- General protocol for the synthesis of functionalized magnetic nanoparticles for magnetic resonance imaging from protected metal-organic precursors
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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.
- Hu, He,Zhang, Chongkun,An, Lu,Yu, Yanrong,Yang, Hong,Sun, Jin,Wu, Huixia,Yang, Shiping
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Read Online
- Photochemistry of MTM- and MTE-esters of ωphthalimido carboxyhc acids: Macrocyclization versus deprotection
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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.
- Griesbeck,Oelgemoeller,Lex
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Read Online
- Live-Cell Protein Modification by Boronate-Assisted Hydroxamic Acid Catalysis
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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.
- Adamson, Christopher,Kajino, Hidetoshi,Kanai, Motomu,Kawashima, Shigehiro A.,Yamatsugu, Kenzo
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p. 14976 - 14980
(2021/09/29)
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- ω-Quinazolinonylalkyl aryl ureas as reversible inhibitors of monoacylglycerol lipase
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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.
- Dato, Florian M.,Neud?rfl, J?rg-Martin,Gütschow, Michael,Goldfuss, Bernd,Pietsch, Markus
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- HETEROCYCLIC COMPOUNDS AS PRMT5 INHIBITORS
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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.
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Paragraph 082; 156; 209
(2020/12/11)
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- Oxidative damage of proline residues by nitrate radicals (NO3): A kinetic and product study
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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.
- Nathanael, Joses G.,Nuske, Madison R.,Richter, Annika,White, Jonathan M.,Wille, Uta
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p. 6949 - 6957
(2020/10/02)
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- 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
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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.
- Tomar, Radha,Bhattacharya, Debabrata,Babu, Srinivasarao Arulananda
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p. 2447 - 2465
(2019/03/26)
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- ω-Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase
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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.
- 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
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p. 1833 - 1847
(2018/09/10)
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- 2-AMINO-1,3,4-THIADIAZINE AND 2-AMINO-1,3,4-OXADIAZINE BASED ANTIFUNGAL AGENTS
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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.
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Page/Page column 102; 103
(2017/02/09)
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- Separation material comprising phosphoryl choline derivatives
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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.
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Paragraph 0090; 0091
(2016/01/11)
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- Decarboxylative fluorination of aliphatic carboxylic acids via photoredox catalysis
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The direct conversion of aliphatic carboxylic acids to the corresponding alkyl fluorides has been achieved via visible light-promoted photoredox catalysis. This operationally simple, redox-neutral fluorination method is amenable to a wide variety of carboxylic acids. Photon-induced oxidation of carboxylates leads to the formation of carboxyl radicals, which upon rapid CO2-extrusion and F? transfer from a fluorinating reagent yield the desired fluoroalkanes with high efficiency. Experimental evidence indicates that an oxidative quenching pathway is operable in this broadly applicable fluorination protocol.
- Ventre, Sandrine,Petronijevic, Filip R.,Macmillan, David W. C.
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supporting information
p. 5654 - 5657
(2015/05/20)
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- [3H]UR-DE257: Development of a tritium-labeled squaramide-type selective histamine H2 receptor antagonist
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A series of new piperidinomethylphenoxypropylamine-type histamine H2 receptor (H2R) antagonists with different substituted "urea equivalents" was synthesized and characterized in functional in vitro assays. Based on these data as selection criteria, radiosynthesis of N-[6-(3,4-dioxo-2-{3-[3-(piperidin-1-ylmethyl)phenoxy]propylamino}cyclobut-1-enylamino)hexyl]-(2,3-3H2)propionic amide ([3H]UR-DE257) was performed. The radioligand (specific activity: 63Cimmol-1) had high affinity for human, rat, and guinea pig H2R (hH2R, Sf9 cells: Kd, saturation binding: 31 nM, kinetic studies: 20 nM). UR-DE257 revealed high H2R selectivity on membranes of Sf9 cells, expressing the respective hHxR subtype (Ki values: hH1R: > 10000 nM, hH2R: 28 nM, hH3R: 3800 nM, hH4R: > 10000 nM). In spite of insurmountable antagonism, probably due to rebinding of [3H]URDE257 to the H2R (extended residence time), the title compound proved to be a valuable pharmacological tool for the determination of H2R affinities in competition binding assays.
