Synthetic Studies of the Marine Alkaloids, Madangamines with Anti Tumor Activities

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 15590025
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: Tokyo University of Pharmacy and Life Sciences
• Principal Investigator: YAMAZAKI Naoki Tokyo University of Pharmacy and Life Sciences, 薬学部, 講師 (30277264)
• Project Period (FY): 2003 – 2006
• Keywords: marine alkaloid / madangamine / macrocyclization / cross-coupling reaction / N, O-acetalization / hydrogenation of bridge head iminium ion / intramolecular reductive amination / anti tumor activities

Research Abstract

Madangamine A is a pentacyclic alkaloids that was isolated from the marine sponge Xestospongia ingens by Andersen in 1994. Soon after, new constituents of this alkaloid type, madangamines B-E, were isolated from the same organism. Madangamine A exhibits cytotoxic activities against P388, A549, U373, and MCF-7 tumor cell lines. In this research project, I have accomplished the construction of the ABC and ACE-ring frameworks of madangamines. N, O-Acetalization of the keto-aminophenol allows rapid construction of the 2-azabicyclo[3.3.1]nonane skeleton with a quaternary carbon center at C4. This strategy enabled the stereoselective construction of the central diazatricyclic core (ABC-ring) of the madangamine alkaloids. In the next stage of our investigation, an efficient construction of the madangamine tricyclic ring, 4-azatricyclo[11.2.2.0^<4.14>]heptadec-12-ene, including an 11-membered macrocycle (ACE-ring) has been accomplished via construction of the 2-azabicyclo[3.3.1]nonane skeleton by N, O-acetalization of a cyclohexanone derivative, geometry-retained cross-coupling reaction, and intramolecular reductive amination. From the results obtained above, my future studies will be focused on the construction of a 15-membered macrocycle (D-ring) for the total synthesis of madangamines.

Research Products

• [Journal Article] Synthesis of the 11-Membered Ring of the Marine Alkaloids, Madangamines (2006)
  • Author(s): Yoshimura, Y., Inoue, J., Yamazaki, N., Aoyagi, S., Kibayashi, C.
  • Journal Title: Tetrahedron Letters 47 Pages: 3489-3492
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Synthesis of the 11-Membered Ring of the Marine Alkaloids, Madangamines (2006)
  • Author(s): Yoshimura, Y.; Inoue, J.; Yamazaki, N.; Aoyagi, S.; Kibayashi, C.
  • Journal Title: Tetrahedron Letters 47 Pages: 3489-3492
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis of the Diazatricyclic Core of the Marine Alkaloids Madangamines (2004)
  • Author(s): Yamazaki, N., Kusanagi, T., Kibayashi, C.
  • Journal Title: Tetrahedron Letters 45 Pages: 6509-6512
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Synthesis of the Diazatricyclic Core of the Marine Alkaloids Madangamines (2004)
  • Author(s): Yamazaki, N.; Kusanagi, T.; Kibayashi, C.
  • Journal Title: Tetrahedron Letters 45 Pages: 6509-6512
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 環状N,O-アセタールを利用するアルカロイド合成 (2003)
  • Author(s): 山崎直毅, 樹林千尋
  • Journal Title: 有機合成化学協会誌 61・9 Pages: 868-881
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Alkaloid Synthesis Utilizing Cyclic N, O-Acetals (2003)
  • Author(s): Yamazaki, N.; Kibayashi, C.
  • Journal Title: Yuki Gosei Kagaku Kyokaishi 61 Pages: 868-881
  • Description: 「研究成果報告書概要(欧文)」より