Synthesis and anticancer activity of podophyllotoxin derivatives with nitrogen-containing heterocycles

Meng Yin; Yongsheng Fang; Xiaotong Sun; Minggao Xue; Caimei Zhang; Zhiyun Zhu; Yamiao Meng; Lingmei Kong; Yi Yi Myint; Yan Li; Jingfeng Zhao; Xiaodong Yang

doi:10.3389/fchem.2023.1191498

Synthesis and anticancer activity of podophyllotoxin derivatives with nitrogen-containing heterocycles

Front Chem. 2023 May 10:11:1191498. doi: 10.3389/fchem.2023.1191498. eCollection 2023.

Authors

Affiliations

¹ Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Pharmacy, Yunnan University, Kunming, China.
² Department of Chemistry, University of Mandalay, Mandalay, Myanmar.

Abstract

Three series of podophyllotoxin derivatives with various nitrogen-containing heterocycles were designed and synthesized. The antitumor activity of these podophyllotoxin derivatives was evaluated in vitro against a panel of human tumor cell lines. The results showed that podophyllotoxin-imidazolium salts and podophyllotoxin-1,2,4-triazolium salts a1-a20 exhibited excellent cytotoxic activity. Among them, a6 was the most potent cytotoxic compound with IC₅₀ values of 0.04-0.29 μM. Podophyllotoxin-1,2,3-triazole derivatives b1-b5 displayed medium cytotoxic activity, and podophyllotoxin-amine compounds c1-c3 has good cytotoxic activity with IC₅₀ value of 0.04-0.58 μM. Furthermore, cell cycle and apoptosis experiments of compound a6 were carried out and the results exhibited that a6 could induce G2/M cell cycle arrest and apoptosis in HCT-116 cells.

Keywords: antitumor activity; imidazolium salts; podophyllotoxin; structure-activity relationships; triazoles.

Grants and funding

This work was supported by grants from the National Key R&D Program of China (2019YFE0109200), the Central Government Guides Local Science and Technology Development Fund (202207AA110007, 202207AB110002), Yunnan Science and Technology Department and Yunnan University Joint Fund Project (2019FY003010), Program for Xingdian Talents (Yun-Ling Scholars) and IRTSTYN, and the Project of Yunnan Characteristic Plant Screening and R&D Service CXO Platform (2022YKZY001).