The structure-based design of 1, 2, 3, 4-tetrahydroisoquinoline derivatives as selective DDR1 inhibitors is reported. One of the representative compounds, 6j, binds to DDR1 with a Kd value of 4.7 nM and suppresses its kinase activity with an IC50 value of 9.4 nM, but it is significantly less potent for a panel of 400 nonmutated kinases. 6j also demonstrated reasonable pharmacokinetic properties and a promising oral therapeutic effect in a bleomycin-induced mouse pulmonary fibrosis model.
Amino sugars and D-amino acid enantiomers are major components of bacterial and fungal cell walls (i.e. peptidoglycan and chitin) and are often used as biomarkers of microbial residue turnover in soils. However, little is known about the in situ decomposition rates of microbial cell wall residues and how soil physicochemical properties affect this process. In this study, we investigated the in situ gross production and consumption rates of free amino sugars (glucosamine and muramic acid) and amino acids (meso-diaminopimelic acid, l-alanine, and d-alanine) by a novel isotope pool dilution assay using 15N-labeled amino compounds. Soils were obtained from six sites differing in land management (cropland, pasture, and forest) and bedrock (silicate and limestone) and incubated at three temperatures (5, 15, and 25 °C). Free glucosamine released during the decomposition of peptidoglycan and chitin contributed significantly to the extractable soil organic nitrogen pool. Gross production and consumption rates of glucosamine were higher than those of individual amino acids, i.e. L- and D-alanine. Muramic acid had a longer mean residence time (68 h compared to 2.7 h for glucosamine, L- and D-alanine) and made a negligible contribution to soil organic nitrogen fluxes, indicating that free muramic acid was not a major decomposition product of peptidoglycan in soils. Meso-diaminopimelic acid and D-alanine exhibited comparable gross production and consumption rates with L-alanine. These amino acids can be used as indicators to estimate the decomposition of peptidoglycan from bacterial cell wall residues. We found that chitin decomposition was greater in silicate soils, while peptidoglycan decomposition dominated in limestone soils. Glucosamine production rates were not correlated with soil total amino sugars, microbial community structure, or hydrolytic enzyme activities, but were highest in soils with low pH and high sand content, indicating that soil texture and soil pH may strongly influence the decomposition of amino sugar polymers. In contrast, mDAP, L- and D-alanine gross production and consumption rates were positively correlated with soil pH and clay content, due to greater depolymerization of peptidoglycan stem peptides in limestone soils. This isotope pool dilution approach strongly improves our understanding of the mechanisms and environmental controls on microbial cell wall decomposition in soils.
Schwertmannite-mediated removal of arsenic from contaminated water has attracted increasing attention. However, schwertmannite chemical synthesis behavior under different H2O2 supply rates for ferrous ions oxidation is unclear. This study investigated pH, ferrous ions oxidation efficiency, and total iron precipitation efficiency during schwertmannite synthesis by adding H2O2 into FeSO4·7H2O solution at different supply rates. Specific surface area and arsenic (III) removal capacity of schwertmannite have also been studied. Results showed that pH decreased from ~3.48 to ~1.96, ~2.06, ~2.12, ~2.14, or ~2.17 after 60 h reaction when the ferrous ions solution received the following corresponding amounts of H2O2: 1.80 mL at 2 h (treatment 1); 0.90 mL at 2 h and 14 h (treatment 2); 0.60 mL at 2, 14, and 26 h (treatment 3); 0.45 mL at 2, 14, 26, and 38 h (treatment 4), or 0.36 mL at 2, 14, 26, 38, and 50 h (treatment 5). Slow H2O2 supply significantly inhibited the total iron precipitation efficiency but improved the specific surface area or arsenic (III) removal capacity of schwertmannite. For the initial 50.0 μg/L arsenic (III)-contaminated water under pH ~7.0 and using 0.25 g/L schwertmannite as an adsorbent, the total iron precipitation efficiency, specific surface area of the harvested schwertmannite, and schwertmannite arsenic(III) removal efficiency were 29.3%, 2.06 m2/g, and 81.1%, respectively, in treatment 1. However, the above parameters correspondingly changed to 17.3%, 16.30 m2/g, and 96.5%, respectively, in treatment 5.
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