1. Academic Validation
  2. N-2-(phenylamino) benzamide derivatives as novel anti-glioblastoma agents: Synthesis and biological evaluation

N-2-(phenylamino) benzamide derivatives as novel anti-glioblastoma agents: Synthesis and biological evaluation

  • Eur J Med Chem. 2021 Dec 15:226:113817. doi: 10.1016/j.ejmech.2021.113817.
Junfang Li 1 Xiaoling Hu 1 Tian Luo 1 Yingmei Lu 1 Yiyue Feng 1 Honghua Zhang 1 Dan Liu 1 Xiaohong Fan 1 Yuqing Wang 1 Liming Jiang 1 Yuying Wang 2 Xiangyong Hao 3 Tao Shi 4 Zhen Wang 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
  • 2 State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China.
  • 3 Department of General Surgery, Gansu Provincial Hospital, Lanzhou, 730000, China.
  • 4 School of Pharmacy, Lanzhou University, Lanzhou, 730000, China. Electronic address: shit18@lzu.edu.cn.
  • 5 School of Pharmacy, Lanzhou University, Lanzhou, 730000, China; State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: zhenw@lzu.edu.cn.
Abstract

Glioblastoma is one of the most lethal brain tumors. The crucial chemotherapy is mainly alkylating agents with modest clinical success. Given this desperate need and inspired by the encouraging results of a phase II trial via concomitant Topo I Inhibitor plus COX-2 Inhibitor, we designed a series of N-2-(phenylamino) benzamide derivatives as novel anti-glioblastoma agents based on structure modification on 1,5-naphthyridine derivatives (Topo I inhibitors). Notably, the target compounds I-1 (33.61 ± 1.15 μM) and I-8 (45.01 ± 2.37 μM) were confirmed to inhibit COX-2, while a previous reported compound (1,5-naphthyridine derivative) resulted nearly inactive towards COX-2 (IC50 > 150 μM). Besides, I-1 and I-8 exhibited higher anti-proliferation, anti-migration, anti-invasion effects than the parent compound 1,5-naphthyridine derivative, suggesting the success of modification based on the parent. Moreover, I-1 obviously repressed tumor growth in the C6 glioma orthotopic model (TGI = 66.7%) and U87MG xenograft model (TGI = 69.4%). Besides, I-1 downregulated PGE2, VEGF, MMP-9, and STAT3 activation, upregulated E-cadherin in the orthotopic model. More importantly, I-1 showed higher safety than temozolomide and different mechanism from temozolomide in the C6 glioma orthotopic model. All the evidence demonstrated that N-2-(phenylamino) benzamide derivatives as novel anti-glioblastoma agents could be promising for the glioma management.

Keywords

COX-2 inhibitor; Glioma; N-2-(phenylamino) benzamide; Pseudocycle; Topoisomerase I inhibitor.

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