Design and Synthesis of a Novel PLK1 Inhibitor Scaffold Using a Hybridized 3D-QSAR Model

Polo-like kinase 1 (PLK1) plays an important role in cell cycle progression and proliferation in cancer cells. PLK1 also contributes to anticancer drug resistance and is a valuable target in anticancer therapeutics. To identify additional effective PLK1 inhibitors, we performed QSAR studies of two series of known PLK1 inhibitors and proposed a new structure based on a hybridized 3D-QSAR model. Given the hybridized 3D-QSAR models, we designed and synthesized 4-benzyloxy-1-(2-arylaminopyridin-4-yl)-1H-pyrazole-3-carboxamides, and we inspected its inhibitory activities to identify novel PLK1 inhibitors with decent potency and selectivity.     

Antioxidant activity and antiproliferative action of methanol extracts of 4 different colored bell peppers (Capsicum annuum l.)

Methanol extracts of 4 different colored (red, orange, yellow, and green) bell peppers (Capsicum annuum L.) were examined to (1) determine the total phenolic content (TPC), (2) compare the antioxidant activities, (3) assess the protective effects of extracts on H₂O₂-induced and 4-hydroxy-2-nonenal (HNE)-induced DNA damage using the Comet assay, and (4) examine the antiproliferative action of their extracts on HT-29 cells. Red and orange bell peppers had significantly higher levels of TPC than yellow or green bell peppers. Orange bell pepper exhibited the highest level of radical scavenging activity and total antioxidant activity, while green bell pepper exhibited the highest superoxide dismutase-like activity. These results suggest that the difference in antioxidant activities may depend on the kinds of antioxidant compounds related to the color of the pepper. It was found a significant negative correlation between TPC and radical scavenging activity inhibiting capacity (IC)₅₀, and a significant positive corretation between TPC and total antioxidant activity. All extracts of bell pepper inhibited H₂O₂-induced and 4-hydroxy-2-nonenal-induced DNA damage in human leukocytes and showed potential toxicity on HT-29 cells. These findings suggest that the 4 different colored bell peppers may be useful as antioxidants and cancer prevention in food.     

Effect of temperature and ph on interconversion between fructose and mannose catalyzed by Thermotoga neapolitana mannose-6-phosphate isomerase

The purpose of this study was to evaluate the antioxidant activity of Maillard reaction products (MRPs) in both aqueous and ethanolic glucose-glycine oligomer solutions. The reduction in pH was higher in aqueous MRP solutions than ethanolic MRP solutions. The samples in ethanolic MRP solutions had greater Abs_{294 nm} and Abs_{420 nm} than those in aqueous MRP solutions. The ferrous ion chelating activity of all MRP samples was much higher than the cupric ion chelating ability in both aqueous and ethanolic solutions. The antioxidant activity in ethanolic MRP solutions was higher than that in aqueous MRP solutions. MRPs derived from the diglycine were found to be effective antioxidants in different in vitro assays with regard to the ABTS and DPPH radical scavenging activities, and ferric reducing/antioxidant power.     

Discovery of a Potent and Selective JNK3 Inhibitor with Neuroprotective Effect Against Amyloid β-Induced Neurotoxicity in Primary Rat Neurons

As members of the MAPK family, c-Jun-N-terminal kinases (JNKs) regulate the biological processes of apoptosis. In particular, the isoform JNK3 is expressed explicitly in the brain at high levels and is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In this study, we prepared a series of five 6-dihydroxy-1H-benzo[d]imidazoles as JNK3 inhibitors and found them have potential as neuroprotective agents. Following a previous lead scaffold, benzimidazole moiety was modified with various aryl groups and hydroxylation, and the resulting compounds exhibited JNK3 inhibitory activity with improved potency and selectivity. Out of 37 analogues synthesized, (S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin -6-yl)-5,6-dihydroxy-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino) piperidin-1-yl)methanone (35b) demonstrated the highest JNK3 inhibition (IC₅₀ = 9.7 nM), as well as neuroprotective effects against Aβ-induced neuronal cell death. As a protein kinase inhibitor, it also showed excellent selectivity over other protein kinases including isoforms JNK1 (>1000 fold) and JNK2 (−10 fold).     

