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Synthesis and antitumor activity of novel pyridinium fullerene derivatives

Authors Yasuno T, Ohe T, Ikeda H, Takahashi K, Nakamura S, Mashino T

Received 12 April 2019

Accepted for publication 9 July 2019

Published 7 August 2019 Volume 2019:14 Pages 6325—6337


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Dr Thomas J. Webster

Takumi Yasuno,1 Tomoyuki Ohe,1 Hitomi Ikeda,1 Kyoko Takahashi,1 Shigeo Nakamura,2 Tadahiko Mashino1

1Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo, Japan; 2Department of Chemistry, Nippon Medical School, Tokyo, Japan

Purpose: 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

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