Bicyclol promotes toll-like 2 receptor recruiting inosine 5'-monophosphate dehydrogenase II to exert its anti-inflammatory effect.

The aim was to investigate potential targets and anti-inflammatory mechanisms of bicyclol, which has been extensively used in clinic for decades in China. Tar-Fis-Dock, virtual molecular docking system, showed that inosine 5'-monophosphate dehydrogenase II (IMPDH II) has the highest probability of binding to bicyclol. To investigate the possible role of IMPDH II in mechanisms of bicyclol, recombinant enzyme models, mice splenic lymphocytes, and human lymphocytes were used. Bicyclol (1-5 µM) significantly inhibited the proliferation of mice splenic lymphocytes stimulated by concanavalin A (conA). However, bicyclol did not show inhibitory effects on proliferation of human peripheral blood mononuclear cells (hPBMC) induced by phytohemagglutinin (PHA). IMPDH II enzyme kinetic model showed that bicyclol only had a slight regulatory effect on IMPDH II enzyme activity. These results revealed that bicyclol may be not a conventional inhibitor of IMPDH II. Further studies showed that bicyclol could promote recruitment of IMPDH II by active toll-like 2 receptor (TLR2) complex. Such effects lead to the reduction of nuclear factor κB (NF-κB) expression, increase in I-κB expression, and decrease in cytokine release, including tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß). It may be a new mechanism of bicyclol for its anti-inflammatory effect.

[Design, synthesis and pharmacological investigation of isoindoline derivatives as 5-HT/NE double reuptake inhibitors].

A series of isoindoline derivatives were designed, synthesized, and evaluated for their double inhibitory activities. All of them were new compounds, and their structures were confirmed by 1H NMR and HR-MS. Preliminary in vitro pharmacological tests showed that all compounds exhibited 5-HT or NE reuptake inhibition activity. Among the tested compounds, compound I-3 exhibited potent inhibitory activity against 5-HT and NE reuptake in vitro, and exhibited potent antidepressant activity in vivo. These compounds designed can be further optimized for finding more potent 5-HT/NE dual reuptake inhibitors and antidepressant candidates as well.

Synthesis and inhibitory effect of piperine derivates on monoamine oxidase.

A series of piperine derivates (1-19) have been designed, synthesized and evaluated in vitro for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity. It is worth noting that most of the small amine moieties substituted on the piperidine ring proved to be potent and selective inhibitors of MAO-B rather than of MAO-A. 5-(3,4-methylenedioxyphenyl)-2E,4E-pentadienoic acid n-propyl amide (3) showed the greatest MAO-B inhibitory activity (IC(50)(MAO-B)=0.045 µM) and good selectivity (IC(50)(MAO-A)=3.66 µM). The conjugated double bond and carbonyl group of piperine are proved to be an essential feature for piperine and related alkylamides to exhibit MAO-inhibitory activity. Binding mode of the titled compounds was predicted using FlexX algorithm. The design and optimization of novel small molecule monoamine oxidase inhibitors will be guided by the results of this report.

The adenosine derivative 2',3',5'-tri-O-acetyl-N6-(3-hydroxylaniline) adenosine activates AMPK and regulates lipid metabolism in vitro and in vivo.

