Design, synthesis and biological evaluation of N-anthraniloyl tryptamine derivatives as pleiotropic molecules for the therapy of malignant glioma
- Eur J Med Chem. 2021 Oct 15:222:113564. doi: 10.1016/j.ejmech.2021.113564.
- 1. School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
- 2. School of Pharmaceutical Science, University of South China, Hengyang, 421001, China.
- 3. School of Pharmacy, Lanzhou University, Lanzhou, 730000, China. Electronic address: [email protected].
- 4. School of Pharmaceutical Science, University of South China, Hengyang, 421001, China. Electronic address: [email protected].
- 5. School of Pharmaceutical Science, University of South China, Hengyang, 421001, China; School of Pharmacy, Lanzhou University, Lanzhou, 730000, China. Electronic address: [email protected].
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.