- Baumeister, Paul,Erdmann, Daniela,Biselli, Sabrina,Kagermeier, Nicole,Elz, Sigurd,Bernhardt, Günther,Buschauer, Armin
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supporting information
p. 83 - 93
(2015/06/01)
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- Stereoselective synthesis of β-alkylated α-amino acids via palladium-catalyzed alkylation of unactivated methylene C(sp3)-H Bonds with Primary Alkyl Halides
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We report a new set of reactions based on the Pd-catalyzed alkylation of methylene C(sp3)-H bonds of aliphatic quinolyl carboxamides with α-haloacetate and methyl iodide and applications in the stereoselective synthesis of various β-alkylated α-amino acids. These reactions represent the first generally applicable method for the catalytic alkylation of unconstrained and unactivated methylene C-H bonds with high synthetic relevance. When applied with simple isotope-enriched reagents, they also provide a convenient and powerful means to site-selectively incorporate isotopes into the carbon scaffolds of amino acid compounds.
- Zhang, Shu-Yu,Li, Qiong,He, Gang,Nack, William A.,Chen, Gong
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supporting information
p. 12135 - 12141
(2013/09/02)
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- Compositions Including 6-Aminohexanoic Acid Derivatives As HDAC Inhibitors
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This invention relates to compounds of Formula (I) wherein Cy1, L1, Y, R1, L2, and Ar2 are defined herein, for the treatment of cancers, inflammatory disorders, and neurological conditions.
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Page/Page column 46
(2012/04/23)
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- Copper-catalyzed carboxylation of alkylboranes with carbon dioxide: Formal reductive carboxylation of terminal alkenes
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Carboxylation of alkylboron compounds (alkyl-9-BBN) with CO2 proceeded in the presence of catalytic amounts of CuOAc/1,10-phenanthroline and a stoichiometric amount of KOtBu. The alkylboranes are easily and widely available through the alkene hydroboration, and thus the overall process represents a reductive carboxylation of alkenes with CO2. The broad functional group compatibility and the inexpensiveness of the Cu/1,10-phenathoroline catalyst system are attractive features of this protocol.(Figure Presented)
- Ohmiya, Hirohisa,Tanabe, Masahito,Sawamura, Masaya
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p. 1086 - 1088
(2011/04/23)
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- Syntheses of phosphonic esters of alendronate, pamidronate and neridronate
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Several synthetic pathways for obtaining phosphonic esters of the amino bisphosphonic acids (NBPs) pamidronate, alendronate and neridronate were investigated. The general guideline was to react N-protected amino acids activated as phthalimide esters or as acyl chlorides. Succinimide esters were found less reactive and quickly abandoned. γ-Lactam formation arises when starting from Boc- or Cbz-protected amino acids. The phthalimide N-protecting group allowed access to alkyl or aryl mono-, di- (symmetric or not) and triesters of these three NBPs in high yields. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Guenin, Erwann,Monteil, Maelle,Bouchemal, Nadia,Prange, Thierry,Lecouvey, Marc
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p. 3380 - 3391
(2008/02/10)
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- POLYBIOTIN COMPOUNDS FOR MAGNETIC RESONANCE IMAGINING AND DRUG DELIVERY
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The invention relates generally to biotin-containing compounds that are useful as imaging agents and drug-delivery agents. Another aspect of the invention relates to the aforementioned compounds chelated to a metal atom. In a preferred embodiment, the metal atom is a gadolinium. Another aspect of the invention relates to a compound comprising three biotin moieties and a pharmaceutical agent covalently bound to a heterocyclic core. In certain embodiments, the pharmaceutical agent is an antibiotic, antiviral, or radionuclide. Another aspect of the present invention relates to a method of treating disease involving administering the compounds of the invention to a mammal. Another aspect of the present invention relates to a method of acquiring a magnetic resonance image using the compounds of the invention.
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Page/Page column 74; 75
(2008/06/13)
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- 3-mercaptoacetylamino-1,5-substituted-2-oxo-azepan derivatives useful as inhibitors of matrix metalloproteinase
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The present invention relates to certain novel 3-mercaptoacetylamino-1,5-substituted-2-oxo-azepan derivatives useful as inhibitors of matrix metalloproteinase. Pharmaceutical compositions containing said compounds as well as methods of treating various disease states responding to inhibition of matrix metalloproteinase are also claimed herein.
