4443-26-9Relevant articles and documents
General protocol for the synthesis of functionalized magnetic nanoparticles for magnetic resonance imaging from protected metal-organic precursors
Hu, He,Zhang, Chongkun,An, Lu,Yu, Yanrong,Yang, Hong,Sun, Jin,Wu, Huixia,Yang, Shiping
, p. 7160 - 7167 (2014)
The development of magnetic nanoparticles (MNPs) with functional groups has been intensively pursued in recent years. Herein, a simple, versatile, and cost-effective strategy to synthesize water-soluble and amino-functionalized MNPs, based on the thermal decomposition of phthalimide-protected metal-organic precursors followed by deprotection, was developed. The resulting amino-functionalized Fe3O4, MnFe2O4, and Mn3O4 MNPs with particle sizes of about 14.3, 7.5, and 6.6 nm, respectively, had narrow size distributions and good dispersibility in water. These MNPs also exhibited high magnetism and relaxivities of r 2=107.25 mM-1 s-1 for Fe3O 4, r2=245.75 mM-1 s-1 for MnFe 2O4, and r1=2.74 mM-1 s-1 for Mn3O4. The amino-functionalized MNPs were further conjugated with a fluorescent dye (rhodamine B) and a targeting ligand (folic acid: FA) and used as multifunctional probes. Magnetic resonance imaging and flow-cytometric studies showed that these probes could specifically target cancer cells overexpressing FA receptors. This new protocol opens a new way for the synthesis and design of water-soluble and amino-functionalized MNPs by an easy and versatile route.
Photochemistry of MTM- and MTE-esters of ωphthalimido carboxyhc acids: Macrocyclization versus deprotection
Griesbeck,Oelgemoeller,Lex
, p. 9028 - 9032 (2000)
The photochemistry of five linear methylthiomethyl (MTM)-esters of ω-phthalimido carboxylic acids Pht=N-(CH2)nCOOCH2SCH3 1a-e (n = 1, 2, 3, 5, and 10), of the two methylthioethyl (MTE)-esters Pht=N- (CH2)nCOOCH2CH2SCH3 2a,b (n = 1, 2), and of the two methyl-substituted MTM/MTE esters 3a and 3b was investigated. Two reaction channels were observed: (i) photocyclization to give medium-sized and macrocyclic rings, (ii) photochemical deprotection to give the free carboxylic acids. Photocyclization of 1b and 1c (n = 2, 3) resulted in 4b,c in excellent yields whereas the substrates 1a and 1d,e with shorter as well as longer spacer groups (n = 1, 5, 10) gave preferentially the deprotected products 5a,d,e. Subsequent photolysis afforded N-methylphthalimide (6) from 5a. The MTE-esters 2a and 2b gave the macrocyclic lactones 7 and E-8. Thus, the competition between cyclization and deprotection strongly depended on the chain length of the hydrocarbon linker between phthalimido chromophore and ester group. To examine the influence of the position of the ester group in the linker chain the model substrates 3a and 3b with identical number of atoms separating electron donor and acceptor group were investigated. The more flexible MTE-derivative 3b cyclized to give a 4:1 diastereoisomeric mixture of cis/trans-9b, whereas photolysis of the more reluctant MTM-ester 3a resulted in cis-9a only after prolonged irradiation. These results show that MTM can function as a photolabile protecting group whereas MTE cannot be removed photochemically. The distance dependence of the secondary reaction steps indicates that the primary electron transfer is not necessarily induced starting from close contact geometries.
