Synthesis and Biological Evaluation of Gentiopicroside Derivatives as Novel Cyclooxygenase-2 Inhibitors with Anti-Inflammatory Activity.

Purpose: Nonsteroidal anti-inflammatory drugs cause a series of adverse reactions. Thus, the search for new cyclooxygenase-2 selective inhibitors have become the main direction of research on anti-inflammatory drugs. Gentiopicroside is a novel selective inhibitor of cyclooxygenase-2 from Chinese herbal medicine. However, it is highly hydrophilic owing to the presence of the sugar fragment in its structure that reduces its oral bioavailability and limits efficacy. This study aimed to design and synthesize novel cyclooxygenase-2 inhibitors by modifying gentiopicroside structure and reducing its polarity. Materials and Methods: We introduced hydrophobic acyl chloride into the gentiopicroside structure to reduce its hydrophilicity and obtained some new derivatives. Their in vitro anti-inflammatory activities were evaluated against NO, TNF-α, PGE2, and IL-6 production in the mouse macrophage cell line RAW264.7 stimulated by lipopolysaccharide. The in vivo inhibitory activities were further tested against xylene-induced mouse ear swelling. Molecular docking predicted that whether new compounds could effectively bind to target protein cyclooxygenase-2. The inhibitory activity of new compounds to cyclooxygenase-2 enzyme were verified by the in vitro experiment. Results: A total of 21 novel derivatives were synthesized, and exhibit lower polarities than the gentiopicroside. Most compounds have good in vitro anti-inflammatory activity. The in vivo activity results demonstrated that 8 compounds were more active than gentiopicroside. The inhibition rate of some compounds was higher than celecoxib. Molecular docking predicted that 6 compounds could bind to cyclooxygenase-2 and had high docking scores in accordance with their potency of the anti-inflammatory activity. The confirmatory experiment proved that these 6 compounds had significant inhibitory effect against cyclooxygenase-2 enzyme. Structure-activity relationship analysis presumed that the para-substitution with the electron-withdrawing groups may benefit the anti-inflammatory activity. Conclusion: These gentiopicroside derivatives especially PL-2, PL-7 and PL-8 may represent a novel class of cyclooxygenase-2 inhibitors and could thus be developed as new anti-inflammatory agents.

Effects of butylphthalide on the levels of serum C-reactive protein, Parkinson disease protein 7 and neurotrophin-3 and neurological function in patients with acute cerebral infarction.

To explore the effects of butylphthalide on the levels of serum CRP, PAPK7, NT-3 and neurological function in patients with acute cerebral infarction (ACI). 120 patients with ACI who were treated at Peking University First Hospital from September 2014 to June 2016 were selected as the research objects. The patients were randomly divided into a control group and an observation group, with 60 cases in each group. Conventional methods were adopted in the control group, and the observation group used butylphthalide for treatment. Two months later, the clinical efficacy, serum C-reactive protein (CRP), Parkinson's disease protein 7 (PAPK7), neurotrophic factor-3 (NT-3) levels, and the National Institutes of Health Stroke Scale (NIHSS) score before and after treatment were put into comparison and analysis. Before treatment, the NIHSS score showed no significant difference between the two groups (p>0.05); An observably higher NIHSS score of the observation group compared with the control group was seen after treatment (p=0.000). Butylphthalide has a significant therapeutic effect on patients with ACI. It can effectively restore the patients' neurological function, and remarkably improve the serum CRP, PAPK7 and NT-3 levels, which is worthy of clinical promotion.