Drug design efforts in the emerging 2-aminothiazole-4-carboxamide class of CHK1 inhibitors have uncovered specific combinations of key substructures within the molecule; resulting in significant ...improvements in cell-based activity while retaining a greater than one hundred-fold selectivity against CDK2. The X-ray crystal structure of a complex between compound 39 and the CHK1 protein detailing a ‘U-shaped’ topology and key interactions with the protein surface at the ATP site is also reported.
Antibiotic resistant hospital acquired infections are on the rise, creating an urgent need for novel bactericidal drugs. Enzymes involved in lipopolysaccharide (LPS) biosynthesis are attractive ...antibacterial targets since LPS is the major structural component of the outer membrane of Gram-negative bacteria. Lipid A is an essential hydrophobic anchor of LPS and the first committed step in lipid A biosynthesis is catalyzed by a unique zinc dependent metalloamidase, UDP-3-
O-(
R-3-hydroxymyristoyl)-
N-acetylglucosamine deacetylase (LpxC). LpxC is an attractive Gram-negative only target that has been chemically validated by potent bactericidal hydroxamate inhibitors that work by coordination of the enzyme’s catalytic zinc ion. An exploratory chemistry effort focused on expanding the SAR around hydroxamic acid zinc-binding ‘warheads’ lead to the identification of novel compounds with enzyme potency and antibacterial activity similar to CHIR-090.
A novel series of hydantoin TACE inhibitors is disclosed. The initial design and SAR optimization of the series, as well as accompanying X-ray structural and modeling considerations, are described.
...We disclose inhibitors of TNF-α converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.
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•A rapid and single step process was developed for purification of l-asparaginase.•The optimum temperature and pH of enzyme was determined as 40°C and 8.5.•The enzyme showed good ...scavenging activity and the total antioxidant capacity.•The purified TPP l-asparaginase showed anti-proliferative activity in cancer cell lines.•The IC50 for (Hela, A549, and KB) were evaluated.
In this study, three phase partitioning (TPP) as an efficient bioseparation method, was explored for the first time to purify stable uncontaminated l-asparaginase from Capsicum annuum L., and its antitumor activity was evaluated. With the optimized system parameters, the enzyme was purified to homogeneity and having 6.83-fold with 567.4% recovery of its activity. The optimum pH and temperature of the TPP purified enzyme were determined as 8.5 and 40°C, respectively. The stability studies of the enzyme activity envisaged that the enzyme is stable up to 45°C and retained its activity over a wide range of pH (5.0–9.0). The purified enzyme showed good scavenging activity, and its total antioxidant capacity was found to be 88.58μM ascorbic acid equivalent. The antiproliferative activity of the purified l-asparaginase was also investigated against the three human cancerous cell lines.
Objectives
This report highlights phytoconstituents present in Cissus quadrangularis (CQ) extract and examines biphasic (proliferative and anti‐proliferative) effects of its extract on bone cell ...proliferation, differentiation, mineralization, ROS generation, cell cycle progression and Runx2 gene expression in primary rat osteoblasts.
Materials and methods
Phytoconstituents were identified using gas chromatography–mass spectroscopy (GC‐MS). Osteoblasts were exposed to different concentrations (10–100 μg/ml) of CQ extract and cell proliferation and cell differentiation were investigated at different periods of time. Subsequently, intracellular ROS intensity, apoptosis and matrix mineralization of osteoblasts were evaluated. We performed flow cytometry for DNA content and real‐time PCR for Runx2 gene expression analysis.
Results
CQ extract's approximately 40 bioactive compounds of fatty acids, hydrocarbons, vitamins and steroidal derivatives were identified. Osteoblasts exposed to varying concentrations of extract exhibited biphasic variation in cell proliferation and differentiation as a function of dose and time. Moreover, lower concentrations (10–50 μg/ml) of extract slightly reduced ROS intensity, although they enhanced matrix mineralization, DNA content in S phase of the cell cycle, and levels of Runx2 expression. However, higher concentrations (75–100 μg/ml) considerably induced the ROS intensity and nuclear condensation in osteoblasts, while it reduced mineralization level, proportion of cells in S phase and Runx2 level of the osteogenic gene.
Conclusions
These findings suggest that CQ extract revealed concentration‐dependent biphasic effects, which would contribute notably to future assessment of pre‐clinical efficacy and safety studies.
A series of substituted imidazo1,2-
apyrazin-8-amines were discovered as novel breast tumor kinase (Brk)/protein tyrosine kinase 6 (PTK6) inhibitors. Tool compounds with low-nanomolar Brk inhibition ...activity, high selectivity towards other kinases and desirable DMPK properties were achieved to enable the exploration of Brk as an oncology target.
Novel high-entropy alloy compositions having the same valence electron concentration (Al
0.5
FeCrNiTi
0.25 –
x
Si
x
) were developed with molar ratio
x
= 0.09, 0.125, and 0.25. Microstructure and ...corrosion behaviour were investigated using X-ray diffraction analysis, scanning electron microscopy, and electrochemical studies in 3.5 wt % NaCl solution at room temperature. Increasing the molar ratio
x
in Al
0.5
FeCrNiTi
0.25 –
x
Si
x
alloys stabilised face-centred cubic phase. Among the studied compositions, Al
0.5
FeCrNiTi
0.12
Si
0.12
offered good corrosion resistance exhibiting the least corrosion current density (
I
corr
), the highest charge transfer resistance (
R
ct
) with double layer capacitive value (
C
dl
), and the lowest Warburg coefficient (σ).
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We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency ...(Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series.
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