Synthesis and antitumor activity of novel pyridinium fullerene derivatives

Takumi Yasuno, Tomoyuki Ohe, Hitomi Ikeda, Kyoko Takahashi, Shigeo Nakamura, Tadahiko Mashino

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)6325-6337
Number of pages13
JournalInternational journal of nanomedicine
Volume14
DOIs
Publication statusPublished - 2019 Jan 1

Fingerprint

Fullerenes
Derivatives
Heterografts
Cell Line
Lead compounds
Lung Neoplasms
Neoplasms
Cells
Structure-Activity Relationship
Pharmaceutical Preparations
Antineoplastic Agents
Doxorubicin
Cisplatin
Oxidative Stress
Oxidative stress

Keywords

  • Anticancer agents
  • Cisplatin-resistant cancer
  • Doxorubicin-resistant cancer
  • Fullerene
  • P-glycoprotein

ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Biomaterials
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

Cite this

Synthesis and antitumor activity of novel pyridinium fullerene derivatives. / Yasuno, Takumi; Ohe, Tomoyuki; Ikeda, Hitomi; Takahashi, Kyoko; Nakamura, Shigeo; Mashino, Tadahiko.

In: International journal of nanomedicine, Vol. 14, 01.01.2019, p. 6325-6337.

Research output: Contribution to journalArticle

@article{6d0ac271b7db431aac8c25708d86c825,
title = "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 = "Anticancer agents, Cisplatin-resistant cancer, Doxorubicin-resistant cancer, Fullerene, P-glycoprotein",
author = "Takumi Yasuno and Tomoyuki Ohe and Hitomi Ikeda and Kyoko Takahashi and Shigeo Nakamura and Tadahiko Mashino",
year = "2019",
month = "1",
day = "1",
doi = "10.2147/IJN.S212045",
language = "English",
volume = "14",
pages = "6325--6337",
journal = "International Journal of Nanomedicine",
issn = "1176-9114",
publisher = "Dove Medical Press Ltd.",

}

TY - JOUR

T1 - Synthesis and antitumor activity of novel pyridinium fullerene derivatives

AU - Yasuno, Takumi

AU - Ohe, Tomoyuki

AU - Ikeda, Hitomi

AU - Takahashi, Kyoko

AU - Nakamura, Shigeo

AU - Mashino, Tadahiko

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Anticancer agents

KW - Cisplatin-resistant cancer

KW - Doxorubicin-resistant cancer

KW - Fullerene

KW - P-glycoprotein

UR - http://www.scopus.com/inward/record.url?scp=85071192014&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071192014&partnerID=8YFLogxK

U2 - 10.2147/IJN.S212045

DO - 10.2147/IJN.S212045

M3 - Article

VL - 14

SP - 6325

EP - 6337

JO - International Journal of Nanomedicine

JF - International Journal of Nanomedicine

SN - 1176-9114

ER -