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<p>A series of tetrahydrobenzo[<i>cd</i>]indole derivatives was synthesized by condensation of a fungal metabolite hyphodermin A, a naphtho[1,2-<i>c</i>]furan-3,9-dione derivative, and various anilines in methanol. Using this approach, ten analogs (<b>3a</b>–<b>3j</b>) were synthesized and tested as inhibitors against glycogen phosphorylase (GP). While compounds <b>3e</b> and <b>3i</b> bearing hydrophobic bromo and trifluoromethyl groups showed moderated inhibition (<i>K</i><sub>i</sub> = 32.3–57.4 μΜ), compound <b>3g</b> with hydroxy group had the most potent activity with a <i>K</i><sub>i</sub> value of 7.9 ± 0.7 μΜ against human liver GPa. An X-ray crystallography study of the rabbit muscle GPb-<b>3g</b> complexes revealed that this inhibitor binds at a subsite within the indole binding site of GP which has not been previously observed to bind ligands.</p><p></p>

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Synthesis and evaluation of tetrahydrobenzo[cd]indole derivatives as glycogen phosphorylase inhibitors

  • 期刊论文

  • 发表日期：

    2025年2月8日

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  • Panarat Arunrattiyakorn,
  • Chanitha Juiprasert,
  • Symeon M. Koulas,
  • Pornthip Boonsri,
  • Thammarat Aree,
  • Maho Yagi-Utsumi,
  • Koichi Kato,
  • Demetres D. Leonidas

摘要

A series of tetrahydrobenzo[cd]indole derivatives was synthesized by condensation of a fungal metabolite hyphodermin A, a naphtho[1,2-c]furan-3,9-dione derivative, and various anilines in methanol. Using this approach, ten analogs (3a–3j) were synthesized and tested as inhibitors against glycogen phosphorylase (GP). While compounds 3e and 3i bearing hydrophobic bromo and trifluoromethyl groups showed moderated inhibition (Ki = 32.3–57.4 μΜ), compound 3g with hydroxy group had the most potent activity with a Ki value of 7.9 ± 0.7 μΜ against human liver GPa. An X-ray crystallography study of the rabbit muscle GPb-3g complexes revealed that this inhibitor binds at a subsite within the indole binding site of GP which has not been previously observed to bind ligands.