Development of anti-tumor agents based on biological response modification.

• Project/Area Number: 17016013
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: HASHIMOTO Yuichi The University of Tokyo, 分子細胞生物学研究所, 教授 (90164798)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI Hisayoshi 東京大学, 分子細胞生物学研究所, 助教 (80225531) ; NOGUCHI Tomomi 東京大学, 分子細胞生物学研究所, 技術職員 (20401284)
• Project Period (FY): 2005 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥43,400,000 (Direct Cost: ¥43,400,000); Fiscal Year 2009: ¥8,600,000 (Direct Cost: ¥8,600,000); Fiscal Year 2008: ¥8,600,000 (Direct Cost: ¥8,600,000); Fiscal Year 2007: ¥8,600,000 (Direct Cost: ¥8,600,000); Fiscal Year 2006: ¥8,600,000 (Direct Cost: ¥8,600,000); Fiscal Year 2005: ¥9,000,000 (Direct Cost: ¥9,000,000)
• Keywords: がん治療 / 構造展開 / 構造活性相関 / サリドマイド / アポトーシス / 核内受容体 / チュブリン重合阻害剤 / 阻害剤 / 分化誘導 / ペプチダーゼ / 抗アンドロゲン / 血管新生阻害 / ヒストン脱アセチル化酵素 / 核内受容体リガンド / レチノイド / 代謝物 / チュブリン重合阻害 / ビタミンD

Research Abstract

Various kinds of biologically active compounds were prepared based on biological response modification, so as to avoid possible side effects elicited specifically by cytotoxic anti-tumor agents. Nuclear receptor ligands and thalidomide (and/or its metabolite) were selected as major seeds compounds, and their structural development and activity expansion studies were performed.

Research Products

• [Journal Article] Identification of binding proteins of fusarielin A as actin and tubulin (2010)
  • Author(s): Tomomi Noguchi-Yachide, 他6名
  • Journal Title: Chemical & Pharmaceutical Bulletin 58 Pages: 129-134
  • Peer Reviewed
• [Journal Article] Discovery of tetramethyltetrahydronaphthalene analogs as adult T-cell leukemia cells-selective proliferation inhibitors in a small chemical library constructed based on multi-template hypothesis. (2009)
  • Author(s): Nakamura M, Hamasaki T, Tokitou M, Baba M, Hashimoto Y, Aoyama H
  • Journal Title: Bioorg. Med. Chem. 17(13) Pages: 4740-4746
  • Peer Reviewed
• [Journal Article] Enhancement of chemically-induced HL-60 cell differentiation by 3, 3'-diindolulmethane derivatives. (2009)
  • Author(s): Noguchi-Yachide T, Tetsuhashi M, Aoyama H, Hashimoto Y
  • Journal Title: Chem. Pharm. Bull. 57(5) Pages: 536-540
  • Peer Reviewed
• [Journal Article] Structure-activity relationship of bis-galloyl derivatives related to(-)-epi-gallocatechin gallate (2009)
  • Author(s): Kosuke Dodo, Taro Minato, Yuichi Hashimoto
  • Journal Title: Chemical & Pharmaceutical Bulletin 57 Pages: 190-194
  • NAID: 110007042048
  • Peer Reviewed
• [Journal Article] Enhancement of chemically-induced HL-6o cell differentiation by 3,3'-diindolylmethane derivatives (2009)
  • Author(s): Tomomi Noguchi-Yachide, 他3名
  • Journal Title: Chemical & Pharmaceutical Bulletin 57 Pages: 536-540
  • Peer Reviewed
• [Journal Article] PPARδ選択的アゴニストの創製と受容体-リガンド複合体構造情報を踏まえた選択性発現機構解明 (2009)
  • Author(s): 春日淳一, 他9名
  • Journal Title: 薬学雜誌 129 Pages: 709-718
  • Peer Reviewed
• [Journal Article] Suppression of β-catenin signaling by liver X receptor ligands (2009)
  • Author(s): Shigeyuki Uno, 他6名
  • Journal Title: Biochemical Pharmacology 77 Pages: 186-195
  • Peer Reviewed
