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, Ken ichi
AU - Simizu, Siro
N1 - Funding Information:
We thank Shuji Noguchi and Mizuki Kimura for preparing compounds 1 – 7 and taking the spectral measurements. This work was supported by the Molecular Profiling Committee, a Grant-in-Aid for Scientific Research on Innovative Areas (“Platform of Advanced Animal Model Support”) from The Ministry of Education, Culture, Sports, Science and Technology , Japan ( JSPS KAKENHI Grant Number JP16H06276 ), and a Grant-in-Aid for Young Scientists (B) under Grant Number JP17K15094 , a Grant-in-Aid for Scientific Research (C) under Grant Number JP18K06137 , and the Amano Institute of Technology .
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/8/1
Y1 - 2019/8/1
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
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U2 - 10.1016/j.bmc.2019.06.014
DO - 10.1016/j.bmc.2019.06.014
M3 - Article
C2 - 31204230
AN - SCOPUS:85067206079
VL - 27
SP - 3334
EP - 3338
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 15
ER -
