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

Heping Zhu; Xiaomin Song; Yihui Pan; Ming Li; Liang Chen; Pan Xiao; Rong Du; Ze Dong; Cai-Guang Yang

doi:10.1016/j.ejmech.2023.115595

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. Epub 2023 Jun 25.

Authors

Heping Zhu¹, Xiaomin Song¹, Yihui Pan¹, Ming Li¹, Liang Chen², Pan Xiao¹, Rong Du¹, Ze Dong³, Cai-Guang Yang⁴

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.

MeSH terms

Animals
Antineoplastic Agents* / therapeutic use
Apoptosis
Blood-Brain Barrier / metabolism
Brain Neoplasms* / pathology
Cell Death
Cell Line, Tumor
Cell Proliferation
Glioblastoma* / pathology
Humans
Mice
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents