2. Academic Validation
  3. Discovery of N-Trifluoromethylated Noscapines as Novel and Potent Agents for the Treatment of Glioblastoma

Discovery of N-Trifluoromethylated Noscapines as Novel and Potent Agents for the Treatment of Glioblastoma

  • J Med Chem. 2025 Jan 9;68(1):247-260. doi: 10.1021/acs.jmedchem.4c01786.
Guangwei Cui 1,  Yuhang Fan 2,  Yue Yang 1,  Yiwen Ma 1,  Haiyang Deng 1,  Pan Wang 1,  Yuxin Zhu 1,  Jian Li 2,  Jinlian Wei 2,  Yongqiang Zhang 1
Affiliations

Affiliations

  • 1 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.
  • 2 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.
PMID: 39688535 DOI: 10.1021/acs.jmedchem.4c01786
Abstract

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 N-trifluoromethylated noscapines has been disclosed. Among them, 9'-bromo-N-trifluoromethyl noscapine 15c displayed superior in vitro anti-GBM potency. Unexpectedly, in contrast with the general N-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 N-methyl could be bioisosterically replaced with trifluoromethyl. Furthermore, 15c showed excellent BBB permeability and good in vivo 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 15c 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.

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