Preparaion of Novel Anticancer Agents based on Isoquinoline Marine Natural Products

• Project/Area Number: 15K07873
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: Meiji Pharmaceutical University
• Principal Investigator: Saito Naoki 明治薬科大学, 薬学部, 教授 (80142545)
• Co-Investigator(Kenkyū-buntansha): 木村 真也 明治薬科大学, 薬学部, 助手 (10632739)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 海洋天然物 / 抗腫瘍活性 / テトラヒドロイソキノリン / 全合成 / 殺細胞活性 / エクチナサイジン / レニエラマイシン / ラジカル反応 / 化学変換 / 構造活性相関 / 反応機構 / 構造解析

Outline of Final Research Achievements

① Preparation of eleven new ecteinascidin derivatives to receive some additional proof of cytotoxicity profiles; ② Preparation of a variety of renieramycin derivatives for discovering highly potent anticancer activity; ③ The first total synthesis of renieramycin T; ④ Preparation of both right-half and left-had models of saframycin-renieramycins along with evaluation for cytotoxicity profiles; ⑤Total synthesis of renieramycin I and also Structure determination of 7-desmethylrenieramycin O; ⑥ Discovered a novel photo-transformation from methoxy-p-quinone into a characteristic highly substituted A-ring of ecteinascidins and renieramycin T.

