Identification of topoisomerases as molecular targets of cytosporolide C and its analog

Keisuke Otake, Kana Yamada, Kazuki Miura, Yukiko Sasazawa, So Miyazaki, Yuki Niwa, Akihiro Ogura, Kenichi Takao, Siro Simizu

Research output: Contribution to journalArticle

Abstract

Cytosporolide (Cytos) A–C, isolated from the fungus Cytospora sp., have anti-microbial activity, but their molecular targets in mammalian cells are unknown. We have previously reported the total synthesis of Cytos A by biomimetic hetero-Diels-Alder reaction. In this study, to examine the novel bioactivity of Cytos, we synthesized Cytos C and measured cell growth-inhibiting activities of 7 compounds, including Cytos A and C, in several human cancer cell lines. Among these compounds, Cytos C and tetradeoxycytosporolide A (TD-Cytos A), a model compound for the synthesis of Cytos A, had anti-proliferative effects on cancer cells, and TD-Cytos A exhibited stronger activity than Cytos C. In vitro topoisomerase-mediated DNA relaxing experiments showed that TD-Cytos A inhibited the activities of topoisomerase I and II, whereas Cytos C targeted only topoisomerase I. These data suggest that the anti-proliferative activities of Cytos correlate with the inhibition of topoisomerases and implicated TD-Cytos A as a novel anti-cancer drug that suppresses the activities of topoisomerase I and II.

Original languageEnglish
JournalBioorganic and Medicinal Chemistry
DOIs
Publication statusPublished - 2019 Jan 1

Fingerprint

Type I DNA Topoisomerase
Type II DNA Topoisomerase
Cells
Neoplasms
Biomimetics
Cycloaddition Reaction
Cell growth
Bioactivity
Fungi
cytosporolide C
Cell Line
DNA
Growth
Pharmaceutical Preparations
cytosporolide A
Experiments

Keywords

  • Anti-cancer drug
  • Cytosporolide
  • Natural product
  • Topoisomerase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Identification of topoisomerases as molecular targets of cytosporolide C and its analog. / Otake, Keisuke; Yamada, Kana; Miura, Kazuki; Sasazawa, Yukiko; Miyazaki, So; Niwa, Yuki; Ogura, Akihiro; Takao, Kenichi; Simizu, Siro.

In: Bioorganic and Medicinal Chemistry, 01.01.2019.

Research output: Contribution to journalArticle

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AU - Miyazaki, So

AU - Niwa, Yuki

AU - Ogura, Akihiro

AU - Takao, Kenichi

AU - Simizu, Siro

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