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

IF 4.9 3区化学 Q1 CHEMISTRY, MEDICINAL

Natural Products and Bioprospecting Pub Date : 2025-08-08 DOI:10.1007/s13659-025-00534-7

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

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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.

Graphical Abstract

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丹参酮吡啶盐衍生物的合成及生物活性研究。

天然产物丹参酮I效力弱，类药物性质差，限制了其作为抗癌药物的临床开发。本文设计合成了20个新型丹参酮吡啶盐衍生物和一个吡啶盐前体，并对其抗肿瘤活性进行了评价。在这些丹参酮i -吡啶盐中，化合物a4在吡啶环的N-1位置上含有一个4-溴苯甲酰甲基取代基，对乳腺癌（MDA-MB-231）、肝癌（HepG2）和前列腺癌（22RV1）细胞系的细胞毒性最强，IC50值为1.40 ~ 1.63 μM。初步机制研究表明，a4靶向PI3Kα的IC50值为9.24±0.20 μM，可有效抑制PI3K/Akt/mTOR关键信号蛋白的磷酸化。此外，a4显著下调免疫检查点蛋白PD-L1的表达，表明其具有激活肿瘤免疫的潜力。这些发现表明，丹参酮i -吡啶盐衍生物a4是一种新型的PI3Kα抑制剂，为进一步开发抗肿瘤药物提供了坚实的基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Natural Products and Bioprospecting CHEMISTRY, MEDICINAL-

CiteScore

8.30

自引率

2.10%

发文量

审稿时长

13 weeks

期刊介绍： Natural Products and Bioprospecting serves as an international forum for essential research on natural products and focuses on, but is not limited to, the following aspects: Natural products: isolation and structure elucidation Natural products: synthesis Biological evaluation of biologically active natural products Bioorganic and medicinal chemistry Biosynthesis and microbiological transformation Fermentation and plant tissue cultures Bioprospecting of natural products from natural resources All research articles published in this journal have undergone rigorous peer review. In addition to original research articles, Natural Products and Bioprospecting publishes reviews and short communications, aiming to rapidly disseminate the research results of timely interest, and comprehensive reviews of emerging topics in all the areas of natural products. It is also an open access journal, which provides free access to its articles to anyone, anywhere.