• [Journal Article] Discovery of tetramethyltatrahydronaphthalene analogs as adult T-cell leukemia cells-selective proliferation inhibitors in a small chemical library constructed based on multi-template hypothesis (2009)
  • Author(s): Masahiko Nakamura, 他5名
  • Journal Title: Bioorganic & Medicinal Chemistry 17 Pages: 4740-4746
  • Peer Reviewed
• [Journal Article] Adaptability and selectivity of human peroxisome proliferator-activated receptor(PPAR)pan agonists revealed from crystal structures (2009)
  • Author(s): Takuji Oyama, 他8名
  • Journal Title: Acta Crystallographica(D) D65 Pages: 786-795
  • Peer Reviewed
• [Journal Article] Novel biphenylcarboxylic acid peroxisome proliferator-activated receptor(PPAR)δ selective antagonists (2009)
  • Author(s): 春日淳一, 他6名
  • Journal Title: Bioorganic & Medicinal Chemistry Letters 19 Pages: 6595-6599
  • Peer Reviewed
• [Journal Article] Structure-activity relationship of bis-galloyl derivatives related to (-)-epigallocatechin gallate (2009)
  • Author(s): Dodo, K., Minato, T., Hashimoto, Y.
  • Journal Title: Chemical and Pharmaceutical Bulletin 57(2) Pages: 190-194
  • NAID: 110007042048
  • Peer Reviewed
• [Journal Article] Structural development of benzhydrol-type 1'-acetoxychavicol acetate (ACA) analogs as human leukemia cell-growth inhibitors based on quantitative structure-activity relationship (QSAR) analysis. (2008)
  • Author(s): Misawa T, Aoyama H, Furuyama T, Dodo K, Sagawa M, Miyachi H, Kizaki M, Hashimoto Y
  • Journal Title: Chem. Pharm. Bull. 56(10) Pages: 1490-1495
  • NAID: 110006936309
  • Peer Reviewed
• [Journal Article] Thalidomide as a multi-template for development of biologically active compounds. (2008)
  • Author(s): Hashimoto Y
  • Journal Title: Arch. Pharm. Life Sci. 341(9) Pages: 536-547
  • Peer Reviewed
• [Journal Article] Anriproliferative and apoptosis-inducing activities of alkyl gallate and gallamide derivatives related to (-)-epigallocatechin gallate. (2008)
  • Author(s): Dodo K, Minato T, Noguchi-Yachide T, Suganuma M, Hashimoto Y
  • Journal Title: Bioorg. Med. Chem. 16(17) Pages: 7975-7982
  • Peer Reviewed
• [Journal Article] 4-(Anilino)pyrrole-2-carboxiamides: novel non-steroidal/non-anilide type androgen antagonisits effective upon human prostate tumor LNCaP cells with mutated nuclear androgen receptor. (2008)
  • Author(s): Wakabayashi K, Imai K, Miyachi H, Hashimoto Y, Tanatani A
  • Journal Title: Bioorg. Med. Chem. 16(14) Pages: 7046-7054
  • Peer Reviewed
• [Journal Article] New tubulin-polymerization inhibitor derived from thalidomide: implication for anti-myeloma therapy. (2008)
  • Author(s): Kizaki M, Hashimoto Y
  • Journal Title: Curr. Med. Chem. 15(8) Pages: 754-765
  • Peer Reviewed
• [Journal Article] Novel tubulin polymerization inhibitor derived from thalidomide directly induces apoptosis in human myeloma cells (2008)
  • Author(s): Iguchi, T., 他6名
  • Journal Title: International Journal of Molecular Medicine 21(2) Pages: 163-168
  • Peer Reviewed
• [Journal Article] Fusarielin A as an anti-angiogenic and antiproliferative agent (2008)
  • Author(s): Fujimoto, H. , 他4名
  • Journal Title: Chemical and Pharmaceutical Bulletin 56(3) Pages: 298-304
  • Peer Reviewed
• [Journal Article] New tubulin polymerization inhibitor derived from thalidomide : Implications for anti-myeloma therapy (2008)
  • Author(s): Kizaki, M. and Hashimoto, Y.