Naegleria fowleri Cathepsin B Induces a Pro-Inflammatory Immune Response in BV-2 Microglial Cells via NF-κB and AP-1 Dependent-MAPK Signaling Pathway

Naegleria fowleri is a ubiquitous protozoa parasite that can cause primary amoebic meningoencephalitis (PAM), a fatal brain infection in humans. Cathepsin Bs of N. fowleri (NfCBs) are multifamily enzymes. Although their pathogenic mechanism in PAM is not clearly understood yet, NfCBs have been proposed as pathogenic factors involved in the pathogenicity of amoeba. In this study, the immune response of BV-2 microglial cells induced by NfCB was analyzed. Recombinant NfCB (rNfCB) evoked enhanced expressions of TLR-2, TLR-4, and MyD88 in BV-2 microglial cells. This enzyme also induced an elevated production of several pro-inflammatory cytokines such as TNF-α, IL-1α, IL-1β, and IL-6 and iNOS in cells. The inhibition of mitogen-activated protein kinases (MAPKs), including JNK, p38, and ERK, effectively reduced the production of these pro-inflammatory cytokines. The rNfCB-induced production of pro-inflammatory cytokines in BV-2 microglial cells was suppressed by inhibiting NF-kB and AP-1. Phosphorylation and nuclear translocation of p65 in cells were also enhanced by rNfCB. These results suggest that NfCB can induce a pro-inflammatory immune response in BV-2 microglial cells via the NF-κB- and AP-1-dependent MAPK signaling pathways. Such a NfCB-induced pro-inflammatory immune response in BV-2 microglial cells might contribute to the pathogenesis of PAM caused by amoeba, by exacerbating deleterious immune responses and tissue damages in N. fowleri-infected foci of the brain.     

Generation of Non-Nucleotide CD73 Inhibitors Using a Molecular Docking and 3D-QSAR Approach

Radiotherapy and chemotherapy are conventional cancer treatments. Around 60% of all patients who are diagnosed with cancer receive radio- or chemotherapy in combination with surgery during their disease. Only a few patients respond to the blockage of immune checkpoints alone, or in combination therapy, because their tumours might not be immunogenic. Under these circumstances, an increasing level of extracellular adenosine via the activation of ecto-5’-nucleotidase (CD73) and consequent adenosine receptor signalling is a typical mechanism that tumours use to evade immune surveillance. CD73 is responsible for the conversion of adenosine monophosphate to adenosine. CD73 is overexpressed in various tumour types. Hence, targetting CD73’s signalling is important for the reversal of adenosine-facilitated immune suppression. In this study, we selected a potent series of the non-nucleotide small molecule inhibitors of CD73. Molecular docking studies were performed in order to examine the binding mode of the inhibitors inside the active site of CD73 and 3D-QSAR was used to study the structure–activity relationship. The obtained CoMFA (q² = 0.844, ONC = 5, r² = 0.947) and CoMSIA (q² = 0.804, ONC = 4, r² = 0.954) models showed reasonable statistical values. The 3D-QSAR contour map analysis revealed useful structural characteristics that were needed to modify non-nucleotide small molecule inhibitors. We used the structural information from the overall docking and 3D-QSAR results to design new, potent CD73 non-nucleotide inhibitors. The newly designed CD73 inhibitors exhibited higher activity (predicted pIC₅₀) than the most active compound of all of the derivatives that were selected for this study. Further experimental studies are needed in order to validate the new CD73 inhibitors.     

Preparation and properties of emulsifier-/solvent-free slightly crosslinked waterborne polyurethane-acrylic hybrid emulsions for footwear adhesives (III)–effect of trimethylol propane (TMP)/ethylene diamine (EDA) content

Stable emulsions of emulsifier-/solvent-free slightly crosslinked waterborne polyurethane-acrylic hybrids (WPU/AC-Ts) with a fixed acrylic monomer content (20 wt.%) and different trimethylol propane (TMP)/ethylene diamine (EDA) (0/0.20, 0.02/0.17, 0.04/0.14, 0.06/0.11, 0.08/0.08, the number indicated the mole% of TMP/EDA) for footwear adhesive materials were successfully prepared in this study. The as-polymerized hybrid emulsion containing 0.10/0.05 mole% of TMP/EDA content was found to be unstable, indicating that near 0.10/0.05 mole% of TMP/EDA content was beyond the limit value of crosslinkable TMP component for self-emulsifing. This study examined the effect of mole% of TMP/EDA on the stability and viscosity of hybrid emulsions, the tensile properties and dynamic mechanical thermal properties of hybrid film samples, and the adhesive strengths of formulated adhesives for footwear at both dry and wet states. As TMP content increased, the tensile strength/modulus/storage modulus/hardness of WPU/AC-Ts film samples increased, however, their elongation at break and water swelling% decreased significantly. The adhesive strength (peel strength) of formulated adhesives was found to be dependent upon the degree of drying, but almost not upon the TMP content in WPU/AC-Ts. The adhesive strength of footwear (EVA/leather) dried at room temperature for 24 h was higher than that of footwear dried for 30 min. However, the adhesive strength at wet state increased significantly with increasing TMP content. The optimum TMP/EDA contents were found to be 0.06/0.11 and 0.08/0.08 mole% to achieve the desired high performance adhesive properties such as high strength in wet state.