1576-47-2Relevant articles and documents
N-Leucinyl Benzenesulfonamides as Structurally Simplified Leucyl-tRNA Synthetase Inhibitors
Charlton, Michael H.,Aleksis, Rihards,Saint-Leger, Adéla?de,Gupta, Arya,Loza, Einars,Ribas De Pouplana, Lluís,Kaula, Ilze,Gustina, Daina,Madre, Marina,Lola, Daina,Jaudzems, Kristaps,Edmund, Grace,Randall, Christopher P.,Kime, Louise,O'Neill, Alex J.,Goessens, Wil,Jirgensons, Aigars,Finn, Paul W.
, p. 84 - 88 (2018)
N-Leucinyl benzenesulfonamides have been discovered as a novel class of potent inhibitors of E. coli leucyl-tRNA synthetase. The binding of inhibitors to the enzyme was measured by using isothermal titration calorimetry. This provided information on enthalpy and entropy contributions to binding, which, together with docking studies, were used for structure-activity relationship analysis. Enzymatic assays revealed that N-leucinyl benzenesulfonamides display remarkable selectivity for E. coli leucyl-tRNA synthetase compared to S. aureus and human orthologues. The simplest analogue of the series, N-leucinyl benzenesulfonamide (R = H), showed the highest affinity against E. coli leucyl-tRNA synthetase and also exhibited antibacterial activity against Gram-negative pathogens (the best MIC = 8 μg/mL, E. coli ATCC 25922), which renders it as a promising template for antibacterial drug discovery.
Contribution of Energy Transfer from the Singlet State to the Sensitization of Eu3+and Tb3+Luminescence by Sulfonylamidophosphates
Kasprzycka, Ewa,Trush, Victor A.,Amirkhanov, Vladimir M.,Jerzykiewicz, Lucjan,Malta, Oscar L.,Legendziewicz, Janina,Gawryszewska, Paula
, p. 1318 - 1330 (2017)
A series of stable lanthanide complexes Na[Ln(L)4] (Ln=La3+, Eu3+, Gd3+, Tb3+, with L=dimethyl(4-methylphenylsulfonyl)amidophosphate and dimethyl-2-naphthylsulfonylamidophosphate) were synthesized. The compounds were characterized by single-crystal X-ray diffraction, IR, absorption, and emission spectroscopy at 293 and 77 K. In contrast to the usual and well-known dominant role of the ligand triplet state in intramolecular energy transfer processes in Ln complexes, in this particular new class of Ln compounds with sulphonylamidophosphate ligands, strong experimental and detailed theoretical evidence suggest a dominant role is played by the ligand first excited singlet state. The importance of the role played by the7F5level in the case of the Tb3+compound in this process is shown. The theoretical approach for the energy transfer rates was successfully applied to the rationalization of the experimental data. The higher-lying excited levels of Eu (5DJ,5LJ,5GJ) and Tb (5DJ,5GJ,5LJ,5HJ,5FJ,5IJ) were included in the calculations for the first time. Both the multipolar and exchange mechanisms were taken into account. The experimental intensity parameters (Ωλ), emission lifetimes (τ), radiative (Arad) and non-radiative (Anrad) decay rates, and quantum yields (theoretical and experimental) were determined and are discussed in detail.
ARYL AND HETEROARYL COMPOUNDS, AND THERAPEUTIC USES THEREOF IN CONDITIONS ASSOCIATED WITH THE ALTERATION OF THE ACTIVITY OF GALACTOCEREBROSIDASE
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Page/Page column 120; 121, (2021/06/04)
The application is directed to compounds of formulae (IA) and (IB): (IA) and (IB), and their salts and solvates, wherein R1a, R2a, A1, A2, A3, A4, R1b, R2b, B1, B2, B3, and G are as set forth in the specification, as well as to methods for their preparation, pharmaceutical compositions comprising the same, and use thereof for the treatment and/or prevention of, e.g., lysosomal storage diseases, such as Krabbe's disease, and α-synucleinopathies, such as Parkinson's disease.
Development of succinimide-based inhibitors for the mitochondrial rhomboid protease PARL
Andrews, Charlotte L.,Cardozo, Joaquin M.,Chow, Alyssa S.,Crainic, Jennifer A.,Parsons, William H.,Rutland, Nicholas T.,Sheehan, Brendan K.
supporting information, (2021/08/04)
While the biochemistry of rhomboid proteases has been extensively studied since their discovery two decades ago, efforts to define the physiological roles of these enzymes are ongoing and would benefit from chemical probes that can be used to manipulate the functions of these proteins in their native settings. Here, we describe the use of activity-based protein profiling (ABPP) technology to conduct a targeted screen for small-molecule inhibitors of the mitochondrial rhomboid protease PARL, which plays a critical role in regulating mitophagy and cell death. We synthesized a series of succinimide-containing sulfonyl esters and sulfonamides and discovered that these compounds serve as inhibitors of PARL with the most potent sulfonamides having submicromolar affinity for the enzyme. A counterscreen against the bacterial rhomboid protease GlpG demonstrates that several of these compounds display selectivity for PARL over GlpG by as much as two orders of magnitude. Both the sulfonyl ester and sulfonamide scaffolds exhibit reversible binding and are able to engage PARL in mammalian cells. Collectively, our findings provide encouraging precedent for the development of PARL-selective inhibitors and establish N-[(arylsulfonyl)oxy]succinimides and N-arylsulfonylsuccinimides as new molecular scaffolds for inhibiting members of the rhomboid protease family.
