Yuanxin Tian

Pyranocoumarins isolated from Peucedanum praeruptorum Dunn suppress lipopolysaccharide-induced inflammatory response in murine macrophages through inhibition of NF-κB and STAT3 activation.

Praeruptorin C, D, and E (PC, PD, and PE) are three pyranocoumarins isolated from the dried root of Peucedanum praeruptorum Dunn of Umbelliferae. In the present study, we investigated the anti-inflammatory effect of these compounds in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Pyranocoumarins significantly inhibited LPS-induced production of nitric oxide, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). The mRNA and protein expressions of inducible nitric oxide synthase, IL-6, and TNF-α were also suppressed by these compounds. Both PD and PE exhibited greater anti-inflammatory activities than PC. Further study showed that pyranocoumarins suppressed the cytoplasmic loss of inhibitor κB-α protein and inhibited the translocation of NF-κB from cytoplasm to nucleus. In addition, pyranocoumarins suppressed LPS-induced STAT3 tyrosine phosphorylation. Taken together, the results suggest that pyranocoumarins may exert anti-inflammatory effects in LPS-stimulated RAW 264.7 macrophages through the inhibition of NF-κB and STAT3 activation.

Indazoles as potential c-met inhibitors: Design, synthesis and molecular docking studies

Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of indazoles were designed, synthesized and evaluated as novel c-Met inhibitors. The results showed that the majority of the compounds exhibited significant inhibition on c-Met and compound 4d showed highest activity against c-Met with IC50 value of 0.17 μM in TR-FRET-based assay and IC50 value of 5.45 μM in cell-based assay as compared to other tested compounds. Molecular docking experiments verified the results and explained the molecular mechanism of pretty activities to c-Met.

Praeruptorin D and E attenuate lipopolysaccharide/hydrochloric acid induced acute lung injury in mice.

Acute lung injury is a life-threatening syndrome characterized by overwhelming lung inflammation and increased microvascular permeability, which causes a high mortality rate worldwide. The dry root of Peucedanum praeruptorum Dunn has been long used to treat respiratory diseases in China. In the present study, Praeruptorin A, C, D and E (PA, PC, PD and PE), four pyranocoumarins extracted from this herb, have been investigated for the pharmacological effects in experimental lung injury mouse models. In lipopolysaccharide (LPS) challenged mice, PA and PC did not show protective effect against lung injury at the dose of 80 mg/kg. However, PD and PE significantly inhibited the infiltration of activated polymorphonuclear leukocytes (PMNs) and decreased the levels of TNF-α and IL-6 in bronchoalveolar lavage fluid at the same dose. There was no statistically significant difference between PD and PE group. Further study demonstrated that PD and PE suppressed protein extravasations in bronchoalveolar lavage fluid, attenuated myeloperoxidase (MPO) activity and the pathological changes in the lung. Both PD and PE suppressed LPS induced Nuclear Factor-kappa B (NF-κB) pathway activation in the lung by decreasing the cytoplasmic loss of Inhibitor κB-α (IκB-α) protein and inhibiting the translocation of p65 from cytoplasm to nucleus. We also extended our study to acid-induced acute lung injury and found that these two compounds protected mice from hydrochloric acid (HCl)-induced lung injury by inhibiting PMNs influx, IL-6 release and protein exudation. Taken together, these results suggested that PD and PE might be useful in the therapy of lung injury.

Molecular dynamics simulation and free energy calculation studies of kinase inhibitors binding to active and inactive conformations of VEGFR-2

Vascular endothelial growth factors receptor-2 (VEGFR-2) inhibitors have been proved as very effective anticancer agents. Structurally similar ligands 1 and 2 show almost the same inhibitory activities against VEGFR-2, but they bind to the enzyme in distinct binding mode. Ligand 1 targets DFG-in active conformation of VEGFR-2, known as Type I inhibitor. On the other hand, ligand 2 targets DFG-out inactive conformation of VEGFR-2, known as Type II inhibitor or allosteric kinase inhibitor. Ligand 2 shows high inhibitory activity, while the compound 3, a close analog of 2 with the cyclopropylamide replaced by tert-butylamide, exhibits drastically diminished potency. In this work, molecular dynamics simulations and free energy calculations were performed on inhibitors 1-3 binding to active and inactive conformation of VEGFR-2. Molecular dynamics simulations find that the active conformation binding to Type I inhibitor 1 appears more flexible when compared to the unbound form. In contrast, binding of Type II inhibitor 2 to the inactive conformation helps to stabilize the inactive conformation of the protein. Binding free energy calculations verify that inhibitors 1 and 2 have almost the same activities against VEGFR-2, and that ligand 1 binds to and stabilizes the DFG-in conformation of VEGFR-2, which is in agree with the experimental observation. Molecular dynamics simulations and binding free energy calculations of 3 binding to VEGFR-2 can give a good explanation of the drastically diminished potency. Free energy analysis revealed that van der Waals interactions provided the substantial driving force for the binding process. The important hydrophobic property of the terminal 4-Cl phenyl was required to be Type II inhibitors. Furthermore, per-residue free energy decomposition analysis revealed that the most favorable contribution came from Leu840, Val848, Ala866, Lys868, Leu889, Val899, Thr916, Phe918, Cys919, Leu1035, Cys1045, Asp1046, and Phe1047. These results are expected to be useful for future rational design of novel potent VEGFR-2 inhibitors.

