2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel spirocyclic compounds as potential anti-glioblastoma agents

Design, synthesis, and biological evaluation of novel spirocyclic compounds as potential anti-glioblastoma agents

  • Eur J Med Chem. 2023 Oct 5;258:115595. doi: 10.1016/j.ejmech.2023.115595.
Heping Zhu 1,  Xiaomin Song 1,  Yihui Pan 1,  Ming Li 1,  Liang Chen 2,  Pan Xiao 1,  Rong Du 1,  Ze Dong 3,  Cai-Guang Yang 4
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; Centre for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 2 Centre for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; Centre for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: dongze@ucas.ac.cn.
  • 4 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; Centre for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: yangcg@simm.ac.cn.
PMID: 37385078 DOI: 10.1016/j.ejmech.2023.115595
Abstract

Glioblastoma (GBM) is an aggressive brain tumor with extremely limited clinical treatment options. Because of the blood-brain barrier (BBB), it is difficult for anti-GBM drug candidates to enter the brain to exert their therapeutic effects. The spirocyclic skeleton structure exhibits good lipophilicity and permeability, enabling small-molecule compounds to cross the BBB. Herein, we designed and synthesized novel 3-oxetanone-derived spirocyclic compounds containing a spiro[3.4]octane ring and determined their structure-activity relationship for antiproliferation in GBM cells. Among these, the chalcone-spirocycle hybrid 10m/ZS44 exhibited high antiproliferative activity in U251 cells and permeability in vitro. Furthermore, 10m/ZS44 activated the SIRT1/p53-mediated Apoptosis pathway to inhibit proliferation in U251 cells, whereas it minimally impaired Other cell-death pathways, such as Pyroptosis or Necroptosis. In a mouse xenograft model, 10m/ZS44 exhibited a substantial inhibitory effect on GBM tumor growth without showing obvious toxicity. Overall, 10m/ZS44 represents a promising spirocyclic compound for the treatment of GBM.

Keywords

Antiproliferation; Drug design; Glioblastoma; Spirocyclic compounds.

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