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Page/Page column 78
(2010/02/14)
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- (2-Amino-phenyl)-amides of ω-substituted alkanoic acids as new histone deacetylase inhibitors
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A variety of ω-substituted alkanoic acid (2-amino-phenyl)-amides were designed and synthesized. These compounds were shown to inhibit recombinant human histone deacetylases (HDACs) with IC50 values in the low micromolar range and induce hyperacetylation of histones in whole cells. They induced expression of p21WAF1/Cip1 and caused cell-cycle arrest in human cancer cells. Compounds in this class showed efficacy in human tumor xenograft models.
- Vaisburg, Arkadii,Bernstein, Naomy,Frechette, Sylvie,Allan, Martin,Abou-Khalil, Elie,Leit, Silvana,Moradei, Oscar,Bouchain, Giliane,Wang, James,Woo, Soon Hyung,Fournel, Marielle,Yan, Pu T.,Trachy-Bourget, Marie-Claude,Kalita, Ann,Beaulieu, Carole,Li, Zuomei,MacLeod, A. Robert,Besterman, Jeffrey M.,Delorme, Daniel
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p. 283 - 287
(2007/10/03)
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- 1-Carboxymethyl-2-oxo-azepan derivatives useful as selective inhibitors of MMP-12
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The present invention relates to certain novel 1-carboxymethyl-2-oxo-azepan derivatives of the formula useful as inhibitors of matrix metalloproteinases (MMPs). The compounds of formula (1) are especially useful as selective inhibitors of MMP-12. Pharmaceutical compositions containing said compounds as well as methods of treating various disease states responding to inhibition of matrix metalloproteinase are also claimed herein.
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Page column 41
(2010/02/07)
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- Fluorescent pirenzepine derivatives as potential bitopic ligands of the human M1 muscarinic receptor
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Following a recent description of fluorescence resonance energy transfer between enhanced green fluorescent protein (EGFP)-fused human muscarinic M1 receptors and Bodipy-labeled pirenzepine, we synthesized seven fluorescent derivatives of this antagonist in order to further characterize ligand-receptor interactions. These compounds carry Bodipy [558/568], Rhodamine Red-X [560/580], or Fluorolink Cy3 [550/570] fluorophores connected to pirenzepine through various linkers. All molecules reversibly bind with high affinity to M1 receptors (radioligand and energy transfer binding experiments) provided that the linker contains more than six atoms. The energy transfer efficiency exhibits modest variations among ligands, indicating that the distance separating EGFP from the fluorophores remains almost constant. This also supports the notion that the fluorophores may bind to the receptor protein. Kinetic analyses reveal that the dissociation of two Bodipy derivatives (10 or 12 atom long linkers) is sensitive to the presence of the allosteric modulator brucine, while that of all other molecules (15-24 atom long linkers) is not. The data favor the idea that these analogues might interact with both the acetylcholine and the brucine binding domains.
- Tahtaoui, Chouaib,Parrot, Isabelle,Klotz, Philippe,Guillier, Fabrice,Galzi, Jean-Luc,Hibert, Marcel,Ilien, Brigitte
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p. 4300 - 4315
(2007/10/03)
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- Synthesis and pharmacological activity of fluorescent histamine H1 receptor antagonists related to mepyramine
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Fluorescently labeled histamine H1 receptor antagonists were synthesized starting from N-demethylmepyramine by introduction of ω-aminoalkyl chains (2-8 methylene groups in length) followed by derivatization of the terminal NH2 group with various fluorophores (fluorescein, naphthofluorescein, rhodamine, tetramethylrhodamine, BODIPY, dansyl, and nitrobenzoxadiazole (NBD)). On the isolated guinea pig ileum and in a Ca2+ assay on U373MG human glioblastoma cells the highest H1 antagonistic activities were found in 5- and 6-carboxyfluorescein labeled compounds with hexa- and octamethylene spacers and in an analogous NBD-aminohexanoyl derivative (pA2 or pKB values in the range: 8.3-9.0; compared to 9.3-9.4 for mepyramine).
