Synthesis and antitumor activity of novel pyridinium fullerene derivatives

Abstract

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

Acknowledgments

This work was supported by the Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and by the Japan Agency for Medical Research and Development (AMED), 2012–2016, and the Platform Project for Supporting Drug Discovery and Life Science Research from AMED, 2017–2018.

Abbreviations

MDR, multidrug resistant; P-gp, P-glycoprotein; SAR, structure activity relationship; DCFH-DA, 2',7'-dichlorodihydrofluorescein diacetate; ROS, reactive oxygen species; ADM, doxorubicin.

Disclosure

The authors report no conflicts of interest in this work.