  • Journal Title: Current Medicianl Chemistry 15(8) Pages: 754-765
  • Peer Reviewed
• [Journal Article] Degradation-promoters of cellular inhibitor of apoptosis protein lbased on bestatin and actinonin (2008)
  • Author(s): Sato, S., 他6名
  • Journal Title: Bioorganic and Medicinal Chemistry 16(8) Pages: 4685-4698
  • Peer Reviewed
• [Journal Article] Demonstration of direct binding of cIAP 1 degradation-promoting bestatin analogs to BIR3 domain (2008)
  • Author(s): Sato, S., 他4名
  • Journal Title: Bioorganic and Medicinal Chemistry Letters 18(11) Pages: 3354-3358
  • Peer Reviewed
• [Journal Article] 4-(Anilino) pyrrole-2-carboxamide : Novel non-steroidal/non-anilide type androgen antagonists effective upon prostate tumor LNCaP cells with mutated nuclear androgen receptor (2008)
  • Author(s): Wakabayashi, K., 他4名
  • Journal Title: Bioorganic and Medicinal Chemistry 16(14) Pages: 6799-6812
  • Peer Reviewed
• [Journal Article] Antiproliferative and apotosis-inducing activities of alkyl gallate and gallamide derivatives .related to (-)-epigallocatechin gallate (2008)
  • Author(s): Dodo, K., 他4名
  • Journal Title: Bioorganic and Medicinal Chemistry 16(17) Pages: 7975-7982
  • Peer Reviewed
• [Journal Article] Thalidomide as a multi-template for development of biologically active compounds (2008)
  • Author(s): Hashimoto, Y.
  • Journal Title: Archives der Pharmazie, Life Science 341(9) Pages: 536-547
  • Peer Reviewed
• [Journal Article] Structural development of benzyl-type 1'-acetoxychavicol acetate (ACA) analogs as human leukemia cell growth inhibitors based on quantitative structure-activity relationship analysis (2008)
  • Author(s): Misawa, T., 他7名
  • Journal Title: Chemical and Pharmaceutical Bulletin 56(10) Pages: 1490-1495
  • Peer Reviewed
• [Journal Article] Novel tubulin-polymerization inhibitor derived from thalidomide directly induces apoptosis in human multiple myeloma cells. (2008)
  • Author(s): T. lguchi, 他6名
  • Journal Title: International Journal of Molecular Medicine 21 Pages: 163-168
  • Peer Reviewed
• [Journal Article] 3, 3-Diphenylpentane skeleton as a steroid substitute: novel inhibitors for human 5α-reductase 1. (2007)
  • Author(s): Hosoda S, Hashimoto Y
  • Journal Title: Bioorg. Med. Chem. Lett. 17(19) Pages: 5414-5418
  • Peer Reviewed
• [Journal Article] Development of tubulin-polymerization inhibitors based on thalidomide skeleton. (2007)
  • Author(s): Aoyama H, Noguchi T, Misawa T, Nakamura T, Miyachi H, Hashimoto Y, Kobayashi H
  • Journal Title: Chem. Pharm. Bull. 55(6) Pages: 844-949
  • NAID: 110006278705
  • Peer Reviewed
• [Journal Article] 3,3-Diphenylpentane skeleton as a steroid skeleton substitute: novel inhibitors of human 5α-reductase. (2007)
  • Author(s): S. Hosoda, 他1名
  • Journal Title: Bioorganic & Medicinal Chemistly Letters 17 Pages: 5414-5418
  • Peer Reviewed
• [Journal Article] Design, synthesis and evaluation of isoindolinone-hydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. (2007)