Research Products

• [Journal Article] Preparation of Chiral Right-half Models of Antitumor Bistetrahydroisoquinolinequinone Natural Products (2018)
  • Author(s): Senbonmatsu Y.、Kimura S.、Akiba M.、Ando S. Saito N.
  • Journal Title: HETEROCYCLES Volume: 97 Issue: 2 Pages: 1050-1067
  • DOI: 10.3987/com-18-s(t)88
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Semisynthesis and biological evaluation of prenylated resveratrol derivatives as multi-targeted agents for Alzheimer's disease (2017)
  • Author(s): Puksasook T., Kimura S., Tadtong S., Jiaranakulwanitch J., Pratungdejkul J., Kitphari W., Suwanborirux K., Saito N. Nukoolkarn V.
  • Journal Title: J. Nat. Med. Volume: 71 Issue: 4 Pages: 665-682
  • DOI: 10.1007/s11418-017-1097-2
  • NAID: 40021337926
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chemistry of renieramycins. 17. A new generation of renieramycins: 5-O-monohydroquinone analogues of renieramycin M as potential cytotoxic agents against non-small-cell lung cancer cells (2017)
  • Author(s): Chamni S., Sirimangkalakitti N., Chanvorachote P., Saito N., Suwanborirux K.
  • Journal Title: J. Nat. Prod. Volume: 80 Pages: 1541-1547
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Apoptosis-inducing Effect of Hydroquinone 5-O-Cinnamoyl Ester Analog of Renieramycin M on Non-small Cell Lung Cancer Cells (2017)
  • Author(s): Matuthed A., Pinkhien T., Chamni S., Suwanborirux K., Saito N., Petpiroon N., Chanvorachote C.
  • Journal Title: Anticancer Research Volume: 37 Issue: 11 Pages: 6259-6267
  • DOI: 10.21873/anticanres.12077
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 天然物をツール・情報源とする低分子医薬品の創薬研究 (2017)
  • Author(s): 齋藤直樹
  • Journal Title: ファルマシア Volume: 53 Pages: 555-559
• [Journal Article] Chemistry of renieramycins. 16. Structure of 7-desmethylrenieramycin O (= 14a-hydroxyrenieramycin S) from blue sponge, Xestospongia sp. (2017)
  • Author(s): Saito N., Hiramatsu A., Hirade H., Kubota M., Toyoshima R., Fujino A., Sirimangkalakitti N., Suwanborirux K., Concepcion G. P..
  • Journal Title: Heterocycels Volume: 95 Issue: 2 Pages: 748-752
  • DOI: 10.3987/com-16-s(s)77
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Chemistry of renieramycins. 17. A new generation of renieramycins: Hydroquinone 5-O-monoester analogues of renieramycin M as potential cytotoxicity agents against non-small -cell lung cancer cell (2017)
  • Author(s): Chamni S., Sirimangkalakitti N., Chanvorachote P., Saito N., Suwanborirux k.
  • Journal Title: J. Nat. Prod. Volume: 80 Issue: 5 Pages: 1541-1547
  • DOI: 10.1021/acs.jnatprod.7b00068
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Chemistry of renieramycins. Part 15. Synthesis of 22-O-ester derivatives of jorunnamycin A and their cytotoxicity against nonsmall lung cancer cells (2016)
  • Author(s): Sirimangkalakitti N., Chamni S., Charupant K., Chanvorachote P., Mori N., Saito N., Suwanborirux K.
  • Journal Title: J. Nat. Prod., Volume: 79 Issue: 8 Pages: 2089-2093
  • DOI: 10.1021/acs.jnatprod.6b00433
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Bishydroquinone renieramycin M induced human lung cancer cell apoptosis through mitochondria-dependent pathway (2016)
  • Author(s): Pinkhien T., Maiuthes A., Chamni S., Suwanborirux K., Saito N., Chanvorachote P.
  • Journal Title: Anticancer Res. Volume: 36 Issue: 12 Pages: 6327-6333
  • DOI: 10.21873/anticanres.11229
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Practical synthesis of tricyclic lactam model of antitumor renieramycin-saframycin natural products (2016)
  • Author(s): Yokoya M., Fujino A., Yaguchi A., Yamazaki M., Saito N.
  • Journal Title: Heterocycles Volume: 93 Issue: 2 Pages: 802-802
  • DOI: 10.3987/com-15-s(t)53
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Stereoselective total synthesis of (-)-renieramycin T (2016)
  • Author(s): Yokoya M., Toyoshima R., Suzuki T., Le V. H., Williams R. M., Saito N.
  • Journal Title: J. Org. Chem. Volume: 81 Issue: 10 Pages: 0001-0009
  • DOI: 10.1021/acs.joc.6b00327
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Chemistry of ecteinascidins. Part 5. An additional proof of cytotoxicity evaluation of ecteinascidin 770 derivatives (2016)
  • Author(s): Toyoshima R., Mori N., Suzuki T., Lowtangkicharoen W., Suwanborirux K., Saito N.
  • Journal Title: Chem. Pharm. Bull. Volume: 65 Pages: 0000-0007
  • NAID: 130005160038
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Chemistry of renieramycins. Part 14. Total synthesis of renieramycin I and practical synthesis of cribrostatin 4 (renieramycin H) (2015)
  • Author(s): Yokoya M., Kobayashi K. Sato M., Saito N.
  • Journal Title: Marine Drugs Volume: 13 Issue: 8 Pages: 4915-4933
  • DOI: 10.3390/md13084915
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 抗腫瘍活性レニエラマイシン海洋天然物の化学的研究 (2015)
