Search for new antitumor lead-compounds originated from plant alkaloids

2012 Fiscal Year Final Research Report

• Project/Area Number: 22510224
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Living organism molecular science
• Research Institution: Chiba University
• Principal Investigator: KITAJIMA Mariko 千葉大学, 大学院・薬学研究院, 准教授 (60195261)
• Project Period (FY): 2010 – 2012
• Keywords: 天然物化学 / 生物活性物質

Research Abstract

To discover and develop lead-compounds for new antitumor medicines originated from plant alkaloids, chemical investigation and biological evaluation of Gelsemium alkaloids and colchicinoids were carried out. As results, several novel alkaloids were isolated from Gelsemium plants. Key intermediates of sarpagine-type alkaloids, one of the members of Gelsemium alkaloids, were synthesized utilizing gold-catalyzed cyclization. 4-Halocolchicines and 4-chlorocolchicine derivatives bearing anα-hydroxyacetoamide side chain at C-7 were found to show potent antitumor activities. Pro-drugs of highly-active colchicine derivatives were prepared and their selective toxicity to the tumor cells was evaluated.

Research Products

• [Journal Article] Seven New Monoterpenoid Indole Alkaloids from Gelsemium elegans (2011)
  • Author(s): Y. Yamada, M. Kitajima, N. Kogure, S. Wongseripipatana, and H. Takayama
  • Journal Title: Chem. Asian J Volume: 6 Pages: 166-173
  • DOI: DOI:10.1002/asia.201000538.
  • Peer Reviewed
• [Journal Article] Design, Synthesis, and Antitumor Activity of 4-Halocolchicines and their Pro-drugs Activated by Cathepsin B (2011)
  • Author(s): N. Yasobu, M. Kitajima, N. Kogure, Y. Shishido, T. Matsuzaki, M. Nagaoka, and H. Takayama
  • Journal Title: ACS Med. Chem. Lett Volume: 2 Pages: 348-352
  • DOI: DOI:10.1021/m1100287y.
  • Peer Reviewed
• [Journal Article] Metacolchicine, A New Colchicinoid from Sandersonia aurantiaca (2011)
  • Author(s): M. Kitajima, A. Tanaka, N. Kogure, and H. Takayama
  • Journal Title: Heterocycles Volume: 83 Pages: 1903-1907
  • Peer Reviewed
• [Journal Article] Synthesis and Biological Evaluation of Indole Alkaloids from Gelsemiumrankinii (2010)
  • Author(s): H. Nishiyama, M. Ono, T. Sugimoto, T.Sasai, N. Asakawa, T. Matsumoto, T. Yaegashi, M. Nagaoka, T. Matsuzaki, N. Kogure, M. Kitajima, and H. Takayama
  • Journal Title: Tetrahedron Volume: 66 Pages: 5987-5992
  • DOI: DOI:10.1016/j.tet.2010.06.032.
  • Peer Reviewed
• [Journal Article] New Oxindole and Indole Alkaloids from Gelsemium rankinii (2010)
  • Author(s): M. Kitajima, H. Kobayashi, N. Kogure, and H. Takayama
  • Journal Title: Tetrahedron Volume: 66 Pages: 5987-5992
  • DOI: DOI:10.1016/j.tet.2010.06.032.
  • Peer Reviewed
• [Presentation] 腫瘍細胞選択性を有するコルヒチン系ダブルプロドラッグ化合物の合成研究 (2013)
  • Author(s): 遠藤慎平,八十歩直子,北島満里子,小暮紀行,高山廣光
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-29
• [Presentation] がん細胞選択毒性を有するColchicine系抗腫瘍薬の創製研究 (2012)
  • Author(s): 北島満里子,八十歩直子,小暮紀行,宍戸祐之,松崎健,長岡正人,高山廣光
  • Organizer: 第54回天然有機化合物討論会
  • Place of Presentation: 東京
  • Year and Date: 2012-09-19
• [Presentation] 新規colchicine誘導体を利用した腫瘍細胞選択的プロドラッグ化合物の創製研究 (2012)
  • Author(s): 八十歩直子,北島満里子,小暮紀行,宍戸祐之,松崎健,長岡正人,高山廣光
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-30
• [Presentation] New Monoterpenoid Indole Alkaloids from Gelsemium elegans (2011)
  • Author(s): N. Kogure, Y. Yamada, M. Kitajima, S.Wongseripipatana and H. Takayama
  • Organizer: The 6^<th> International Conference on Cutting-Edge Organic Chemistry in Asia and 2^<nd> New Phase International Conference on Cutting-Edge Organic Chemistry in Asia (ICCEOCA-6/NICCEOCA-2)
  • Place of Presentation: HongKong, China
  • Year and Date: 2011-12-12
