3024-72-4Relevant articles and documents
Discovery and Mechanism of Action of Small Molecule Inhibitors of Ceramidases**
Arenz, Christoph,Basu, Shibom,Bechara, Cherine,Bossis, Guillaume,Cong, Xiaojing,Del Nero, Elise,Drapeau, Marion,Fontanel, Simon,Gabellier, Ludovic,Golebiowski, Jér?me,Granier, Sebastien,Healey, Robert D.,Hornemann, Thorsten,Jeannot, Sylvain,Karsai, Gergely,Leyrat, Cedric,Maurel, Damien,Saied, Essa M.,Saint-Paul, Julie
supporting information, (2021/12/09)
Sphingolipid metabolism is tightly controlled by enzymes to regulate essential processes in human physiology. The central metabolite is ceramide, a pro-apoptotic lipid catabolized by ceramidase enzymes to produce pro-proliferative sphingosine-1-phosphate. Alkaline ceramidases are transmembrane enzymes that recently attracted attention for drug development in fatty liver diseases. However, due to their hydrophobic nature, no specific small molecule inhibitors have been reported. We present the discovery and mechanism of action of the first drug-like inhibitors of alkaline ceramidase 3 (ACER3). In particular, we chemically engineered novel fluorescent ceramide substrates enabling screening of large compound libraries and characterized enzyme:inhibitor interactions using mass spectrometry and MD simulations. In addition to revealing a new paradigm for inhibition of lipid metabolising enzymes with non-lipidic small molecules, our data lay the ground for targeting ACER3 in drug discovery efforts.
Structure-Activity Study of Nitazoxanide Derivatives as Novel STAT3 Pathway Inhibitors
Lü, Zirui,Li, Xiaona,Li, Kebin,Wang, Cong,Du, Tingting,Huang, Wei,Ji, Ming,Li, Changhong,Xu, Fengrong,Xu, Ping,Niu, Yan
supporting information, p. 696 - 703 (2021/05/04)
We identified nitazoxanide (NTZ) as a moderate STAT3 pathway inhibitor through immunoblot analysis and a cell-based IL-6/JAK/STAT3 pathway activation assay. A series of thiazolide derivatives were designed and synthesized to further validate the thiazolide scaffold as STAT3 inhibitors. Eight out of 25 derivatives displayed potencies greater than that of NTZ, and their STAT3 pathway inhibitory activities were found to be significantly correlated with their antiproliferative activities in HeLa cells. Derivatives 15 and 24 were observed to be more potent than the positive control WP1066, which is under phase I clinical trials. Compared with NTZ, 15 also exhibited much improved in vivo pharmacokinetic parameters in rats and efficacies against proliferations in multiple cancer cell lines, indicating a broad-spectrum effect of these thiazolides as antitumor agents targeted on STAT3.
Synthesis and structure-activity relationship studies of n-monosubstituted aroylthioureas as urease inhibitors
Dawalamu,Fang, Hai-Lian,Fu, Zi-Juan,Li, Fang,Li, Ke,Li, Wei-Yi,Liu, Li,Ni, Wei-Wei,Ouyang, Hui,Xiao, Zhu-Ping,Ye, Ya-Xi,Zhu, Hai-Liang,Zhu, Wen-Yan,Zou, Xia
, p. 1046 - 1059 (2021/11/30)
Background: Thiourea is a classical urease inhibitor which is usually used as a positive control, and many N,N'-disubstituted thioureas have been determined as urease inhibitors. However, due to steric hindrance, N,N'-disubstituted thiourea motif could not bind urease as thiourea. On the contrary, N-monosubstituted thiourea with a tiny thiourea motif could theoretically bind into the active pocket as thiourea. Objective: A series of N-monosubstituted aroylthioureas were designed and synthesized for evaluation as urease inhibitors. Methods: Urease inhibition was determined by the indophenol method and IC50 values were calculated using computerized linear regression analysis of quantal log dose-probit functions. The kinetic parameters were estimated via surface plasmon resonance (SPR) and by nonlinear regression analysis based on the mixed type inhibition model derived from Michaelis-Menten kinetics. Results: Compounds b2, b11, and b19 reversibly inhibited urease with a mixed mechanism, and showed excellent potency against both cell-free urease and urease in the intact cell, with IC50 values being 90-to 450-fold and 5-to 50-fold lower than the positive control acetohydroxamic acid, respectively. The most potent compound b11 showed an IC50 value of 0.060 ± 0.004μM against cell-free urease, which bound to urea binding site with a very low KD value (0.420±0.003nM) and a very long residence time (6.7 min). Compound b11 was also demonstrated to have very low cytotoxicity to mammalian cells. Conclusion: The results revealed that N-monosubstituted aroylthioureas bound to the active site of urease as expected, and represent a new class of urease inhibitors for the development of potential therapeutics against infections caused by urease-containing pathogens.