- Li, Liantao,Kracht, Julia,Peng, Shiqi,Bernhardt, Guenther,Buschauer, Armin
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p. 1245 - 1248
(2007/10/03)
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- 3-(THIO-SUBSTITUTED AMIDO)-LACTAMS USEFUL AS INHIBITORS OF MATRIX METALLOPROTEINASE
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The present invention provides novel thio-substituted amido lactam derivatives of formula (1) useful in as inhibitors of matrix metallo-proteinases (MMPs).
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- 3-MERCAPTOACETYLAMINO-1,5-SUBSTITUTED-2-OXO-AZEPAN DERIVATIVES USEFUL AS INHIBITORS OF MATRIX METALLOPROTEINASE
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The present invention relates to certain novel 3-mercaptoacetylamino-1,5-substituted-2-oxo-azepan derivatives useful as inhibitors of matrix metalloproteinase. Pharmaceutical compositions containing said compounds as well as methods of treating various disease states responding to inhibition of matrix metalloproteinase are also claimed herein.
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- N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase
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The present invention provides a method of inhibiting matrix metallo-proteinases (MMPs) in a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibiting amount of the N-carboxymethyl substituted benzolactams of formula (1): wherein A is —OH or —NRR′. Such inhibitors are useful in treating neoplasms, atherosclorosis, and chronic inflammatory diseases. The present invention also provides novel N-carboxymethyl substituted benzolactams of formula (1a): wherein A is —NRR′.
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- Peptide folding induces high and selective affinity of a linear and small β-peptide to the human somatostatin receptor 4
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β-Peptides with side chains in the 2- and 3-positions on neighboring residues (of (S) configuration) are known to fold and form a turn (similar to an α-peptidic β-turn). Thus, we have synthesized an appropriately substituted β-tetrapeptide derivative to mimic the hormone somatostatin in its binding to the human receptors hsst1-5, which is known to rest upon a turn containing the amino acid residues Thr, Lys, Trp, and Phe. The N-acetyl-peptide amide Acβ3-HThr-β2-HLys-β3 -HTrp-β3-HPhe-NH2 (1) indeed shows all characteristics of the targeted turnmimic: Lys CH2 groups are in the shielding cone of the Trp indole ring (by NMR analysis, Figure 2) and there is high and specific nanomolar affinity for hsst4 receptor (Table 1). In contrast, the isomer 2 bearing the Lys side chain in 3-, rather than in the 2-position, has a 1000-fold smaller affinity to hsst4. The syntheses of the required Fmoc-protected β-amino acids (8-11, 17) are described (Schemes 1-3). Coupling of the β-amino acids was achieved by the manual solid-phase technique, on Rink resin.
- Gademann,Kimmerlin,Hoyer,Seebach
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p. 2460 - 2468
(2007/10/03)
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- 3-(thio-substitutedamido)-lactams useful as inhibitors of matrix metalloproteinase
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The present invention provides novel thio-substitutedamido lactam derivatives of the formula useful in as inhibitors of matrix metallo-proteinases (MMPs).
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- Development of monoclonal ELISAs for azinphos-methyl. 1. Hapten synthesis and antibody production
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The development of monoclonal antibody-based enzyme-linked immunosorbent assays for azinphosmethyl is described. A panel of haptens was synthesized for immunoconjugate preparation, and a series of haptens for heterologous, coating or tracer, conjugates was also prepared. Hapten synthesis was based on a strategy in which only a fragment of the whole target molecule was present (fragmentary haptens). From immunized mice, a set of monoclonal antibodies was obtained and ELISA sensitivities were assayed in different formats. Affinities estimated as I50 values in the low nanomolar range for azinphos-methyl and phosmet were observed for several monoclonal antibodies in the conjugate-coated format and in the antibody-coated format under nonoptimized assay conditions.