Live-Cell Protein Modification by Boronate-Assisted Hydroxamic Acid Catalysis
Adamson, Christopher,Kajino, Hidetoshi,Kanai, Motomu,Kawashima, Shigehiro A.,Yamatsugu, Kenzo
, p. 14976 - 14980 (2021/09/29)
Selective methods for introducing protein post-translational modifications (PTMs) within living cells have proven valuable for interrogating their biological function. In contrast to enzymatic methods, abiotic catalysis should offer access to diverse and new-to-nature PTMs. Herein, we report the boronate-assisted hydroxamic acid (BAHA) catalyst system, which comprises a protein ligand, a hydroxamic acid Lewis base, and a diol moiety. In concert with a boronic acid-bearing acyl donor, our catalyst leverages a local molarity effect to promote acyl transfer to a target lysine residue. Our catalyst system employs micromolar reagent concentrations and affords minimal off-target protein reactivity. Critically, BAHA is resistant to glutathione, a metabolite which has hampered many efforts toward abiotic chemistry within living cells. To showcase this methodology, we installed a variety of acyl groups inE. colidihydrofolate reductase expressed within human cells. Our results further establish the well-known boronic acid-diol complexation as abona fidebio-orthogonal reaction with applications in chemical biology and in-cell catalysis.
HETEROCYCLIC COMPOUNDS AS PRMT5 INHIBITORS
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Paragraph 082; 156; 209, (2020/12/11)
The present disclosure describes novel heterocyclic PRMT5 inhibitors and methods for preparing them. The pharmaceutical compositions comprising such PRMT5 inhibitors and methods of using them for treating cancer, infectious diseases, and other PRMT5 associated disorders are also described.
ω-Quinazolinonylalkyl aryl ureas as reversible inhibitors of monoacylglycerol lipase
Dato, Florian M.,Neud?rfl, J?rg-Martin,Gütschow, Michael,Goldfuss, Bernd,Pietsch, Markus
, (2019/11/13)
The serine hydrolase monoacylglycerol lipase (MAGL) is involved in a plethora of pathological conditions, in particular pain and inflammation, various types of cancer, metabolic, neurological and cardiovascular disorders, and is therefore a promising target for drug development. Although a large number of irreversible-acting MAGL inhibitors have been discovered over the past years, there are only few compounds known so far which inhibit the enzyme in a reversible manner. Therefore, much effort is put into the development of novel chemical entities showing reversible inhibitory behavior, which is thought to cause less undesired side effects. To explore a wide range of chemical structures as MAGL binders, we have applied a virtual screening approach by docking small molecules into the crystal structure of human MAGL (hMAGL) and envisaged a library of 45 selected compounds which were then synthesized. Biochemical investigations included the determination of the inhibitory potency on hMAGL and two related hydrolases, i.e. human fatty acid amide hydrolase (hFAAH) and murine cholesterol esterase (mCEase). The most promising candidates from theses analyses, i.e. three ω-quinazolinonylalkyl aryl ureas bearing alkyl spacers of three to five methylene groups, exhibited IC50 values of 20–41 μM and reversible, detergent-insensitive behavior towards hMAGL. Among these compounds, the inhibitor 1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)butyl)urea (96) was selected for further kinetic characterization, yielding a dissociation constant Ki = 15.4 μM and a mixed-type inhibition with a pronounced competitive component (α = 8.94). This mode of inhibition was further supported by a docking experiment, which suggested that the inhibitor occupies the substrate binding pocket of hMAGL.
Oxidative damage of proline residues by nitrate radicals (NO3): A kinetic and product study
Nathanael, Joses G.,Nuske, Madison R.,Richter, Annika,White, Jonathan M.,Wille, Uta
, p. 6949 - 6957 (2020/10/02)
Tertiary amides, such as in N-acylated proline or N-methyl glycine residues, react rapidly with nitrate radicals (NO3) with absolute rate coefficients in the range of 4-7 × 108 M-1 s-1 in acetonitrile. The major pathway proceeds through oxidative electron transfer (ET) at nitrogen, whereas hydrogen abstraction is only a minor contributor under these conditions. However, steric hindrance at the amide, for example by alkyl side chains at the α-carbon, lowers the rate coefficient by up to 75%, indicating that NO3-induced oxidation of amide bonds proceeds through initial formation of a charge transfer complex. Furthermore, the rate of oxidative damage of proline and N-methyl glycine is significantly influenced by its position in a peptide. Thus, neighbouring peptide bonds, particularly in the N-direction, reduce the electron density at the tertiary amide, which slows down the rate of ET by up to one order of magnitude. The results from these model studies suggest that the susceptibility of proline residues in peptides to radical-induced oxidative damage should be considerably reduced, compared with the single amino acid.
