Twelve novel hybrids of slowly releasing hydrogen sulfide donor ADT-OH combined with nicotinic acid were synthesized. All of their structures had been confirmed by 1H NMR, 13C NMR and MS spectra. The target compounds were evaluated for their neuroprotective effects on hippocampal neuron HT22 cells against glutamate-induced injury at the concentrations of 1–100 μM with MTT assay, and their toxicity on HT22 cells untreated by glutamine at the concentration of 100 μM. The active compound was further investigated for its effect on ischemic infarct volume by intraperitoneal injection at 3 h after ischemia in mice models of permanent middle cerebral artery occlusion (pMCAO). The results showed that all the compounds significantly protected HT22 cells from glutamate-induced damage at most of the experimental concentrations, and had no or little neurotoxicity on normal HT22 cells at the high concentration. More importantly, compound A6 significantly reduced infarct volume in the pMCAO model. These results suggested that compound A6 may be promising for further evaluation for the intervention of cerebral ischemic injury.

A cascade method that includes nucleophilic aromatic substitution and Smiles rearrangement reaction has been developed. The method shows good functional group tolerance with different electronic properties, providing efficient and practical access to dibenzoxazepinone architecture. Comparison of the products from cascade and step-by-step protocols demonstrates Smiles rearrangement is the pivotal step in the formation of heterocyclic products.

A type of novel α,β-unsaturated cyclohexanone analogous, which designed based on the curcumin core structure, have been discovered as potential EGFR inhibitors. These compounds exhibit potent antiproliferative activity in two human tumor cell lines (Hep G2 and B16-F10). Among them, compounds I3 and I12 displayed the most potent EGFR inhibitory activity (IC50 = 0.43 μM and 1.54 μM, respectively). Molecular docking of I12 into EGFR TK active site was also performed. This inhibitor nicely fitting the active site might well explain its excellent inhibitory activity.A type of novel α,β-unsaturated cyclohexanone analogous, which designed based on the curcumin core structure, have been discovered as potential EGFR inhibitors. These compounds exhibit potent antiproliferative activity in two human tumor cell lines (Hep G2 and B16-F10). Among them, compounds I3 and I12 displayed the most potent EGFR inhibitory activity (IC50 = 0.43 μM and 1.54 μM, respectively). Molecular docking of I12 into EGFR TK active site was also performed. This inhibitor nicely fitting the active site might well explain its excellent inhibitory activity.

•2-(3′,5′-Dimethoxybenzylidene) (DMBC) produces neuroprotection against pMCAO insult.•DMBC directly protects HT22 cell and astrocytes against OGD insult.•DMBC inhibits the ischemia or OGD-induced activation of cathepsin B.•DMBC treatment blocks the ischemia or OGD-induced release of cathepsin B.2-(3′,5′-Dimethoxybenzylidene) cyclopentanone (DMBC) is a novel small-molecule compound synthesized by our group. Here, we found that in rat models of permanent middle cerebral artery occlusion (pMCAO), intraperitoneal injection (ip) of DMBC at 1 h after ischemia reduced infarct volume, improved neurological deficits and increased the protein levels of microtubule-associated protein 2 (MAP 2) and glial fibrillary acid protein (GFAP) in the ischemic cortex. Post-treatment of DMBC still produced neuroprotective effects even when administered at 6 h after ischemia. In the oxygen–glucose deprivation (OGD)-induced astrocytes or HT22 cell injury, DMBC treatment decreased the OGD-induced lactate dehydrogenase (LDH) leakage and increased the GFAP levels in astrocytes. In addition, Annexin-V-Fluos staining analysis revealed that DMBC treatment attenuated both OGD-induced apoptosis and necrosis in astrocytes. Western blotting analysis showed DMBC treatment inhibited the ischemia or OGD-induced increases in active cathepsin B in the ischemic cortex or in astrocytes or HT22 cells. Immunofluorescence analysis demonstrated that DMBC treatment blocked the ischemia or OGD-induced release of cathepsin B from the lysosomes into the cytoplasm in the ischemic cortex or in astrocytes or HT22 cells. Taken together, our results indicate that DMBC can offer neuroprotective effects against cerebral ischemia with an extended therapeutic window and its mechanism might be associated with inhibition of the cathepsin B activation.Download high-res image (97KB)Download full-size image