  • Author(s): S. Lee, 他8名
  • Journal Title: Bioorganic & Medicinal Chemistry Letters 17 Pages: 4895-4900
  • Peer Reviewed
• [Journal Article] Development of tubulin-polymerization inhibitors based on thalidomide skeleton. (2007)
  • Author(s): H. Aoyama, 他6名
  • Journal Title: Chemical & Pharmaceutical Bulletin 55 Pages: 944-949
  • Peer Reviewed
• [Journal Article] Hydrolyzed metabolites of thalidomide: synthesis and TNF-α production-inhibitory activity. (2007)
  • Author(s): T. Nakamura, 他3名
  • Journal Title: Chemical & Pharmaceutical Bulletin 55 Pages: 651-654
  • Peer Reviewed
• [Journal Article] Structural development studies of nuclear receptor ligands. (2007)
  • Author(s): S. Hosoda, 他6名
  • Journal Title: Pure & Applied Chemistry 79 Pages: 615-626
  • Peer Reviewed
• [Journal Article] 3,3-Diphenylpentane skeleton as a steroid skeleton substitute: novel inhibitors for human 5α-reductase 1. (2007)
  • Author(s): S. Hosoda, 他1名
  • Journal Title: Bioorganic & Medicinal Chemistry Letters 17 Pages: 4895-4900
  • Peer Reviewed
• [Journal Article] Effects of immunomodulatory derivatives of thalidomide (IMiDs) and their analogs on cell-differentiation, cyclooxygenase activity and angiogenesis. (2006)
  • Author(s): Fujimoto H, Noguchi T, Kobayashi H, Miyachi H, Hashimoto Y
  • Journal Title: Chem. Pharm. Bull. 54(6) Pages: 855-860
  • NAID: 110004836392
  • Peer Reviewed
• [Journal Article] Mono- and dihydroxylated metabolites of thalidomide : Synthesis and TNF-α production-inhibitory activity. (2006)
  • Author(s): T.Nakamura, 他4名
  • Journal Title: Chemical ＆ Pharmaceutical Bulletin 54・12 Pages: 1709-1714
• [Journal Article] Anti-angiogenic activity of basic type, selective cyclooxygenase (COX)-1 inhibitors. (2006)
  • Author(s): H.Sano, 他4名
  • Journal Title: Bioorganic ＆ Medicinal Chemistry Letters 16・11 Pages: 3068-3072
• [Journal Article] Design, synthesis and evaluation of cyclic amide/imide-bearing hydroxamic acid derivatgives as class-selective histone deacetylase (HDAC) inhibitors. (2006)
  • Author(s): C.Shinji, 他5名
  • Journal Title: Bioorganic ＆ Medicinal Chemistry 14・22 Pages: 7625-7651
• [Journal Article] Tubulin polymerization inhibitors with a fluorinated phthalimide skeleton derived from thalidomide. (2006)
  • Author(s): T.Yanagawa, 他4名
  • Journal Title: Bioorganic ＆ Medicinal Chemistry Letters 16・18 Pages: 4748-4751
• [Journal Article] Ligands with a 3,3-diphenylpentane skeleton for nuclear vitamin D and androgen receptors : Dual activities and metabolic activation. (2006)
  • Author(s): S.Hosoda, 他7名
  • Journal Title: Bioorganic ＆ Medicinal Chemistry 14・16 Pages: 5489-5502
• [Journal Article] Effects of immunomodulatory derivatives of thalidomide (IMiDs) and their analogs on cell-differentiation, cyclooxygenase activity and angiogenesis. (2006)
  • Author(s): H.Fujimoto, 他4名
  • Journal Title: Chemical ＆ Pharmaceutical Bulletin 54・6 Pages: 855-860
