Zhao Huimin, Wang Yuyang, Liu Zining, Lin Lin, Xiang Jiasi, Zhu Zihao, Yang Xiongli, Fang Yongsheng, Kong Lingmei, Li Yan
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.
Nat Prod Bioprospect. 2025 Aug 8;15(1):51. doi: 10.1007/s13659-025-00534-7.
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 IC values of 1.40-1.63 μM. Preliminary mechanistic studies suggest that a4 targets PI3Kα with the IC 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.
天然产物丹参酮I表现出较弱的活性和不良的类药性质，这限制了其作为抗癌药物的临床开发。在此，设计并合成了20种新型丹参酮I-吡啶盐衍生物和一种吡啶盐前体，并评估了它们的抗肿瘤活性。在这些丹参酮I-吡啶盐中，化合物a4在吡啶环的N-1位带有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）细胞系表现出最强的细胞毒性，IC值为1.40 - 1.63μM。初步机制研究表明，a4以9.24±0.20μM的IC靶向PI3Kα，并有效抑制关键PI3K/Akt/mTOR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。
