Identification of a novel histone H2A mono-ubiquitination-inhibiting cell-active small molecule.

Histone H2A mono-ubiquitination plays important roles in epigenetic gene expression and is also involved in tumorigenesis. Small molecules controlling H2A ubiquitination are of interest as potential chemical tools and anticancer drugs. To identify novel small molecule inhibitors of H2A ubiquitination, we synthesized and evaluated several compounds designed based on PRT4165 (1), which is a reported histone ubiquitin ligase RING1A inhibitor. We found that compound 11b strongly inhibited the viability and reduced histone H2A mono-ubiquitination in human osteosarcoma U2OS cells. Therefore, compound 11b is a promising lead compound for the development of H2A histone ubiquitination-inhibiting small molecules.

Identification of Novel Histone Deacetylase 6-Selective Inhibitors Bearing 3,3,3-Trifluorolactic Amide (TFLAM) Motif as a Zinc Binding Group.

Pharmacological inhibition of histone deacetylase 6 (HDAC6) is an effective therapeutic strategy for cancer and immunological diseases. Most of the previously reported HDAC6 inhibitors have a hydroxamate group as a zinc binding group (ZBG), which coordinates to the catalytic zinc ion of HDAC6. The hydroxamate group is liable to metabolically generate mutagenetic hydroxylamine; therefore, non-hydroxamate HDAC6 inhibitors would be advantageous. In this study, to identify novel non-hydroxamate HDAC6-selective inhibitors, screening of a chemical library and the subsequent structural optimization were performed, which led to the identification of HDAC6-selective inhibitors with 3,3,3-trifluorolactic amide (TFLAM) as a novel ZBG. The identified inhibitor showed potent and selective HDAC6-inhibitory activity in cells and induced regulatory T (Treg) cell differentiation.

Gradient-Modified HfC-SiC Mixed Bi-Interlayers Synthesized under Different TMS Flow Rate Increment for Depositing Diamond Coating onto WC-Co Substrate.

To deposit well-adhered diamond coating, gradient-modified hafnium carbide-silicon carbide (HfC-SiC) mixed bi-interlayers were prepared on cemented carbides (WC-Co) by plasma surface metallurgy technique under the different tetramethylsiline (TMS) flow rate increment. The effects of the TMS flow rate increment on the composition, microstructure, adhesion, and hardness of the bi-interlayers were investigated. Then, the well-adhered bi-interlayer was chosen for the deposition of the diamond coating. It was found that the HfC-SiC mixed bi-interlayers consisted of a diffusion-modified HfC-riched inner layer and a SiC-riched outer layer. The TMS flow rate increment played a key role in tailoring the surface morphology, thickness, and interface character of the bi-interlayer. The dense nanocrystalline diamond coating was formed on the optimized bi-interlayer at the increment of 0.20 sccm/2 min. The diamond coating showed excellent adhesion, which was benefited from the cobalt (Co) diffusion inhibition, gradient composition distribution, and mechanical interlocking.

Preparation, Microstructure, Mechanical Properties and Biocompatibility of Ta-Coated 3Y-TZP Ceramic Deposited by a Plasma Surface Alloying Technique.

A Ta coating has been successfully fabricated on the surface of zirconia polycrystals ceramic (3 mol% yttria, 3Y-TZP) by a plasma surface alloying technique. The X-ray diffraction (XRD) and scanning electron microscopy (SEM) results showed that a α-Ta coating with a continuous and compact surface morphology which consisted of a deposited layer with a thickness of 390 nm and a diffusion layer with a thickness of 200 nm covered the 3Y-TZP. Due to the effect of inhabitation the t→m transformation by the deposited Ta coating, the biaxial flexural strength caused by the phase transformation during hydrothermal aging is reduced e.g. p < 0.05 after 20 h and/or 100 h. In addition, the Ta coating shows non-cytotoxicity and improved proliferation ability of osteoblasts.

Synthesis and Evaluation of the Anticonvulsant Activities of 4-(2-(Alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones.

In this study, a novel series of 4-(2-(alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones (4a-m) was designed and synthesized. The anticonvulsant activities of these compounds were evaluated by using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. The neurotoxicity of these compounds was evaluated using the rotarod neurotoxicity test. The majority of compounds showed anti-MES activities at 100 or 300 mg/kg. Compound 4g was considered to be the most promising, based on its potency against MES- and PTZ-induced seizures with ED50 values of 23.7 and 18.9 mg/kg, respectively. The TD50 value of 4g was 284.0 mg/kg, which resulted in a higher protective index (PI = TD50/ED50) value than that of carbamazepine and valproate. In an ELISA test, compound 4g significantly increased the γ-aminobutyric acid (GABA) content in mouse brain. In addition, pretreatment with thiosemicarbazide (an inhibitor of the GABA synthesizing enzyme) significantly decreased the activity of 4g in the MES model, which suggests that the mechanism through which compound 4g elicits its anticonvulsive action is at least in part through increasing the GABA level in the brain.