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Abstract <p>Heterocyclic enediynes are promising analogues of natural enediyne antibiotics. Here, we report on the synthesis of a benzothiophene-fused azaenediyne with an iso-position of NTs function within the enediyne cycle. The iso-<i>N</i>-enediyne was obtained using the iodoalkyne approach, i.e. iodocyclization of the functionalized iodoalkyne followed by two subsequent one-pot Sonogashira reactions with diiodobenzothiophene, and then the Nicholas cyclization. Despite the successful synthesis of starting acyclic enediyne, the synthetic accessibility of cyclic iso-<i>N</i>-enediyne was poorer than that of its known isomer due to lower regioselectivity during the cobalt complexation stage. The obtained iso-<i>N</i>-enediyne exhibits lower reactivity in Bergman cyclization and it is less cytotoxic against the HeLa cell line. Therefore, the previously reported <i>N</i>-enediyne has advantages over the newly synthesized iso-<i>N</i>-enediyne for the further development of anticancer agents.</p>

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Benzothiophene-Fused iso-N-Enediyne via Iodoalkyne Approach

  • 期刊论文

  • 发表日期：

    2026年2月9日

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  • Ekaterina A. Khmelevskaya,
  • Natalia A. Danilkina,
  • Sergey A. Silonov,
  • Alexander F. Khlebnikov,
  • Irina A. Balova

摘要

Abstract

Heterocyclic enediynes are promising analogues of natural enediyne antibiotics. Here, we report on the synthesis of a benzothiophene-fused azaenediyne with an iso-position of NTs function within the enediyne cycle. The iso-N-enediyne was obtained using the iodoalkyne approach, i.e. iodocyclization of the functionalized iodoalkyne followed by two subsequent one-pot Sonogashira reactions with diiodobenzothiophene, and then the Nicholas cyclization. Despite the successful synthesis of starting acyclic enediyne, the synthetic accessibility of cyclic iso-N-enediyne was poorer than that of its known isomer due to lower regioselectivity during the cobalt complexation stage. The obtained iso-N-enediyne exhibits lower reactivity in Bergman cyclization and it is less cytotoxic against the HeLa cell line. Therefore, the previously reported N-enediyne has advantages over the newly synthesized iso-N-enediyne for the further development of anticancer agents.