2. Academic Validation
  3. Novel piperazine based benzamide derivatives as potential anti-glioblastoma agents inhibiting cell proliferation and cell cycle progression

Novel piperazine based benzamide derivatives as potential anti-glioblastoma agents inhibiting cell proliferation and cell cycle progression

  • Eur J Med Chem. 2022 Jan 5:227:113908. doi: 10.1016/j.ejmech.2021.113908.
Yingmei Lu 1,  Yiyue Feng 1,  Zhao Li 1,  Junfang Li 1,  Honghua Zhang 1,  Xiaoling Hu 1,  Weifan Jiang 2,  Tao Shi 1,  Zhen Wang 3
Affiliations

Affiliations

  • 1 School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
  • 2 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 3 School of Pharmacy, Lanzhou University, Lanzhou, 730000, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China. Electronic address: zhenw@lzu.edu.cn.
PMID: 34656900 DOI: 10.1016/j.ejmech.2021.113908
Abstract

Highly efficacious and tolerable agents for the treatment of glioblastoma (GBM), the most common and aggressive primary brain tumor, are urgently needed. Herein, we reveal the design, synthesis and biological evaluation of several piperazine based benzamide derivatives, which are based on the non-classical isostere principle and combination principle for GBM therapy. After structure-activity relationship (SAR) study, compound L19 was demonstrated as the most promising compound with IC50 values of 0.15 μM, 0.29 μM, 1.25 μM against GBM C6, U87-MG, U251 cells, respectively. Moreover, compound L19 could inhibit the proliferation, migration and invasion, as well as induce Apoptosis and cell cycle arrest of GBM cell lines in vitro. From mechanism perspective, compound L19 could regulate the cell cycle-related proteins and influence the p16INK4a-CDK4/6-pRb pathway by western blotting experiment. What is worth mentioning is that compound L19 could penetrate the blood-brain barrier (BBB) with an exceptional brain-to-plasma ratio of 1.07 in vivo. Besides, the superior anti-glioblastoma potency in vivo of compound L19 was identified on U87-MG-xenograft model without any apparent host toxicity. Overall, the potential of compound L19 warrants further pre-clinical investigation for GBM therapy.

Keywords

Combination principle; Glioblastoma; Non-classical isostere principle; Piperazine based benzamide derivatives; Structure-activity relationship.

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