Chemistry of Ecteinascidins. Part 4: Preparation of 2′-<i>N</i>-Acyl Ecteinascidin 770 Derivatives with Improved Cytotoxicity Profiles

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  • Tsujimoto Mitsuhiro
    Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University
  • Lowtangkitcharoen Witaya
    Center for Bioactive Natural Products from Marine Organisms and Endophytic Fungi (BNPME), Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University
  • Mori Nanae
    Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University
  • Pangkruang Waree
    Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Khon Kaen University
  • Putongking Ploenthip
    Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Khon Kaen University
  • Suwanborirux Khanit
    Center for Bioactive Natural Products from Marine Organisms and Endophytic Fungi (BNPME), Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University
  • Saito Naoki
    Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University

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  • Chemistry of Ecteinascidins(Part 4)Preparation of 2'-N-Acyl Ecteinascidin 770 Derivatives with Improved Cytotoxicity Profiles

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Abstract

We report herein eleven 2′-N-acyl derivatives that were prepared from ecteinascidin 770 (Et 770: 1b) via 18,6′-O-bisallyl protected compound (4) in excellent yields. 2′-N-Acyl derivatives (6a–k) generally showed higher cytotoxicity than 1b. Among them, 3-quinolineacyl derivative (6g) and 4-fluorocinnamoyl derivative (6h) exhibited approximately 50- and 70-fold higher cytotoxicity to the HCT116 human colon carcinoma cell line, respectively, than 1b. Both compounds are potent inhibitors of the in vitro growth of several tumor cells and are therefore promising leads for further optimization. We also report the transformation of 1b into Et 788 (3), which is the first example of an ecteinascidin derivative having a primary amide at C-21 position.

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