2. Academic Validation
  3. Design, synthesis and biological evaluation of N-anthraniloyl tryptamine derivatives as pleiotropic molecules for the therapy of malignant glioma

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.
Xiaohong Fan 1,  Junfang Li 1,  Lin Long 2,  Tao Shi 3,  Dan Liu 1,  Wen Tan 1,  Honghua Zhang 1,  Xiaoyan Wu 1,  Xiaoyong Lei 4,  Zhen Wang 5
Affiliations

Affiliations

  • 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: shit18@lzu.edu.cn.
  • 4 School of Pharmaceutical Science, University of South China, Hengyang, 421001, China. Electronic address: 1622214323@qq.com.
  • 5 School of Pharmaceutical Science, University of South China, Hengyang, 421001, China; School of Pharmacy, Lanzhou University, Lanzhou, 730000, China. Electronic address: zhenw@lzu.edu.cn.
PMID: 34091208 DOI: 10.1016/j.ejmech.2021.113564
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.

Keywords

COX-2; Glioma; STAT3; Structure-activity relationship; Tryptamine.

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