1576-47-2Relevant academic research and scientific papers
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.
Amides and Sulfonamides: Efficient Molecular Padlocks for the Template Synthesis of Azacyclam (1,3,5,8,12-Pentaazacyclotetradecane) Macrocycles
Blas, Andres De,Santis, Giancarlo De,Fabbrizzi, Luigi,Licchelli, Maurizio,Lanfredi, Anna Maria Manotti,et al.
, p. 1411 - 1416 (1993)
Amides and sulfonamides, both aliphatic and aromatic, acted as efficient locking fragments, in the presence of formaldehyde and base (triethylamine), in closing the open-chain tetramine 1,9-diamino-3,7-diazanonane around labile metal centres prone to a square type of co-ordination, i.e.NiII and CuII, to give a pentaazamacrocyclic complex to the azacyclam family.The product of the copper(II) template reaction involving methanesulfonamide as a locking fragment (3-methanesulfonyl-1,3,5,8,12-pentaazacyclotetradecane)dinitratocopper(II), was obtained in crystalline form and its crystal and molecular structure determined from single-crystal X-ray diffraction data, collected with the use of Cu-Kα radiation: trigonal, space group R3c, a = b = c = 14.997(3) Angstroem, α = β = γ = 98.48(2) deg, Z = 6.Only the four secondary amine nitrogen atoms of the macrocycle are bound to the CuII, giving a regular square stereochemistry.The tertiary nitrogen atom N(1), which presents distinct sp2 structural features, is not involved in the co-ordination.The axial positions of the elongated octahedron are occupied by oxygen atoms of the nitrate ions.A kinetic investigation was carried out on the copper(II) template reactions involving diprotic acids as locking fragments, including amides, amines and carbon acids, such as nitroethane and diethyl malonate: for the systems investigated the rate of the template reaction seems to be related to the strength of the diprotic acid.This suggests that the monodeprotonated form of the acid is present in the rate-determining step of the cyclisation process.
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.
Chemoselective Cleavage of Acylsulfonamides and Sulfonamides by Aluminum Halides
Sang, Dayong,Dong, Bingqian,Liu, Yunfeng,Tian, Juan
, p. 3586 - 3595 (2022/02/25)
The chemoselective cleavage of C-N bonds of amides, sulfonamides, and acylsulfonamides by aluminum halides is described. AlCl3and AlI3display complementary reactivities toward N-alkyl and N-acyl moieties. N-Alkylacylsulfonamides, sec
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.
Synthesis, biological evaluation, and docking studies of novel pyrrolo[2,3-b]pyridine derivatives as both ectonucleotide pyrophosphatase/phosphodiesterase inhibitors and antiproliferative agents
Ullah, Saif,El-Gamal, Mohammed I.,El-Gamal, Randa,Pelletier, Julie,Sévigny, Jean,Shehata, Mahmoud K.,Anbar, Hanan S.,Iqbal, Jamshed
, (2021/03/22)
Ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) together with nucleoside triphosphate diphosphohydrolases (NTPDases) and alkaline phosphatases (APs) are nucleotidases located at the surface of the cells. NPP1 and NPP3 are important members of NPP family that are known as druggable targets for a number of disorders such as impaired calcification, type 2 diabetes, and cancer. Sulfonylurea derivatives have been reported as antidiabetic and anticancer agents, therefore, we synthesized and investigated series of sulfonylurea derivatives 1a-m possessing pyrrolo[2,3-b]pyridine core as inhibitors of NPP1 and NPP3 isozymes that are over-expressed in cancer and diabetes. The enzymatic evaluation highlighted compound 1a as selective NPP1 inhibitor, however, 1c was observed as the most potent inhibitor of NPP1 with an IC50 value of 0.80 ± 0.04 μM. Compound 1l was found to be the most potent and moderately selective inhibitor of NPP3 (IC50 = 0.55 ± 0.01 μM). Furthermore, in vitro cytotoxicity assays of compounds 1a-m against MCF-7 and HT-29 cancer cell lines exhibited compound 1c (IC50 = 4.70 ± 0.67 μM), and 1h (IC50 = 1.58 ± 0.20 μM) as the most cytotoxic compounds against MCF-7 and HT-29 cancer cell lines, respectively. Both of the investigated compounds showed high degree of selectivity towards cancer cells than normal cells (WI-38). Molecular docking studies of selective and potent enzyme inhibitors revealed promising mode of interactions with important binding sites residues of both isozymes i.e., Thr256, His380, Lys255, Asn277 residues of NPP1 and His329, Thr205, and Leu239 residues of NPP3. In addition, the most potent antiproliferative agent, compound 1h, doesn't produce hypoglycemia as a side effect when injected to mice. This is an additional merit of the promising compound 1h.
