Xu Qianhe, Liu Pei, Nie Qiuying, Chu Yajun, Yao Xiaojun, Fang Jianguo, Zhang Junmin
School of Pharmacy, and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, China.
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, 999078, China.
Eur J Med Chem. 2025 Jun 5;290:117551. doi: 10.1016/j.ejmech.2025.117551. Epub 2025 Mar 22.
Quaternary benzophenanthridine alkaloids (QBAs), such as sanguinarine, chelerythrine, and nitidine, possess diverse pharmacological activities. This study presents a simplified structure for QBAs, yielding twelve three-membered phenanthridine alkaloids. Notably, compound 6f demonstrates enhanced potency in selectively inhibiting thioredoxin reductase (TrxR, TXNRD) and exhibits significant cytotoxicity against non-small cell lung cancer (NSCLC) cells. While TrxR is a selenoenzyme, many of its inhibitors react with biological thiols; however, 6f shows minimal reactivity with thiols such as glutathione (GSH) and cysteine. Mechanistic investigations reveal that 6f stimulates reactive oxygen species production, reduces intracellular thiols, and decreases the GSH/GSSG ratio, leading to cell apoptosis through oxidative stress. Moreover, significant tumor regression has been observed in nude mice with NSCLC following treatment with 6f. The pronounced anticancer activity and possible mechanism of action of 6f suggest its potential as a candidate for further development in NSCLC therapy.
季铵型苯并菲啶生物碱（QBAs），如血根碱、白屈菜红碱和去甲斑蝥素，具有多种药理活性。本研究提出了一种简化的QBAs结构，得到了12种三元菲啶生物碱。值得注意的是，化合物6f在选择性抑制硫氧还蛋白还原酶（TrxR，TXNRD）方面表现出增强的效力，并对非小细胞肺癌（NSCLC）细胞表现出显著的细胞毒性。虽然TrxR是一种含硒酶，但其许多抑制剂会与生物硫醇发生反应；然而，6f与谷胱甘肽（GSH）和半胱氨酸等硫醇的反应性最小。机制研究表明，6f刺激活性氧的产生，减少细胞内硫醇，并降低GSH/GSSG比值，通过氧化应激导致细胞凋亡。此外，在用6f治疗的NSCLC裸鼠中观察到明显的肿瘤消退。6f显著的抗癌活性和可能的作用机制表明其有潜力作为NSCLC治疗中进一步开发的候选药物。