• [Presentation] Isolation, Structure Elucidaiton, Chemical Transformation and Biological Evaluation of Novel Gelsemium Alkaloids (2011)
  • Author(s): Y. Yamada, M. Kitajima, N. Kogure, S.Wongseripipatana, and H. Takayama
  • Organizer: 8th AFMC International Medicinal Chemistry Symposium (AIMECS11)
  • Place of Presentation: Tokyo
  • Year and Date: 2011-11-30
• [Presentation] Synthesis of4-Halocolchicines and Their Pro-drugDerivatives having Potent Antitumor Activity (2011)
  • Author(s): N. Yasobu, M. Kitajima, N. Kogure, Y.Shishido, T. Matsuzaki, M. Nagaoka, and H. Takayama
  • Organizer: 8th AFMC International Medicinal Chemistry Symposium (AIMECS11)
  • Place of Presentation: Tokyo
  • Year and Date: 2011-11-30
• [Presentation] アカネ科Ophiorrhiza trichocarpon含有新規インドールアルカロイド配糖体の構造解析 (2011)
  • Author(s): 北島満里子,尾原聡子,小暮紀行,Dammrong Santiarworn,高山廣光
  • Organizer: 第53回天然有機化合物討論会
  • Place of Presentation: 大阪
  • Year and Date: 2011-09-27
• [Presentation] Gelsemium elegans含有新規アルカロイドの成分探索および化学的研究 (2011)
  • Author(s): 山田洋介,小暮紀行,北島満里子,高山廣光,Sumphan Wongseripipatana
  • Organizer: 日本生薬学会第58回年会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2011-09-24
• [Presentation] 薬用資源植物含有生物活性アルカロイドの探索と創薬先導化合物の創製研究 (2011)
  • Author(s): 北島満里子
  • Organizer: 第28回和漢医薬学会学術大会シンポジウム
  • Place of Presentation: 富山
  • Year and Date: 2011-08-27
• [Presentation] Colchicine誘導体を基盤としたプロドラッグ化合物の創製研究 (2011)
  • Author(s): 八十歩直子,北島満里子,小暮紀行,高山廣光
  • Organizer: 第46回天然物化学談話会
  • Place of Presentation: 熱川
  • Year and Date: 2011-07-07
• [Presentation] Sempervirine誘導体の合成研究 (2011)
  • Author(s): 山田洋介,小暮紀行,北島満里子,高山
  • Organizer: 第46回天然物化学談話会
  • Place of Presentation: 熱川
  • Year and Date: 2011-07-07
• [Presentation] ゲルセミウムアルカロイドSempervirineをシードとした抗腫瘍薬の創製研究-1- (2011)
  • Author(s): 山田洋介,北島満里子,小暮紀行,高山廣光
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
  • Year and Date: 2011-03-31
• [Presentation] 新規colchicine誘導体を利用したプロドラッグ化合物の創製 (2011)
  • Author(s): 八十歩直子,北島満里子,小暮紀行,宍戸祐之,松崎健,長岡正人,高山廣光
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
  • Year and Date: 2011-03-29
• [Presentation] Isolation, Spectroscopic analyses, Chemical Transformation and Biological Evaluation of Novel Gelsemium Alkaloids (2010)
  • Author(s): Y. Yamada, M. Kitajima, N. Kogure, S.Wongseripipatana, H. Takayama
  • Organizer: 2010 International Chemical Congress of Pacific Basin Societies (PACIFICHEM2010)
  • Place of Presentation: Hawaii, USA
  • Year and Date: 2010-12-18
• [Presentation] がん細胞選択毒性を有するcolchicine系抗腫瘍薬の創製研究 (2010)
  • Author(s): 八十歩直子,小暮紀行,北島満里子,松崎健,長岡正人,高山廣光
  • Organizer: 第29回メディシナルケミストリーシンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2010-11-17
• [Presentation] ゲルセミ (2010)
  • Author(s): 山田洋介,北島満里子,小暮紀行,小林宏美,石井直子,Sumphan Wongseripipatana,高山廣光
  • Organizer: 第52回天然有
  • Place of Presentation: 静岡
  • Year and Date: 2010-10-01
• [Presentation] Novel Monoterpenoid Indole Alkaloids from Gelsemium elegans (2010)
  • Author(s): Y. Yamada, M. Kitajima, N. Kogure, S.Wongseripipatana, H. Takayama
  • Organizer: The 57^<th> Annual Meeting of the Japanese Society of Pharmacognosy (Tokushima, 2010), and The 5th JSP-CCTNM-KSP Joint Symposium on Pharmacognosy
  • Place of Presentation: Tokushima
  • Year and Date: 2010-09-24
• [Remarks]
  • URL: http://www.p.chiba-u.ac.jp/lab/seitai/index.html
• [Patent(Industrial Property Rights)] Colchicine Derivatives (2011)
  • Inventor(s): H. Takayama et al.
  • Industrial Property Rights Holder: 千葉大学 他
  • Industrial Property Number: PCT Int. Appl.WO 2011021397
  • Filing Date: 2011-02-24
  • Overseas
• [Patent(Industrial Property Rights)] コルヒチン誘導体 (2010)
  • Inventor(s): 高山廣光, 他
  • Industrial Property Rights Holder: 千葉大学 他
  • Industrial Property Number: 出願PCT/JP2010/005136
  • Filing Date: 2010-08-20