Discovery of <i>N</i>‑Trifluoromethylated\nNoscapines as Novel and Potent Agents for the Treatment of Glioblastoma

The search for new and effective chemotherapeutic agents\nfor the\ntreatment of glioblastoma (GBM) represents an unmet need in drug discovery.\nHerein, a class of novel <i>N</i>-trifluoromethylated noscapines\nhas been disclosed. Among them, 9′-bromo-<i>N</i>-trifluoromethyl noscapine <b>15c</b> displayed superior <i>in vitro</i> anti-GBM potency. Unexpectedly, in contrast with\nthe general <i>N</i>-trifluoromethyl amines, these compounds\nexhibited good hydrolytic stability and further investigation of this\ndistinct stability revealed a novel strategy for the structure modification\nof tetrahydroisoquinoline alkaloids, where <i>N</i>-methyl\ncould be bioisosterically replaced with trifluoromethyl. Furthermore, <b>15c</b> showed excellent BBB permeability and good <i>in\nvivo</i> anti-GBM activity and could efficiently suppress the\nmigration of GBM cells, while no apparent toxicity was observed, thus\nrepresenting an attractive lead for further drug discovery. Further\nmechanistic studies revealed that <b>15c</b> exhibited an ability\nto induce G2/M-phase arrest in GBM cells associated with the disruption\nof tubulin polymerization, which is consistent with the mechanism\nof action of noscapine.