Synthesis and biological evaluation of analogues of the potent ADAM8 inhibitor cyclo(RLsKDK) for the treatment of inflammatory diseases and cancer metastasis

Mitogen- and Stress-Activated Kinase 1 (MSK1) is a nuclear kinase, taking part in the activation pathway of the pro-inflammatory transcription factor NF-kB and is demonstrating a therapeutic target potential in inflammatory diseases such as asthma, psoriasis and atherosclerosis. To date, few MSK1 inhibitors were reported. In order to identify new MSK1 inhibitors, a screening of a library of low molecular weight compounds was performed, and the results highlighted the 6-phenylpyridin-2-yl guanidine (compound 1a, IC50~18 µM) as a starting hit for structure-activity relationship study. Derivatives, homologues and rigid mimetics of 1a were designed, and all synthesized compounds were evaluated for their inhibitory activity towards MSK1. Among them, the non-cytotoxic 2-aminobenzimidazole 49d was the most potent at inhibiting significantly: (i) MSK1 activity, (ii) the release of IL-6 in inflammatory conditions in vitro (IC50~2 µM) and (iii) the inflammatory cell recruitment to the airways in a mouse model of asthma.

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Design, synthesis and biological evaluation of enzymatically cleavable NSAIDs prodrugs derived from self-immolative dendritic scaffolds for the treatment of inflammatory diseases

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2013.05.006 ◽

2013 ◽

Vol 21 (14) ◽

pp. 4192-4200 ◽

Cited By ~ 9

Author(s):

Jinbao Wei ◽

Jianyou Shi ◽

Jing Zhang ◽

Gu He ◽

Junzhu Pan ◽

...

Keyword(s):

Inflammatory Diseases ◽

Biological Evaluation ◽

Design Synthesis ◽

Synthesis And Biological Evaluation

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Synthesis and Biological Evaluation of Andrographolide Derivatives as Anti-inflammatory Agent

Current Pharmaceutical Design ◽

10.2174/1381612824666180724130014 ◽

2018 ◽

Vol 24 (30) ◽

pp. 3529-3533 ◽

Cited By ~ 6

Author(s):

Zeyu Zhu ◽

Haibing Duan ◽

Mei Jing ◽

Lipeng Xu ◽

Pei Yu

Keyword(s):

Bacterial Infections ◽

Inflammatory Diseases ◽

Cell Activity ◽

Biological Evaluation ◽

Inflammatory Activity ◽

Special Effects ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

New Compounds ◽

Synthesis And Biological Evaluation

Background: Andrographolide (Andro) is a main active ingredient of the natural plant Andrographis paniculata, which has special effects on bacterial infections and inflammatory diseases. Objective: We previously synthesized Andrographolide derivatives AL-1 and investigated its anti-inflammatory activity. For further research, we decided to modify the structure of AL-1 and expected to have better antiinflammatory activity. Methods: By conjugating with anti-inflammatory and anti-bacterial group, we designed and synthesized the andrographolide derivative AL-2, AL-3 and AL-4. The anti-inflammatory activity of AL-2, AL-3 and AL-4 was also evaluated by detecting cell activity and Nitric Oxide (NO) release. <p> Results: The new compounds AL-2, AL-3 and AL-4 increased cell viability in lipopolysaccharide (LPS)-induced RAW 264.7 cell, which could have a certain anti-inflammatory activity, and inhibited the release of NO in cells to reduce the inflammatory response of cells. Conclusion: The new compounds AL-2, AL-3 and AL-4 may be candidates of anti-inflammatory drugs in the future.

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