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 language | English |
|---|---|
| Journal | Bioorganic and Medicinal Chemistry |
| DOIs | |
| Publication status | Published - 2019 Jan 1 |
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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 journal › Article
}
TY - JOUR
T1 - Identification of topoisomerases as molecular targets of cytosporolide C and its analog
AU - Otake, Keisuke
AU - Yamada, Kana
AU - Miura, Kazuki
AU - Sasazawa, Yukiko
AU - Miyazaki, So
AU - Niwa, Yuki
AU - Ogura, Akihiro
AU - Takao, Kenichi
AU - Simizu, Siro
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
KW - Anti-cancer drug
KW - Cytosporolide
KW - Natural product
KW - Topoisomerase
UR - http://www.scopus.com/inward/record.url?scp=85067206079&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067206079&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2019.06.014
DO - 10.1016/j.bmc.2019.06.014
M3 - Article
AN - SCOPUS:85067206079
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
ER -