Synthesis and antitumor activity of novel pyridinium fullerene derivatives

Takumi Yasuno,1 Tomoyuki Ohe,1 Hitomi Ikeda,1 Kyoko Takahashi,1 Shigeo Nakamura,2 Tadahiko Mashino11Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo, Japan; 2Department of Chemistry, Nippon Medical School, Tokyo, JapanPurpose: We have previously reported that some c...

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Autores principales:	Yasuno T, Ohe T, Ikeda H, Takahashi K, Nakamura S, Mashino T
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	Fullerene anticancer agents cisplatin-resistant cancer doxorubicin-resistant cancer P-glycoprotein Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/beba059426634772b426ccd647ed5342
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spelling	oai:doaj.org-article:beba059426634772b426ccd647ed53422021-12-02T05:02:42ZSynthesis and antitumor activity of novel pyridinium fullerene derivatives1178-2013https://doaj.org/article/beba059426634772b426ccd647ed53422019-08-01T00:00:00Zhttps://www.dovepress.com/synthesis-and-antitumor-activity-of-novel-pyridinium-fullerene-derivat-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Takumi Yasuno,1 Tomoyuki Ohe,1 Hitomi Ikeda,1 Kyoko Takahashi,1 Shigeo Nakamura,2 Tadahiko Mashino11Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo, Japan; 2Department of Chemistry, Nippon Medical School, Tokyo, JapanPurpose: We have previously reported that some cationic fullerene derivatives exhibited anticancer activity, and they are expected to be a potential lead compound for an anti-drug resistant cancer agent. However, they are bis-adducts and a mixture of multiple regioisomers, which cannot be readily separated due to the variability of substituent positions on the fullerene cage. To overcome this issue, we evaluated the antiproliferative activities of a set of mono-adduct derivatives and examined their structure-activity relationship. In addition, the in vivo antitumor activity of selected derivatives was also examined.Methods: Nineteen pyridinium fullerene derivatives were newly designed and synthesized in this study. Their antiproliferative activities were evaluated using several cancer cell lines including drug-resistant cells. Furthermore, in vivo antitumor activity of several derivatives was investigated in mouse xenograft model of human lung cancer.Results: The derivatives inhibited the proliferation of cancer cell lines, including cisplatin-resistant cells and doxorubicin-resistant cells. It was also shown that compound 10 (10 μM), 13 (10 μM) and cis-14 (10 μM) induced the intracellular oxidative stress. In addition, compound 13 (20 mg/kg) and cis-14 (15 mg/kg) significantly exhibited antitumor activity in mouse xenograft model of human lung cancer.Conclusion: We synthesized a novel set of mono-adduct fullerene derivatives functionalized with pyridinium groups and found that most of them show potent antiproliferative activities against cancer cell lines and some of them show significant antitumor activities in vivo. We propose that these fullerene derivatives serve as the lead compounds for a novel type of antitumor agents.Keywords: fullerene, anticancer agents, cisplatin-resistant cancer, doxorubicin-resistant cancer, P-glycoprotein  Yasuno TOhe TIkeda HTakahashi KNakamura SMashino TDove Medical PressarticleFullereneanticancer agentscisplatin-resistant cancerdoxorubicin-resistant cancerP-glycoproteinMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 14, Pp 6325-6337 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Fullerene anticancer agents cisplatin-resistant cancer doxorubicin-resistant cancer P-glycoprotein Medicine (General) R5-920
spellingShingle	Fullerene anticancer agents cisplatin-resistant cancer doxorubicin-resistant cancer P-glycoprotein Medicine (General) R5-920 Yasuno T Ohe T Ikeda H Takahashi K Nakamura S Mashino T Synthesis and antitumor activity of novel pyridinium fullerene derivatives
description	Takumi Yasuno,1 Tomoyuki Ohe,1 Hitomi Ikeda,1 Kyoko Takahashi,1 Shigeo Nakamura,2 Tadahiko Mashino11Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo, Japan; 2Department of Chemistry, Nippon Medical School, Tokyo, JapanPurpose: We have previously reported that some cationic fullerene derivatives exhibited anticancer activity, and they are expected to be a potential lead compound for an anti-drug resistant cancer agent. However, they are bis-adducts and a mixture of multiple regioisomers, which cannot be readily separated due to the variability of substituent positions on the fullerene cage. To overcome this issue, we evaluated the antiproliferative activities of a set of mono-adduct derivatives and examined their structure-activity relationship. In addition, the in vivo antitumor activity of selected derivatives was also examined.Methods: Nineteen pyridinium fullerene derivatives were newly designed and synthesized in this study. Their antiproliferative activities were evaluated using several cancer cell lines including drug-resistant cells. Furthermore, in vivo antitumor activity of several derivatives was investigated in mouse xenograft model of human lung cancer.Results: The derivatives inhibited the proliferation of cancer cell lines, including cisplatin-resistant cells and doxorubicin-resistant cells. It was also shown that compound 10 (10 μM), 13 (10 μM) and cis-14 (10 μM) induced the intracellular oxidative stress. In addition, compound 13 (20 mg/kg) and cis-14 (15 mg/kg) significantly exhibited antitumor activity in mouse xenograft model of human lung cancer.Conclusion: We synthesized a novel set of mono-adduct fullerene derivatives functionalized with pyridinium groups and found that most of them show potent antiproliferative activities against cancer cell lines and some of them show significant antitumor activities in vivo. We propose that these fullerene derivatives serve as the lead compounds for a novel type of antitumor agents.Keywords: fullerene, anticancer agents, cisplatin-resistant cancer, doxorubicin-resistant cancer, P-glycoprotein
format	article
author	Yasuno T Ohe T Ikeda H Takahashi K Nakamura S Mashino T
author_facet	Yasuno T Ohe T Ikeda H Takahashi K Nakamura S Mashino T
author_sort	Yasuno T
title	Synthesis and antitumor activity of novel pyridinium fullerene derivatives
title_short	Synthesis and antitumor activity of novel pyridinium fullerene derivatives
title_full	Synthesis and antitumor activity of novel pyridinium fullerene derivatives
title_fullStr	Synthesis and antitumor activity of novel pyridinium fullerene derivatives
title_full_unstemmed	Synthesis and antitumor activity of novel pyridinium fullerene derivatives
title_sort	synthesis and antitumor activity of novel pyridinium fullerene derivatives
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/beba059426634772b426ccd647ed5342
work_keys_str_mv	AT yasunot synthesisandantitumoractivityofnovelpyridiniumfullerenederivatives AT ohet synthesisandantitumoractivityofnovelpyridiniumfullerenederivatives AT ikedah synthesisandantitumoractivityofnovelpyridiniumfullerenederivatives AT takahashik synthesisandantitumoractivityofnovelpyridiniumfullerenederivatives AT nakamuras synthesisandantitumoractivityofnovelpyridiniumfullerenederivatives AT mashinot synthesisandantitumoractivityofnovelpyridiniumfullerenederivatives
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Synthesis and antitumor activity of novel pyridinium fullerene derivatives

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