Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor

In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2H-benzo[d]imidazole-2-one substructure present in {"type":"entrez-nucleotide","attrs":{"text":"HS203873","term_id":"313347069"}}HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP. The selected compounds were evaluated for their ability to reduce the ATPase activity of human recombinant NLRP3 using a newly developed assay. From this screening, compounds 9, 13 and 18, able to concentration-dependently inhibit IL-1β release in LPS/ATP-stimulated human macrophages, emerged as the most promising NLRP3 inhibitors of the series. Computational simulations were applied for building the first complete model of the NLRP3 inactive state and for identifying possible binding sites available to the tested compounds. The analyses led us to suggest a mechanism of protein–ligand binding that might explain the activity of the compounds.     

5-Formylhonokiol exerts anti-angiogenesis activity via inactivating the ERK signaling pathway

Our previous report has demonstrated that 5-formylhonokiol (FH), a derivative of honokiol (HK), exerts more potent anti-proliferative activities than honokiol in several tumor cell lines. In present study, we first explored the antiangiogenic activities of 5-formylhonokiol on proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) for the first time in vitro. Then we investigated the in vivo antiangiogenic effect of 5-formylhonokiol on zebrafish angiogenesis model. In order to clarify the underlying molecular mechanism of 5-formylhonokiol, we investigated the signaling pathway involved in controlling the angiogenesis process by western blotting assay. Wound-healing results showed that 5-formylhonokiol significantly and dose-dependently inhibited migration of cultured human umbilical vein enthothelial cells. The invasiveness of HUVEC cells was also effectively suppressed at a low concentration of 5-formylhonokiol in the transwell assay. Further F-actin imaging revealed that inhibitory effect of 5-formylhonokiol on invasion may partly contribute to the disruption of assembling stress fiber. Tube formation assay, which is associated with endothelial cells migration, further confirmed the anti-angiogenesis effect of 5-formylhonokiol. In in vivo zebrafish angiogenesis model, we found that 5-formylhonokiol dose-dependently inhibited angiogenesis. Furthermore, western blotting showed that 5-formylhonokiol significantly down-regulated extracellular signal-regulated kinase (ERK) expression and inhibited the phosphorylation of ERK but not affecting the total protein kinase B (Akt) expression and related phosphorylation, suggesting that 5-formylhonokiol might exert anti-angiogenesis capacity via down-regulation of the ERK signal pathway. Taken together, these data suggested that 5-formylhonokiol might be a viable drug candidate in antiangiogenesis and anticancer therapies.     

Synthesis of 6- and 7-propargyloxy derivatives of 4-(3-fluoroanilino)-quinazoline

The preparation of the novel isomeric 6- and 7-propargyloxy derivatives of 4-(3-fluoroanilino)-quinazoline was achieved using a six-step process. An alternate method to the 7-propargyloxy derivative and analogous 7-propargyloxy containing compounds is also described.     

Ocadaic acid treatment causes tyrosine phosphorylation of caveolin-2 and induces internalization of caveolae in rat peritoneal macrophages

In this paper, we provide evidences that protein phosphatases could regulate the internalization cycle of caveolae in rat peritoneal cells. Ocadaic acid (OA)—a serine/threonine phosphatase inhibitor—was used in various concentrations (4 and 100 nM) to study the internalization of horseradish peroxidase (HRP) in resident and elicited macrophages. We have found that OA in both concentrations has significantly decreased HRP uptake in resident and elicited cells. The results of our morphometrical analysis showed that in OA-treated cells, the number of surface-connected caveolae has been dramatically decreased. Simultaneously large, endosome-like vacuoles containing small vesicles appeared in the cytoplasm. The membrane of these small vesicles was labeled with anti-caveolin-1 antibody. Immunoprecipitation and Western blot analysis revealed that in OA-treated cells a 29 kDa protein identified as caveolin-2 in macrophages was phosphorylated on tyrosine residues. These data support the idea that there is a close correlation between the phosphorylation of caveolin-2 and endocytosis of caveolae: the tyrosine phosphorylation of this 29 kDa protein can drive caveolae to pinch off from the plasma membrane and causes accumulation of caveolae in a multivesicular body-like cellular compartment, which was never found to contain lysosomal enzymes. As a result of OA treatment caveolin-2 remains phosphorylated and the phosphorylation of these protein might inhibit the recycling of caveolae.     

Molecular modelling studies on cinnoline-based BTK inhibitors using docking and structure-based 3D-QSAR

ABSTRACT

BTK inhibitors have been proved as an effective target for B-cell malignancies. Ibrutinib is the most advanced irreversible BTK inhibitor for treating mantle cell lymphoma/chronic lymphocytic leukaemia but with existing drug resistance and adverse effects. To design novel effective and safety reversible BTK inhibitors, 115 newly cinnoline analogues were selected to perform molecular docking and 3D-QSAR study because of the main scaffold similarity to Ibrutinib. Both established CoMFA and CoMSIA models obtained high predictive and satisfactory value. CoMFA/CoMSIA contour maps demonstrated that bulky substitutions are preferred at R₁ and R₃ positions, and introducing hydrophilic and negative electrostatic substitutions at R₁ positions is important for improving BTK inhibitory activities. These results will be useful to provide clues for rationally designing novel and high potency BTK inhibitors.     

Stereoselective strategy for the synthesis of (+)-polyoxamic acid and some polyhydroxylated pyrrolidines

An efficient strategy for the synthesis of dihydroxy chiral amino moiety which can be utilized for the synthesis of polyoxamic acid, 1,4-dideoxy-1,4-imino-d-xylitol, and dihydroxy pyrrolidine by using highly diastereoselective nucleophilic addition on chiral imine has been reported.     

One-Pot,Multicomponent Sequential Synthesis of Benzothiazoloquinazolinones

Benzothiazolo[2,3-b]quinazolin-1-ones have been synthesized by a multicomponent reaction of substituted 2-aminobenzothiazoles with cyclic β-diketone and aromatic aldehydes in the presence of absolute ethanol. The structures of the synthesized benzothiazoloquinazolinones have been characterized by elemental analysis and spectral studies.