Assembling of medium/long chain-based β-arylated unnatural amino acid derivatives via the Pd(II)-catalyzed sp3 β-C-H arylation and a short route for rolipram-type derivatives
Tomar, Radha,Bhattacharya, Debabrata,Babu, Srinivasarao Arulananda
, p. 2447 - 2465 (2019/03/26)
In this paper, we report the assembling of libraries of β-arylated short/medium/long chain-based non-α-amino acid (aminoalkanoic acid) derivatives via the Pd(II)-catalyzed, bidentate directing group 8-aminoquinoline-aided sp3 β-C-H activation/arylation method. Short/medium chain-based unnatural amino acid derivatives containing an aryl group at the β-position are promising small molecules with therapeutic properties. Thus, it is necessary to enrich the libraries of short/medium/long chain-based unnatural amino acid derivatives containing an aryl group at the β-position. Considering the importance of β-arylated short/medium/long chain-based non-α-amino acid derivatives, an inclusive attention was paid to explore the Pd(II)-catalyzed sp3 β-C-H arylation of short/medium/long chain-based non-α-amino acids. Representative synthetic transformations including a short route for the assembling of rolipram and related compounds and 3-arylated GABA derivatives such as, baclofen, phenibut and tolibut were shown using selected β-C-H arylated non-α-amino acid derivatives.
ω-Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase
Dato, Florian M.,Sheikh, Miriam,Uhl, Rocky Z.,Schüller, Alexandra W.,Steinkrüger, Michaela,Koch, Peter,Neud?rfl, J?rg-Martin,Gütschow, Michael,Goldfuss, Bernd,Pietsch, Markus
, p. 1833 - 1847 (2018/09/10)
Cholesterol esterase (CEase), a serine hydrolase thought to be involved in atherogenesis and thus coronary heart disease, is considered as a target for inhibitor development. We investigated recombinant human and murine CEases with a new fluorometric assay in a structure–activity relationship study of a small library of ω-phthalimidoalkyl aryl ureas. The urea motif with an attached 3,5-bis(trifluoromethyl)phenyl group and the aromatic character of the ω-phthalimide residue were most important for inhibitory activity. In addition, an alkyl chain composed of three or four methylene groups, connecting the urea and phthalimide moieties, was found to be an optimal spacer for inhibitors. The so-optimized compounds 2 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(3-(1,3-dioxoisoindolin-2-yl)propyl)urea] and 21 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(1,3-dioxoisoindolin-2-yl)butyl)urea] exhibited dissociation constants (Ki) of 1–19 μm on the two CEases and showed either a competitive (2 on the human enzyme and 21 on the murine enzyme) or a noncompetitive mode of inhibition. Two related serine hydrolases—monoacylglycerol lipase and fatty acid amide hydrolase—were inhibited by ω-phthalimidoalkyl aryl ureas to a lesser extent.
2-AMINO-1,3,4-THIADIAZINE AND 2-AMINO-1,3,4-OXADIAZINE BASED ANTIFUNGAL AGENTS
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Page/Page column 102; 103, (2017/02/09)
The invention provides a compound which is a diazine of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for use as an antifungal agent: (I) wherein X, N', C', A and E are as defined herein. The invention also provides a compound of Formula (I) as defined herein.
Separation material comprising phosphoryl choline derivatives
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Paragraph 0090; 0091, (2016/01/11)
The present invention provides phosphoryl choline derivatives of general formula (I), which are suitable to be immobilized on a solid support to provide a separation material, which bind with both high affinity and high specificity to a protein, more specifically to C-reactive protein and anti-phosphoryl choline antibodies. Said separation materials are particularly useful in the extracorporeal removal of C-reactive protein and anti-phosphoryl choline antibodies from a biological fluid of a patient for prophylaxis and/or treatment of immune dysfunctions and cardiovascular diseases. Also claimed is a device containing a column that comprises separation material made from formula (I) wherein L is a linker as defined in the claims; X is selected from: -SH, -NHR3, -C=CH, -CH=CH2, -N3, -CHO. Also claimed is a separation material of general formula (II): wherein A is a solid support; Y is a group obtainable from the reactive group X.
