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.

胶质母细胞瘤是最致命的脑肿瘤之一。关键的化学疗法主要是具有适度临床成功的烷化剂。鉴于这种迫切的需求，并受到通过同时使用 Topo I 抑制剂和 COX-2 抑制剂的 II 期试验令人鼓舞的结果的启发，我们设计了一系列N- 2-（苯氨基）苯甲酰胺衍生物作为基于结构修饰的新型抗胶质母细胞瘤药物1,5-萘啶衍生物（Topo I 抑制剂）。值得注意的是，目标化合物I-1 (33.61 ± 1.15 μM) 和I-8 (45.01 ± 2.37 μM) 被证实可抑制 COX-2，而先前报道的化合物 (1,5-萘啶衍生物) 对 COX 几乎无活性-2 (IC ₅₀  > 150 μM)。此外，I-1和与母体化合物1,5-萘啶衍生物相比， I-8具有更高的抗增殖、抗迁移、抗侵袭作用，表明基于母体的修饰成功。此外，I-1在 C6 胶质瘤原位模型 (TGI = 66.7%) 和 U87MG 异种移植模型 (TGI = 69.4%) 中明显抑制肿瘤生长。此外，在原位模型中， I-1下调 PGE ₂、VEGF、MMP-9 和 STAT3 的活化，上调 E-cadherin。更重要的是，I-1在 C6 胶质瘤原位模型中显示出比替莫唑胺更高的安全性和与替莫唑胺不同的作用机制。所有证据表明，N-2-（苯氨基）苯甲酰胺衍生物作为新型抗胶质母细胞瘤药物可能有望用于胶质瘤治疗。