Myrislignan attenuates lipopolysaccharide-induced inflammation reaction in murine macrophage cells through inhibition of NF-κB signalling pathway activation.

Myrislignan is a new kind of lignan isolated from Myristica fragrans Houtt. Its antiinflammatory effects have not yet been reported. In the present study, the antiinflammatory effects and the underlying mechanisms of myrislignan in lipopolysaccharide (LPS)‐induced inflammation in murine RAW 264.7 macrophage cells were investigated. Myrislignan significantly inhibited LPS‐induced production of nitric oxide (NO) in a dose‐dependent manner. It inhibited mRNA expression and release of interleukin‐6 (IL‐6) and tumour necrosis factor‐α (TNF‐α). This compound significantly inhibited mRNA and protein expressions of inducible NO synthase (iNOS) and cyclooxygenase‐2 (COX‐2) dose‐dependently in LPS‐stimulated macrophage cells. Further study showed that myrislignan decreased the cytoplasmic loss of inhibitor κB‐α (IκB‐α) protein and the translocation of NF‐κB from cytoplasm to the nucleus. Our results suggest that myrislignan may exert its antiinflammatory effects in LPS‐stimulated macrophages cells by inhibiting the NF‐κB signalling pathway activation. Copyright

Natural tanshinone-like heterocyclic-fused ortho-quinones from regioselective Diels–Alder reaction: Synthesis and cytotoxicity evaluation

A series of new natural tanshinone-like oxoheterocyclic-fused ortho-quinone derivatives were synthesized from readily available benzofuranol and N-substituted dienes via IBX oxidation-cycloaddition-aromatization procedure. The regiospecific Diels-Alder cycloaddition reactions of N-dienes were achieved efficiently with a variety of dienophiles. It is found that the amide moiety in the molecular could be preserved or eliminated by control of the aromatization conditions. Selected oxoheterocyclic-fused ortho-quinones as well as several thioheterocyclic-fused ortho-quinones we obtained before were evaluated for their cytotoxicities on different cancer cell lines and the Structure-Activity Relationship (SAR) was discussed.

Design Some New Type-I c-met Inhibitors Based on Molecular Docking and Topomer CoMFA Research.

In this paper, a specific design strategy targeting c‐met kinase was reported based on docking modeling and topomer comparative molecular field analysis (Topomer CoMFA). A novel U‐shape conformation which is distinct from the literature was demonstrated by molecular docking among 68 U‐shape c‐met inhibitors. According to the docking results, two Topomer CoMFA models with high predictive ability were established based on the two fragment rule. The results from both docking and topomer CoMFA showed that the π–π stacking interaction with Tyr1230 and the hydrogen bond with hinge region play an important role in inhibitory activity. Furthermore, the flexible linker and the adjacent solvent group would be favorable to stabilize the conformation and to enhance the two interactions mentioned above. Based on our patent, 14 new compounds were designed by our design strategy. The binding mode exhibited as expected and their activities were predicted by topomer CoMFA model. The preliminary biological tests showed most of them have potent activity to c‐met kinase. Our study would provide guidelines to design some new U‐shaped c‐met inhibitors with new scaffolds and optimize the current molecules.

Understand the acquired resistance of RTK inhibitors by computational receptor tyrosine kinases network

Receptor Tyrosine Kinase inhibitors are the most popular anti-cancer drug types. But the resistance is the major challenge. Our study on the network with 1334 proteins and their 2623 interactions which retrieved from 52 RTKs indicated that most RTKs proteins were the key controllers of the protein-protein network. Direct or indirect interactions with RTKs (shortest path of 2) were often associated with resistance to RTKs inhibitors in the literature. The results based on the KEGG pathway analysis demonstrated the Rap1 signal pathway would also contribute to the resistance of RTKs inhibitor as well as the known Ras pathway and PI3K/Akt pathway. The pathways can crosstalk within and between complex signals transduction networks, then activate the upstream or downstream pathway, and/or activate the other oncogenes, which lead to the acquired resistance. Our results gave a systematically global view to understand the drug resistance and provided a clue to how to combine the different targets or pathways for synergy of targeted RTKs inhibitors.

7,9-Dimethyl-3-phenylnaphtho[1,2-b]furan-4,5-dione

Key Laboratory of Food Quality and Safety of the Education Department of Guangdong Province, Food Quality and Safety Research Institute, South China Agricultural University, Guangzhou, 510642, People’s Republic of China, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, People’s Republic of China, and School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510080, People’s Republic of China Correspondence e-mail: jianlonchem@yahoo.com.cn