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Abstract：
COX-2 and STAT3 are two key culprits in the glioma microenvironment. Herein, to inhibit COX-2 and block STAT3 signaling, we disclosed 27 N-anthraniloyl tryptamine compounds based on the combination of melatonin derivatives and N-substituted anthranilic acid derivatives. Among them, NP16 showed the best antiproliferative activity and moderate COX-2 inhibition. Of note, NP16 decreased the level of p-JAK2 and p-STAT3, and blocked the nuclear translocation of STAT3 in GBM cell lines. Moreover, NP16 downregulated the MMP-9 expression of BV2 cells in a co-culture system of BV2 and C6 glioma cells, abrogated the proliferative/invasive/migratory abilities of GBM cells, induced apoptosis by ROS and the Bcl-2-regulated apoptotic pathway, and induced obvious G2/M arrest in glioma cells in vitro. Furthermore, NP16 displayed favorable pharmacokinetic profiles covering long half-life (11.43 ± 0.43 h) and high blood-brain barrier permeability. Finally, NP16 effectively inhibited tumor growth, promoted the survival rate, increased the expression of E-cadherin and reduced overproduction of PGE2, MMP-9, VEGF-A and the level of p-STAT3 in tumor tissue, and improved the anxiety-like behavior in C6 glioma model. All these evidences demonstrated N-anthraniloyl tryptamine derivatives as multifunctional anti-glioma agents with high potency could drain the swamp to beat glioma.
摘要：
COX-2和STAT3是胶质瘤微环境中的两个关键罪魁祸首。在这里，抑制COX-2和阻断STAT3信号，我们公开了27种基于褪黑激素衍生物和N-取代的邻氨基苯甲酸衍生物组合的N-邻氨基苯酰色胺化合物。其中,NP16显示出最好的抗增殖活性和中度COX-2抑制。值得注意的是，NP16降低了p-JAK2和p-STAT3的水平，并阻断了GBM细胞系中STAT3的核转位。此外，在BV2和C6胶质瘤细胞共培养系统中，NP16下调BV2细胞的MMP-9表达，消除了GBM细胞的增殖/侵袭/迁移能力，ROS诱导的凋亡和Bcl-2调节的凋亡途径，并在体外诱导胶质瘤细胞明显的G2/M期阻滞。此外，NP16显示出良好的药代动力学特征，包括长半衰期（11.43±0.43h）和高血脑屏障通透性。最后,NP16有效抑制肿瘤生长，提高了存活率，增加E-cadherin的表达,减少肿瘤组织中PGE2、MMP-9、VEGF-A和p-STAT3的过度产生,并改善了C6胶质瘤模型中的焦虑样行为。所有这些证据表明，N-邻氨基甲酰色胺衍生物作为高效的多功能抗神经胶质瘤药物可以排出沼泽以击败神经胶质瘤。
