Design, synthesis, and biological evaluation of novel spirocyclic compounds as potential anti-glioblastoma agents
文献类型：期刊论文
| 作者 | Zhu, Heping1,2,3; Song, Xiaomin1,2,3; Pan, Yihui1,2,3; Li, Ming1,2,3 ; Chen, Liang2,3; Xiao, Pan1,2,3; Du, Rong1,2,3; Dong, Ze1,2,3; Yang, Cai-Guang1,2,3
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2023-10-05 |
| 卷号 | 258页码:22 |
| ISSN号 | 0223-5234 |
| 关键词 | Glioblastoma Spirocyclic compounds Drug design Antiproliferation |
| DOI | 10.1016/j.ejmech.2023.115595 |
| 通讯作者 | Dong, Ze(dongze@ucas.ac.cn) ; Yang, Cai-Guang(yangcg@simm.ac.cn) |
| 英文摘要 | 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 celldeath 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. |
| WOS关键词 | BLOOD-BRAIN-BARRIER ; CANCER ; NECROPTOSIS ; STRATEGIES ; DISCOVERY ; APOPTOSIS ; RELEVANCE ; CHALCONE |
| 资助项目 | National Key Research and Development Program of China[2022YFC2705005] ; National Natural Science Foundation of China[22077133] ; National Natural Science Foundation of China[92153303] ; China National Program for Innovative Talents[BX20220321] ; Shanghai Post-doctoral Excellence Program[2022760] ; Youth Innovation Promotion Association of CAS[2021277] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| WOS记录号 | WOS:001037268200001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/306746]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Dong, Ze; Yang, Cai-Guang |
| 作者单位 | 1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Chem Biol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhu, Heping,Song, Xiaomin,Pan, Yihui,et al. Design, synthesis, and biological evaluation of novel spirocyclic compounds as potential anti-glioblastoma agents[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,258:22. |
| APA | Zhu, Heping.,Song, Xiaomin.,Pan, Yihui.,Li, Ming.,Chen, Liang.,...&Yang, Cai-Guang.(2023).Design, synthesis, and biological evaluation of novel spirocyclic compounds as potential anti-glioblastoma agents.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,258,22. |
| MLA | Zhu, Heping,et al."Design, synthesis, and biological evaluation of novel spirocyclic compounds as potential anti-glioblastoma agents".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 258(2023):22. |
入库方式： OAI收割
来源：上海药物研究所
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