• [Journal Article] Nuclear receptor antagonists designed based on the helix-folding inhibition hypothesis. (2005)
  • Author(s): Miyachi H, Hashimoto Y
  • Journal Title: Bioorg. Med. Chem. 13(17) Pages: 5080-5093
  • Peer Reviewed
• [Journal Article] Tubulin polymerization inhibitors derived from thalidomide (2005)
  • Author(s): S.Inatsuki, T.Nogucchi, H.Miyachi, 他5名
  • Journal Title: Bioorganic & Medicinal Chemistry Letters 15・2 Pages: 321-325
• [Journal Article] Enhancement of all-trans retinoic acid-induced HL-60 cell differentiation by thalidomide and its metabolites. (2005)
  • Author(s): T.Nogucchi, C.Shinji, H.Kobayashi, 他3名
  • Journal Title: Biological & Pharmaceutical Bulletin 28・3 Pages: 563-564
• [Journal Article] Novel non-steroidal/non-anilide type androgen antagonists. (2005)
  • Author(s): K.Wakabayashi, H.Miyachi, 他3名
  • Journal Title: Bioorganic & Medicinal Chemistry 13・8 Pages: 2837-2846
• [Journal Article] Design and synthesis of subtype-selective cyclooxygenase (COX) inhibitors derived from thalidomide. (2005)
  • Author(s): H.Sano, T.Noguchi, A.Tanatani, 他2名
  • Journal Title: Bioorganic & Medicinal Chemistry 13・9 Pages: 3079-3091
• [Journal Article] Cell differentiation inducers derived from thalidomide (2005)
  • Author(s): T.Noguchi, h.Miyachi, R.Katayama, 他2名
  • Journal Title: Bioorganic & Medicinal Chemistry Letters 15・13 Pages: 3121-3215
• [Journal Article] Angiogenesis inhibitors derived from thalidomide. (2005)
  • Author(s): T.Noguchi, H.Fujimoto, H.Sano, 他3名
  • Journal Title: Bioorganic & Medicinal Chemistry Letters 15・24 Pages: 5509-5513
• [Presentation] シーズ創製のためのマルチテンプレート法とドラマタイプ法 (2010)
  • Author(s): 橋本祐一
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-29
• [Presentation] 複素環構造を持つ新規抗C型肝炎ウイルス(HCV)剤の創製研究 (2010)
  • Author(s): 中村政彦, 他6名
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-29
• [Presentation] 低分子化合物を用いたプロテインノックアウト法の開発:CRABP分解誘導剤の創製 (2010)
  • Author(s): 伊藤幸廣, 他3名
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-29
• [Presentation] 新規三置換トリアジン誘導体の構造展開と活性評価 (2010)
  • Author(s): 三澤隆史, 他5名
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-29
• [Presentation] Multi-template and dramatype approaches for lead generation (2010)
  • Author(s): 橋本祐一
  • Organizer: 第3回高度医療都市を創出する未来技術国際シンポジウム
  • Place of Presentation: 岡山
  • Year and Date: 2010-02-03
• [Presentation] 新規ビフェニルカルボン酸型PPARδ選択的アンタゴニストの創製 (2009)
  • Author(s): 春日淳一, 他5名
  • Organizer: 第28回メディシナルケミストリーシンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2009-11-26
• [Presentation] テトラハイドロテトラメチルナフタレン骨格を持つ成人T細胞白血病(ATL)細胞選択的増殖阻害剤の創製研究 (2009)
  • Author(s): 中村政彦, 他5名
  • Organizer: 第28回メディシナルケミストリーシンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2009-11-26
• [Presentation] ビフェニルカルボン酸型PPARδ選択的アンタゴニストの創製 (2009)
  • Author(s): 宮地弘幸, 他5名
  • Organizer: 日本レチノイド研究会第20回学術集会
  • Place of Presentation: 東京
  • Year and Date: 2009-11-20
• [Presentation] CRABP分解誘導剤の創製 (2009)
  • Author(s): 伊藤幸裕, 他3名
  • Organizer: 日本レチノイド研究会第20回学術集会
  • Place of Presentation: 東京