AIMS: Our overall objective was to investigate the effect of the adenosine derivative 2',3',5'-tri-O-acetyl-N6-(3-hydroxylaniline) adenosine (WS010117) on AMP-activated protein kinase (AMPK) activation and lipid metabolism and to also assess the underlying mechanisms involved in these processes. MAIN METHODS: HepG2 cells and hamsters fed a high-fat diet were used to test the effects of WS010117 on lipid metabolism. Western blots, chemical intervention, HPLC, SAMS peptide assay, (14)C-labelled acetate and palmitate assays, molecular docking assay and siRNA targeting the AMPK γ1 subunit were used to investigate the effect of WS010117 on AMPK activation as well as the underlying mechanism involved in this activation. KEY FINDINGS: WS010117 treatment resulted in the dose-dependent activation of AMPK in HepG2 cells, increasing lipid oxidation and decreasing lipid biosynthesis. In hamsters that were fed a high-fat diet, WS010117 treatment (1.5-6 mg/kg) significantly inhibited the increase in lipid accumulation. WS010117-induced AMPK activation was essentially abolished by treatment with compound C, and the addition of WS010117 did not alter the intracellular AMP:ATP ratio. In HeLa cells endogenously lacking LKB1, WS010117-mediated AMPK activation was not impaired, even following co-treatment with STO-609, a selective inhibitor of Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK). The results from the molecular docking assays and experiments targeting the AMPK γ1 subunit with siRNA indicated that WS010117 may activate AMPK by binding to and regulating the γ subunit of AMPK. SIGNIFICANCE: Our data indicate that WS010117 can regulate lipid metabolism through the activation of AMPK. WS010117 may activate AMPK by binding to and regulating the AMPK γ subunit.

[Synthesis and activity of some new histone deacetylases inhibitors].

To explore novel histone deacetylase (HDAC) inhibitors with anti-tumor activity, twelve target compounds were synthesized, and their structures were confirmed by 1H NMR, MS and elemental analyses. Evaluation results in vitro showed that compound Ia exhibited potent inhibition against HDAC and is worth for further investigation. And compounds IIa, IIb, IIIa-IIIi possessed moderate HDAC inhibitory activity.

[Design of multiple targeted drugs].

Drugs designed to act on individual molecular targets usually can not combat multigenic diseases such as cancer, or diseases that affect multiple tissues or cell types such as diabetes. Increasingly, it is being recognised that a balanced modulation of several targets can provide a superior therapeutic effect and side effect profile compared to the action of a selective ligand. The multi-target drugs which impact multiple targets simultaneously are better at controlling complex disease systems and are less prone to drug resistance. Here, we compare the disadvantage of the selective ligands and the predominance of multi-targets drugs in detail and introduce the approaches of designing multiple ligands and the procedure of optimization particularly. A key challenge in the design of multiple ligands is attaining a balanced activity at each target of interest while simultaneously achieving a wider selectivity and a suitable pharmacokinetic profile. On this point, the multi-target approach represents a new challenge for medicinal chemists, pharmacologists, toxicologists, and biochemists.

[Comparative pharmacophore analysis of dual dopamine D2/5-HT(2A) receptor antagonists].

Dual dopamine D2/5-HT2A receptor antagonists have potent activity and are referred to atypical antipsychotics due to their lower propensity to elicit EPS and their moderate efficacy toward negative symptoms. However, an on-going challenge in developing atypical antipsychotics drugs is to maintain the favorable profiles and avoid of cardiovascular risk. In this paper, comparative pharmacophore analysis of dual dopamine D2/5-HT2A receptor antagonists, hERG K+ channel blockers, and alA adrenoceptor antagonists is carried out, and the results could give some insight into multi-target drug design.

[Design, synthesis and activity evaluation of novel matrix metalloproteinases inhibitors based on the structure of enzyme].

A novel inhibitor series for matrix metalloproteinases (MMPs) were designed and synthesized. Using succinate and malonate as zinc binding groups and long hydrophobic substituents to bind with S1' pockets, the compounds showed micromolar inhibition and selectivity for MMP-2 over others. And we found a better activity compound. It is a chance to find a better precursor of MMP-2 inhibitors with activity and bioavailability by further optimization of compounds.

[Using distance comparison method to build pharmacophore model of epidermal growth factor receptor inhibitors].

OBJECTIVE: To build 3D-pharmacophore model of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors using distance comparisons method and design novel EGFR inhibitors. METHODS: Thirteen typical EGFR inhibitors were selected, and their biologically active conformations were obtained by using DOCK5.0 program, then 3D-pharmacophore model of EGFR inhibitors was built using distance comparisons method. RESULTS: Validation of the 3D-pharmacophore model was carried out and novel structures with potential inhibitory activity were selected by means of 3D-searching and docking method. CONCLUSION: This method can improve hit rate of lead compounds discovery and can be used to design novel EGFR inhibitors.