Cui Guangwei, Fan Yuhang, Yang Yue, Ma Yiwen, Deng Haiyang, Wang Pan, Zhu Yuxin, Li Jian, Wei Jinlian, Zhang Yongqiang
Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, and School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. China.
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, and School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. China.
J Med Chem. 2025 Jan 9;68(1):247-260. doi: 10.1021/acs.jmedchem.4c01786. Epub 2024 Dec 17.
The search for new and effective chemotherapeutic agents for the treatment of glioblastoma (GBM) represents an unmet need in drug discovery. Herein, a class of novel -trifluoromethylated noscapines has been disclosed. Among them, 9'-bromo--trifluoromethyl noscapine displayed superior anti-GBM potency. Unexpectedly, in contrast with the general -trifluoromethyl amines, these compounds exhibited good hydrolytic stability and further investigation of this distinct stability revealed a novel strategy for the structure modification of tetrahydroisoquinoline alkaloids, where -methyl could be bioisosterically replaced with trifluoromethyl. Furthermore, showed excellent BBB permeability and good anti-GBM activity and could efficiently suppress the migration of GBM cells, while no apparent toxicity was observed, thus representing an attractive lead for further drug discovery. Further mechanistic studies revealed that exhibited an ability to induce G2/M-phase arrest in GBM cells associated with the disruption of tubulin polymerization, which is consistent with the mechanism of action of noscapine.
寻找用于治疗胶质母细胞瘤（GBM）的新型有效化疗药物是药物研发中尚未满足的需求。在此，公开了一类新型的 - 三氟甲基化那可丁。其中，9'- 溴 - - 三氟甲基那可丁表现出卓越的抗GBM效力。出乎意料的是，与一般的 - 三氟甲基胺不同，这些化合物表现出良好的水解稳定性，对这种独特稳定性的进一步研究揭示了一种用于四氢异喹啉生物碱结构修饰的新策略，其中 - 甲基可以被三氟甲基生物电子等排体取代。此外， 表现出优异的血脑屏障通透性和良好的抗GBM活性，并且可以有效抑制GBM细胞的迁移，同时未观察到明显毒性，因此代表了进一步药物研发的有吸引力的先导物。进一步的机制研究表明， 表现出诱导GBM细胞G2/M期阻滞的能力，这与微管蛋白聚合的破坏有关，这与那可丁的作用机制一致。
