Synthesis and biological activity study of tanshinone I-pyridinium salt derivatives

doi:10.1007/s13659-025-00534-7

Natural Products and Bioprospecting ›› 2025, Vol. 15 ›› Issue (5): 51-51.DOI: 10.1007/s13659-025-00534-7

Synthesis and biological activity study of tanshinone I-pyridinium salt derivatives

Huimin Zhao, Yuyang Wang, Zining Liu, Lin Lin, Jiasi Xiang, Zihao Zhu, Xiongli Yang, Yongsheng Fang, Lingmei Kong, Yan Li

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education;
Yunnan Key Laboratory of Research and Development for Natural Products;
School of Pharmacy, Yunnan University, Kunming, 650500, People's Republic of China

Received:2025-05-06 Online:2025-11-06
Contact: Yongsheng Fang,E-mail:ysfang@ucas.ac.cn;Lingmei Kong,E-mail:konglingmei@ynu.edu.cn;Yan Li,E-mail:yan.li@ynu.edu.cn
Supported by:
National Natural Science Foundation of China, 32260159, Yan Li, 82360725, Lingmei Kong, Applied Basic Research Foundation of Yunnan Province, 202301AS070022, Yan Li, Major Science and Technology Projects in Yunnan Province, 202402AA310025, Yan Li, Yunan Ten Thousand Talents Plan Young and Elite Talents Project, YNWR-QNBJ-2020-084, Lingmei Kong

Synthesis and biological activity study of tanshinone I-pyridinium salt derivatives

Huimin Zhao, Yuyang Wang, Zining Liu, Lin Lin, Jiasi Xiang, Zihao Zhu, Xiongli Yang, Yongsheng Fang, Lingmei Kong, Yan Li

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education;
Yunnan Key Laboratory of Research and Development for Natural Products;
School of Pharmacy, Yunnan University, Kunming, 650500, People's Republic of China

通讯作者: Yongsheng Fang,E-mail:ysfang@ucas.ac.cn;Lingmei Kong,E-mail:konglingmei@ynu.edu.cn;Yan Li,E-mail:yan.li@ynu.edu.cn
基金资助:
National Natural Science Foundation of China, 32260159, Yan Li, 82360725, Lingmei Kong, Applied Basic Research Foundation of Yunnan Province, 202301AS070022, Yan Li, Major Science and Technology Projects in Yunnan Province, 202402AA310025, Yan Li, Yunan Ten Thousand Talents Plan Young and Elite Talents Project, YNWR-QNBJ-2020-084, Lingmei Kong

Abstract

Abstract: Natural product tanshinone I exhibits weak potency and poor drug-like properties, which have restricted its clinical development as an anticancer agent. Herein, twenty novel tanshinone I-pyridinium salt derivatives and a pyridinium salt precursor were designed and synthesized, and their antitumor activities were evaluated. Among these tanshinone I-pyridinium salts, compound a4, bearing a 4-bromobenzoylmethyl substituent at the N-1 position of the pyridine ring, showed the most potent cytotoxicity against breast cancer (MDA-MB-231), hepatocellular carcinoma (HepG2), and prostate cancer (22RV1) cell lines, with IC₅₀ values of 1.40-1.63 μM. Preliminary mechanistic studies suggest that a4 targets PI3Kα with the IC₅₀ of 9.24 ± 0.20 μM and exerts effective inhibition of the phosphorylation of key PI3K/Akt/mTOR signaling proteins. Besides, a4 significantly downregulates the expression of the immune checkpoint protein PD-L1, indicating its potential to activate tumor immunity. These findings demonstrate that tanshinone I-pyridinium salt derivative a4 is a novel PI3Kα inhibitor, providing a solid foundation for further development of antitumor agents.

Key words: Tanshinone I, Pyridinium salts, Structural modification, Antitumor activity, Structure–activity relationship

摘要： Natural product tanshinone I exhibits weak potency and poor drug-like properties, which have restricted its clinical development as an anticancer agent. Herein, twenty novel tanshinone I-pyridinium salt derivatives and a pyridinium salt precursor were designed and synthesized, and their antitumor activities were evaluated. Among these tanshinone I-pyridinium salts, compound a4, bearing a 4-bromobenzoylmethyl substituent at the N-1 position of the pyridine ring, showed the most potent cytotoxicity against breast cancer (MDA-MB-231), hepatocellular carcinoma (HepG2), and prostate cancer (22RV1) cell lines, with IC₅₀ values of 1.40-1.63 μM. Preliminary mechanistic studies suggest that a4 targets PI3Kα with the IC₅₀ of 9.24 ± 0.20 μM and exerts effective inhibition of the phosphorylation of key PI3K/Akt/mTOR signaling proteins. Besides, a4 significantly downregulates the expression of the immune checkpoint protein PD-L1, indicating its potential to activate tumor immunity. These findings demonstrate that tanshinone I-pyridinium salt derivative a4 is a novel PI3Kα inhibitor, providing a solid foundation for further development of antitumor agents.

关键词: Tanshinone I, Pyridinium salts, Structural modification, Antitumor activity, Structure–activity relationship

Huimin Zhao, Yuyang Wang, Zining Liu, Lin Lin, Jiasi Xiang, Zihao Zhu, Xiongli Yang, Yongsheng Fang, Lingmei Kong, Yan Li. Synthesis and biological activity study of tanshinone I-pyridinium salt derivatives[J]. Natural Products and Bioprospecting, 2025, 15(5): 51-51.

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Synthesis and biological activity study of tanshinone I-pyridinium salt derivatives

Synthesis and biological activity study of tanshinone I-pyridinium salt derivatives

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