- Design, synthesis and biological evaluation of N-anthraniloyl tryptamine derivatives as pleiotropic molecules for the therapy of malignant glioma
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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.
- Fan, Xiaohong,Li, Junfang,Long, Lin,Shi, Tao,Liu, Dan,Tan, Wen,Zhang, Honghua,Wu, Xiaoyan,Lei, Xiaoyong,Wang, Zhen
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- Increasing the antioxidant capability via the synergistic effect of coupling diphenylamine with sterically hindered phenol
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A series of novel diphenylamine-phenol antioxidants were synthesised that combined the two antioxidant types into a single molecule. These antioxidants were then functionalised with alkyl chains to aid their solubility in hydrocarbon media. As part of a s
- Higgins, Clare L.,Filip, Sorin V.,Afsar, Ashfaq,Hayes, Wayne
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- Design, synthesis and biological evaluation of 4-amidobenzimidazole acridine derivatives as dual PARP and Topo inhibitors for cancer therapy
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PARP-1 could repair the DNA damages induced by Topo inhibitors, therefore inhibiting Topo and PARP-1 simultaneously might be able to overcome resistance and improve outcomes. In this study a series of 4-amidobenzimidazole acridines were designed and synthesized as dual Topo and PARP-1 inhibitors. Compound 11l displayed good inhibitory activities against Topo and PARP-1, as well as significantly inhibited cancer cells proliferation. Further mechanistic evaluations indicated that 11l treatment in MCF-7 cells induced accumulated DNA double-strand breaks, prompted remarkable apoptosis, and caused prominent G0/G1 cell cycle arrest. Moreover, 11l greatly suppressed tumor growth in mice, and displayed favorable metabolic properties in liver microsomes. Our study suggested that single agents inhibiting Topo and PARP concurrently might be an alternative for cancer therapy and 11l represented a potential lead compound for development of antitumor agents.
- Yuan, Zigao,Chen, Shaopeng,Chen, Changjun,Chen, Jiwei,Chen, Chengken,Dai, Qiuzi,Gao, Chunmei,Jiang, Yuyang
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p. 1135 - 1146
(2017/08/02)
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- Synthesis and biological evaluation of benzimidazole acridine derivatives as potential DNA-binding and apoptosis-inducing agents
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The discovery of new effective DNA-targeted antitumor agent is needed because of their clinical significance. As acridines can intercalate into DNA and benzimidazoles have the ability to bind in the DNA minor groove, a series of novel benzimidazole acridine derivatives were designed and synthesized to be new DNA-targeted compounds. MTT assay indicated that most of the synthesized compounds displayed good antiproliferative activity, among which compound 8l demonstrated the highest activity against both K562 and HepG-2 cells. Further experiments showed that 8l displayed good DNA-binding capability and inhibited topoisomerase I activity. Moreover, compound 8l could induce apoptosis in K562 cell lines through mitochondrial pathway. These data suggested that compound 8l might be potential as new DNA-binding and apoptosis-inducing antitumor agents.
- Gao, Chunmei,Li, Bin,Zhang, Bin,Sun, Qinsheng,Li, Lulu,Li, Xi,Chen, Changjun,Tan, Chunyan,Liu, Hongxia,Jiang, Yuyang
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supporting information
p. 1800 - 1807
(2015/03/30)
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- Sulfonic acid-catalyzed autoxidative carbon-carbon coupling reaction under elevated partial pressure of oxygen
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An aerobic organocatalytic oxidative C-C bond formation reaction of benzylic C-H bonds with various C-nucleophiles is described. The coupling reaction proceeds by simply stirring the substrates under elevated partial pressure of oxygen in the presence of a sulfonic acid catalyst at room temperature. Elevation of the pressure enables the reaction of a broad scope of nucleophile substrates otherwise showing poor reactivity at ambient pressure. The benzylic C-H bonds of xanthene, acridanes, isochromane and related heterocycles could be functionalized with nucleophiles including ketones, 1,3-dicarbonyl compounds and aldehydes. Electron-rich arenes could be utilized as nucleophiles at elevated temperatures. The reactions are believed to proceed via autoxidation of the benzylic C-H bonds to the hydroperoxides and subsequent nucleophilic substitution catalyzed by sulfonic acids. Copyright
- Pinter, Aron,Klussmann, Martin
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supporting information; experimental part
p. 701 - 711
(2012/04/23)
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