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.
METHOD FOR PRODUCING OXIDE USING BETA-MANGANESE DIOXIDE
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Paragraph 0097; 0098, (2021/10/15)
With the object of efficiently producing an oxidation product, the present invention provides a method for producing an oxidation product by oxidizing a raw material compound in the presence of oxygen, wherein the raw material compound is oxidized in the presence of manganese dioxide having a crystal structure of β-type.
Rationally Designed Polypharmacology: α-Helix Mimetics as Dual Inhibitors of the Oncoproteins Mcl-1 and HDM2
Conlon, Ivie L.,Drennen, Brandon,Lanning, Maryanna E.,Hughes, Samuel,Rothhaas, Rebecca,Wilder, Paul T.,MacKerell, Alexander D.,Fletcher, Steven
supporting information, p. 1691 - 1698 (2020/07/04)
Protein–protein interactions (PPIs), many of which are dominated by α-helical recognition domains, play key roles in many essential cellular processes, and the dysregulation of these interactions can cause detrimental effects. For instance, aberrant PPIs involving the Bcl-2 protein family can lead to several diseases including cancer, neurodegenerative diseases, and diabetes. Interactions between Bcl-2 pro-life proteins, such as Mcl-1, and pro-death proteins, such as Bim, regulate the intrinsic pathway of apoptosis. p53, a tumor-suppressor protein, also has a pivotal role in apoptosis and is negatively regulated by its E3 ubiquitin ligase HDM2. Both Mcl-1 and HDM2 are upregulated in numerous cancers, and, interestingly, there is crosstalk between both protein pathways. Recently, synergy has been observed between Mcl-1 and HDM2 inhibitors. Towards the development of new anticancer drugs, we herein describe a polypharmacology approach for the dual inhibition of Mcl-1 and HDM2 by employing three densely functionalized isoxazoles, pyrazoles, and thiazoles as mimetics of key α-helical domains of their partner proteins.
Bone-seeking matrix metalloproteinase inhibitors for the treatment of skeletal malignancy
Laghezza, Antonio,Piemontese, Luca,Brunetti, Leonardo,Caradonna, Alessia,Agamennone, Mariangela,Di Pizio, Antonella,Pochetti, Giorgio,Montanari, Roberta,Capelli, Davide,Tauro, Marilena,Loiodice, Fulvio,Tortorella, Paolo
, (2020/06/18)
Matrix metalloproteinases (MMPs) are a family of enzymes involved at different stages of cancer progression and metastasis. We previously identified a novel class of bisphosphonic inhibitors, selective for MMPs crucial for bone remodeling, such as MMP-2. Due to the increasing relevance of specific MMPs at various stages of tumor malignancy, we focused on improving potency towards certain isoforms. Here, we tackled MMP-9 because of its confirmed role in tumor invasion, metastasis, angiogenesis, and immuno-response, making it an ideal target for cancer therapy. Using a computational analysis, we designed and characterized potent MMP-2/MMP-9 inhibitors. This is a promising approach to develop and clinically translate inhibitors that could be used in combination with standard care therapy for the treatment of skeletal malignancies.