  • Year and Date: 2009-11-20
• [Presentation] マルチテンプレート手法とドラマタイプ手法に基づく生物活性物質の創製 (2009)
  • Author(s): 橋本祐一
  • Organizer: 日本化学会第3回関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2009-09-05
• [Presentation] ネクローシスの分子機構解明を目指した新規細胞死誘導剤の創製 (2009)
  • Author(s): 佐藤伸一, 他4名
  • Organizer: 日本薬学会第129年会
  • Place of Presentation: 京都
  • Year and Date: 2009-03-27
• [Presentation] 1'-Acetoxychavicol acetate (ACA)をリード化合物としたベンズヒドロール型新規細胞増殖抑制剤の創製研究 (2009)
  • Author(s): 三澤隆史, 他7名
  • Organizer: 日本薬学会第129年会
  • Place of Presentation: 京都
  • Year and Date: 2009-03-27
• [Presentation] 3, 3-diindolylmethane (DIM)誘導体におけるHL-60細胞分化促進活性 (2009)
  • Author(s): 谷内出友美、鉄橋正士、青山洋史、橋本祐一
  • Organizer: 日本薬学会第129年会
  • Place of Presentation: 京都
  • Year and Date: 2009-03-27
• [Presentation] 抗がん剤耐性克服を目指した非アポトーシス型細胞死誘導剤の創製研究 (2008)
  • Author(s): 佐藤伸一, 他4名
  • Organizer: 第27回メディシナルケミネトリーシンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2008-11-27
• [Presentation] 1'-Acetoxychavicol acetate (ACA)をリード化合物とした新規細胞増殖抑制剤の創製研究 (2008)
  • Author(s): 三澤隆史, 他7名
  • Organizer: 第27回メディシナルケミストリーシンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2008-11-27
• [Presentation] Biological response modifiers derived from thalidomide. (2007)
  • Author(s): Yuichi Hashimoto
  • Organizer: The 12th Japanese Foundation for Cancer Research International Symposium on Cancer Chemotherapy
  • Place of Presentation: Tokyo
  • Year and Date: 2007-12-04
• [Book] 創薬をめざす有機合成最前線-進化する医薬品づくり (2007)
  • Author(s): 宮地弘幸, 他1名
  • Publisher: 化学同人
• [Book] ケミカルバイオロジー・ケミカルゲノミクス (2005)
  • Author(s): 橋本祐一(分担執筆), 半田宏 編
  • Total Pages: 278
  • Publisher: シュプリンガー・フェアラーク東京
• [Remarks]
  • URL: http://www.iam.u-tokyo.ac.jp/chem/IMCB-8ken-HP/Index.html
• [Remarks]
  • URL: http://www.iam.u-tokyo.ac.jp/chem/index.html
• [Patent(Industrial Property Rights)] C型肝炎治療剤 (2010)
  • Inventor(s): 馬場昌範, 他5名
  • Industrial Property Rights Holder: 鹿児島大学
  • Industrial Property Number: 2010-020502
  • Filing Date: 2010-02-01
• [Patent(Industrial Property Rights)] 新規置挨ビフェニルカルボン酸誘導体 (2009)
  • Inventor(s): 宮地弘幸, 他2名
  • Industrial Property Rights Holder: 岡山大学
  • Industrial Property Number: 2009-132055
  • Filing Date: 2009-06-01
• [Patent(Industrial Property Rights)] 成人T細胞白血病治療薬 (2009)
  • Inventor(s): 馬場昌範, 他2名
  • Industrial Property Rights Holder: 鹿児島大学
  • Filing Date: 2009-08-20
  • Overseas
• [Patent(Industrial Property Rights)] 成人T細胞白血病治療薬 (2008)
  • Inventor(s): 馬場昌範、橋本祐一、永井勝幸
  • Industrial Property Rights Holder: 国立大学法人鹿児島大学
  • Industrial Property Number: 2008-256620
  • Filing Date: 2008-10-01
• [Patent(Industrial Property Rights)] 成人T細胞白血病治療薬 (2008)
  • Inventor(s): 馬場昌範, 他2名
  • Industrial Property Rights Holder: 鹿児島大学
  • Industrial Property Number: 2008-242867
  • Filing Date: 2008-09-22
• [Patent(Industrial Property Rights)] 新規ヒドロキサム酸誘導体 (2007)
  • Inventor(s): 宮地弘幸、他4名
  • Industrial Property Rights Holder: 国立大学法人 東京大学
  • Industrial Property Number: 2007-266460
  • Filing Date: 2007-10-02