06-05
• [Presentation] ケイ素とcisオレフィンの可換性に着目した含ケイ素PPARアゴニストの創製 (2015)
  • Author(s): 梶田大資、中村雅陽、松本洋太郎、石川稔、橋本祐一、藤井晋也
  • Organizer: 日本薬学会第１３５年会
  • Place of Presentation: 神戸（兵庫）
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] ステロイド代替骨格としてのジフェニルメタン骨格―胆汁鬱滞性疾患治療薬への 展開― (2015)
  • Author(s): 小針孝夫、細田信之助、貝沼雅彦、三澤隆、藤井晋也、橋本祐一
  • Organizer: 日本薬学会第１３５年会
  • Place of Presentation: 神戸（兵庫）
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] 核内受容体選択的なCoactivator Binding Inhibitorの創製研究 (2015)
  • Author(s): 福田寛充、槇島誠、石川稔、藤井晋也、橋本祐一
  • Organizer: 日本薬学会第１３５年会
  • Place of Presentation: 神戸（兵庫）
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] カルボラン含有プロゲステロン受容体リガンドのリパーゼによる光学分割 (2015)
  • Author(s): 森修一、高垣亮平、藤井晋也、松村実生、棚谷綾、影近弘之
  • Organizer: 日本薬学会第１３５年会
  • Place of Presentation: 神戸（兵庫）
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] Development of Transcriptional Modulators Using Three Dimensional Architectures (2014)
  • Author(s): Shinya Fujii, Yasuyuki Endo, Hiroyuki Kagechika, Yuichi Hashimoto
  • Organizer: ICCEOCA-9_ACP2014
  • Place of Presentation: クアラルンプール（マレーシア）
  • Year and Date: 2014-12-01 – 2014-12-04
• [Presentation] Synthesis and characterization of novel m-carborane-containing porphyrinoid (2014)
  • Author(s): Shinya Fujii, Shotaro Iihama, Hiroyuki Kagechika
  • Organizer: IMEBORON 15
  • Place of Presentation: プラハ工科大学（チェコ）
  • Year and Date: 2014-08-24 – 2014-08-28
• [Presentation] Design and synthesis of C,C'-diphenylcarborane derivatives as novel progesterone receptor antagonists (2014)
  • Author(s): Hiroyuki Kagechika, Shuichi Mori, Eiichi Nakano, Ayumi Yamada, Yuki Takeuchi, Hiroyuki Masuno, Shinya Fujii
  • Organizer: IMEBORON 15
  • Place of Presentation: プラハ工科大学（チェコ）
  • Year and Date: 2014-08-24 – 2014-08-28
• [Presentation] カルボランを基盤とする非セコステロイド型VDRリガンドの疎水性部位の構造展開 (2014)
  • Author(s): 藤井晋也、八田健司、増野弘幸、河内恵美子、影近弘之
  • Organizer: 日本ビタミン学会第６６回大会
  • Place of Presentation: 姫路商工会議所（兵庫）
  • Year and Date: 2014-06-13 – 2014-06-14
• [Presentation] クルクミン誘導体の構造展開による新規ＰＲアンタゴニストの創製 (2014)
  • Author(s): 藤井晋也、山田歩、森修一、影近弘之
  • Organizer: 日本ケミカルバイオロジー学会第９会年会
  • Place of Presentation: 大阪大学（大阪）
  • Year and Date: 2014-06-11 – 2014-06-13
• [Presentation] カルボランを基盤とした新規ビタミンＤ誘導体の創製 (2014)
  • Author(s): 八田健司，河内恵美子，増野弘幸，藤井晋也，影近弘之
  • Organizer: 日本薬学会第１３４年会
  • Place of Presentation: 熊本市
• [Presentation] クマリン骨格を基盤とした新規アンドロゲン受容体アンタゴニストの創製 (2014)
  • Author(s): 古賀瞳，木下満里絵，藤井晋也，影近弘之，棚谷綾
  • Organizer: 日本薬学会第１３４年会
  • Place of Presentation: 熊本市
• [Presentation] Increased hydrophobicity and estrogenic activity of silicon- and germanium-containing phenols (2013)
  • Author(s): Fujii, S.; Miyajima, Y.; Masuno, H.; Kagechika, H.
  • Organizer: 14th Tetrahedron Symposium
  • Place of Presentation: ウィーン、オーストリア
• [Presentation] Synthesis and characterization of a conjugated macrocyclic compound containing a carborane cage (2013)
  • Author(s): Iihama, S.; Fujii, S.; Kagechika, H.
  • Organizer: 14th Tetrahedron Symposium
  • Place of Presentation: ウィーン、オーストリア
• [Presentation] Development of novel estrogen receptor agonists based on silicon- and germanium-containing hydrophobic functionalities (2013)
  • Author(s): Masuno, H.; Miyajima, Y.; Fujii, S.; Kagechika, H.
  • Organizer: The 2st HD Physiology International Symposium
  • Place of Presentation: 東京
• [Presentation] 球状疎水性ファーマコフォアを有する非セコステロイド型ＶＤＲリガンドの構造活性相関 (2013)
  • Author(s): 藤井晋也，Angsuma Wongmayura，増野弘幸，伊藤茂，加納敦，河内恵美子，棚谷綾，影近弘之
  • Organizer: 日本ビタミン学会第６５回大会
  • Place of Presentation: 東京
• [Presentation] 新規ファーマコフォアの構築に基づくアンドロゲン受容体パンアンタゴニストの創製 (2013)
  • Author(s): 藤井晋也，山田歩，森修一，影近弘之
  • Organizer: 日本ケミカルバイオロジー学会第8回年会
  • Place of Presentation: 東京
• [Presentation] クルクミンの構造要素を基盤とした新規ARアンタゴニストの創製 (2013)
  • Author(s): 藤井晋也，山田歩，森修一，影近弘之
  • Organizer: 第24回日本レチノイド研究会学術集会
  • Place of Presentation: 東京
• [Remarks] 東京大学分子細胞生物学研究所生体有機化学研究分野ＨＰ
  • URL: http://www.iam.u-tokyo.ac.jp/chem/IMCB-8ken-HP/Index.html
• [Remarks] 東京医科歯科大学生体材料工学研究所薬化学分野ＨＰ
  • URL: http://www.tmd.ac.jp/mri/omc/index1.html