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<p>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 <b>a4</b>, bearing a 4-bromobenzoylmethyl substituent at the <i>N</i>-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 IC<sub>50</sub> values of 1.40–1.63&#xa0;μM. Preliminary mechanistic studies suggest that <b>a4</b> targets PI3Kα with the IC<sub>50</sub> of 9.24 ± 0.20&#xa0;μM and exerts effective inhibition of the phosphorylation of key PI3K/Akt/mTOR signaling proteins. Besides, <b>a4</b> 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 <b>a4</b> is a novel PI3Kα inhibitor, providing a solid foundation for further development of antitumor agents.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月8日

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

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.

Graphical Abstract