  • Author(s): 横屋正志、齋藤直樹
  • Journal Title: 有機合成化学協会誌 Volume: 73 Pages: 723-736
  • NAID: 130005093745
  • Peer Reviewed
• [Presentation] 1.3-ジオキサシクロペンタン環を生じる新規光反応前駆体の柔軟な合成法の開発 (2018)
  • Author(s): 高橋昇平、横屋正志、齋藤直樹
  • Organizer: 日本薬学会第138年会
• [Presentation] 含窒素複素環キノンに対する新規光反応の開発 (2018)
  • Author(s): 望月 萌、横屋正志、齋藤直樹
  • Organizer: 日本薬学会第138年会
• [Presentation] Renieramycin類の光学活性CDE環モデルの合成 (2018)
  • Author(s): 松原健治、横屋正志、Nachanun Sirimangkalakitti、齋藤直樹
  • Organizer: 日本薬学会第138年会
• [Presentation] 生物活性イソキノリン抗生物質を基軸とする新規認知症改善薬の創製 (2018)
  • Author(s): Nachanun Sirimangkalakitti、中井啓陽、山﨑未来、紀嘉浩、佐藤準一,、齋藤直樹
  • Organizer: 日本薬学会第138年会
• [Presentation] 新規極微量海洋天然物7-demethylrenieramycin Oと誘導体の合成研究 (2018)
  • Author(s): 門傅研人、横屋正志、佐藤充浩、小林恵一郎、齋藤直樹
  • Organizer: 日本薬学会第138年会
• [Presentation] 抗腫瘍活性を有するテトラヒドロイソキノリン系天然物の合成研究 (2018)
  • Author(s): 木村真也、齋藤直樹
  • Organizer: 日本薬学会第138年会
• [Presentation] 新規極微量海洋天然物レニエラマイシンYの合成アプローチ (2018)
  • Author(s): 小林 翔、横屋正志、丸山 崚、齋藤直樹
  • Organizer: 日本薬学会第138年会
• [Presentation] 生物活性新規イソキノリンアルカロイドFennebricin A及びBの全合成研究 (2017)
  • Author(s): 門傅 研人、横屋 正志、佐藤 充浩、小林 恵一郎、齋藤 直樹
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 東北大学（仙台）
  • Year and Date: 2017-03-24
• [Presentation] 光変換反応を利用した1,3-ジオキサシクロペンタン環の形成 (2017)
  • Author(s): 高橋 昌平、横屋 正志、山﨑 未来、齋藤 直樹
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 東北大学（仙台）
  • Year and Date: 2017-03-24
• [Presentation] 強力な抗腫瘍活性を有するビステトラヒドロイソキノリン系天然物の合成研究 (2017)
  • Author(s): 木村 真也、齋藤 直樹
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 東北大学（仙台）
  • Year and Date: 2017-03-24
• [Presentation] Succcessful international collaborative medicinal chemistry of biologically active marine natural products based on Thai marine oranagisms (2017)
  • Author(s): Saito N
  • Organizer: The JSPS-NRCT follow-up seminar 2017 and 33rd international annual meeting in Pharmaceutical Sciences
  • Place of Presentation: バークレーホテル（バンコク）
  • Year and Date: 2017-03-02
  • Int'l Joint Research / Invited
• [Presentation] Chemistry of biologically active natural 1,2,3,4-tertahydroisoquinoline: Unpredictable photochemical transformation of renieramycin type p-quinone into ecteinscidin type phenol (2017)
  • Author(s): Saito N., Nakai K., Yamazaki M., Yokoya M.
  • Organizer: 26th International synposium of heterocyclic chemistry (ISHC) congress
  • Int'l Joint Research
• [Presentation] 相関移動触媒を用いた光学活性チロシン誘導体の合成 (2017)
  • Author(s): 安齋 凌、横屋正志、齋藤直樹
  • Organizer: 第61回日本薬学会関東支部大会
• [Presentation] Renieramycin類の光学活性CDE環モデルの合成 (2017)
  • Author(s): 松原健治、横屋正志、齋藤直樹
  • Organizer: 第61回日本薬学会関東支部大会
• [Presentation] 抗腫瘍活性イソキノリン系天然物の化学的展開と創薬リードの創製 (2017)
  • Author(s): 横屋正志、Nachanun Sirimangkalakitti、Supakarn Chamni、望月 萌、鈴木俊宏、齋藤直樹
  • Organizer: 第35回メディシナルケミストリーシンポジウム
• [Presentation] 強力な抗腫瘍活性を有するビステロラヒドロイソキノリン天然物の合成研究 (2017)
  • Author(s): 木村真也、齋藤直樹
  • Organizer: 第43回反応と合成の進歩シンポジウム
• [Presentation] 海洋天然物7-デメチルレニエラマイシンOの全合成及びフェネブリシン類の合成 (2017)
  • Author(s): 門傅研人、佐藤充浩、小林恵一郎、横屋正志、齋藤直樹
  • Organizer: 第74回有機合成化学協会関東支部シンポジウム
• [Presentation] 新規海洋天然物レニエラマイシンYの合成研究 (2016)
  • Author(s): 丸山 崚、横屋 正志、齋藤 直樹
  • Organizer: 第42回反応と合成の進歩シンポジウム
  • Place of Presentation: 清水市清水文化会館（静岡）
  • Year and Date: 2016-11-06
• [Presentation] Chemistry of antitumor isoquinoline marine natural products: Total synthesisi of (-)-renieramycin T (2016)
  • Author(s): Saito N.
  • Organizer: 3rd Symposium of Showa Pharmaceutical University (SPU) innovative pharmaceutical analysis of covalent modification in biomolecules
  • Place of Presentation: 昭和薬科大学（東京）
  • Year and Date: 2016-08-31
  • Int'l Joint Research / Invited
• [Presentation] 抗腫瘍活性エクチナサイジン海洋天然物の合成と生物活性 (2015)
  • Author(s): 森ななえ、豊嶋涼子、藤野晃也、鈴木俊宏、横屋正志、齋藤直樹、Khanit Suwanborirux
  • Organizer: 第33回メディシナルケミストリーシンポジウム
  • Place of Presentation: 千葉
  • Year and Date: 2015-11-25
• [Presentation] 海洋天然物クリブロスタチン4の改良合成およびレニエラマイシンIの全合成 (2015)
  • Author(s): 佐藤充浩、小林恵一郎、横屋正志、齋藤直樹
  • Organizer: 第70回記念有機合成化学協会関東支部シンポジウム
  • Place of Presentation: 長岡
  • Year and Date: 2015-11-21
• [Presentation] 抗腫瘍活性微量天然物レニエラマイシンTの不斉全合成 (2015)
  • Author(s): t豊嶋涼子、横屋正志、齋藤直樹、Le. H. V., Williams R. M.
  • Organizer: 第41回反応と合成の進歩シンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2015-10-26
• [Presentation] レニエラマイシン系海洋天然物のキラル合成アプローチ (2015)
  • Author(s): 豊嶋涼子、横屋正志、齋藤直樹
  • Organizer: 第59回日本薬学会関東支部大会
  • Place of Presentation: 千葉
  • Year and Date: 2015-09-12
• [Presentation] Synthetic studies on a total synthesis of antitumor renieramycin T (2015)
  • Author(s): Yokoya M., Toyoshima R., Saito N., Le V. H., Williams R. M.
  • Organizer: 25th International Symposium of Heterocyclic Chemistry
  • Place of Presentation: California (USA)
  • Year and Date: 2015-08-25
  • Int'l Joint Research
• [Book] アルカロイドの科学 (2017)
  • Author(s): 高山 廣光
  • Total Pages: 560
  • Publisher: 化学同人
  • ISBN: 9784759814187