- Mercader, Josep V.,Montoya, Angel
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p. 1276 - 1284
(2007/10/03)
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- Synthesis and neuropeptide Y Y1 receptor antagonistic activity of N,N-disubstituted ω-guanidino- and ω-aminoalkanoic acid amides
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Patent arpromidine-type histamine H2 receptor agonists such as BU-E-76 (He 90481) were among the first non-peptides reported to display weak neuropeptide Y (NPY) Y1 receptor antagonist activity. In search of new chemical leads for the development of more potent NPY antagonists, a series of N,N-disubstituted ω-guanidino and ω-aminoalkanoic acid amides were synthesized on the basis of structure-activity relationships and molecular modeling studies of arpromidine and related imidazolylpropylguanidines. In one group of compounds the imidazole ring was retained whereas in the second group it was replaced with a phenol group representing a putative mimic of Tyr36 in NPY. Although the substitution patterns have not yet been optimized, the title compounds are NPY Y1 antagonists in human erythroleukemia (HEL) cells (Ca2+ assay) achieving pK(B) values in the range of 6.3-6.6. For representative new substances tested in the isolated guinea pig right atrium histamine H2 receptor agonism could not be found. In the N-(diphenylalkyl)amide series, compounds with a trimethylene chain were more active Y1 antagonists than the ethylene homologs. Concerning the spacer in the ω-amino or ω-guanidinoalkanoyl portion, the best activity was found in compounds with a four- or five-membered alkyl chain or a 1,4-cyclohexylene group. Surprisingly, in contrast to the phenol series, in the imidazole series the compounds with a side chain amino group turned out to be considerably mere potent than the corresponding strongly basic guanidines. Thus, the structure-activity relationships appear to be different for the diphenylalkylamide NPY antagonists with one or two basic groups.
- Mueller, Manfred,Knieps, Sebastian,Gessele, Karin,Dove, Stefan,Bernhardt, Guenther,Buschauer, Armin
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p. 333 - 342
(2007/10/03)
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- Synthesis of Medium- and Large-Ring Compounds Initiated by Photochemical Decarboxylation of ω-Phthalimidoalkanoates
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The synthesis of a variety of hydroxylactams from ω-phthalimidoalkanoates using a triplet-sensitized photodecarboxylation reaction initiated by intramolecular photo electron transfer is described. Ring sizes available by this method span from 4 (benzazepine-1,5-dione 7) to 26 (cyclodipeptide 26e). Ground-state template formation is proposed as the explanation for the high efficiency of this reaction and for the decrease in reactivity in the presence of organic bases instead of metal carbonates. The crucial step in this macrocyclization reaction seems to be the protonation of the intermediary ketyl radiais (Scheme 4). Spacer groups investigated were alkyl chains (C3-C11: 5c-h, 11a, 12), ether (16, 18), ester (20, 22), and amide (26a-f) linkages. Within the detection limits, no dimeric (= decarboxylative coupling) products were observed, indicating the high preference for intra-vs. intermolecular photoelectron transfer. The C,C radical combination step proceeds with low stereoselectivity (cf. products 11 and 12) in contrast to comparable singlet reactions. Except for the lactones 22, all products were stable under the photolysis conditions. Prolonged irradiation of 22 led to the formation of the spiro compounds 23, probably via an intermediary acyliminium betaine (Scheme 8). One serious limitation of the decarboxylative macrocyclization is its incompatibility with the glycine spacer (as in 27a and 27b), probably the consequence of a strong intramolecular H-bond (Scheme 10).
- Griesbeck, Axel G.,Henz, Andreas,Kramer, Wolfgang,Lex, Johann,Nerowski, Frank,Oelgemoeller, Michael,Peters, Karl,Peters, Eva-Maria
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p. 912 - 933
(2007/10/03)
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- Application of remote photocyclization with a pair system of phthalimide and methylthio groups. A photochemical synthesis of cyclic peptide models
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Application of regioselective remote photocyclization of a pair system consisting of a phthalimide group and a methylthio group to a homologous series of N-substituted phthalimides (4 and 5) possessing a terminal sulfide function in the amide side chain was investigated. On irradiation, medium to large membered cyclic peptide-like compounds (6, 7 and 9), up to a thirty-eight membered ring product (6f), were synthesized in moderate yields.
- Sato,Nakai,Wada,Mizoguchi,Hatanaka,Kanaoka
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p. 3174 - 3180
(2007/10/02)
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- Imidoperoxycarboxylic acids, processes for their preparation and their use
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Imidopercarboxylic acids or salts thereof of the formula STR1 in which A denotes a group of the formula STR2 n denotes the number 0, 1 or 2, R1 denotes hydrogen, chlorine, bromine, C1 -C20 -alkyl, C2 -C20 -alkenyl, aryl, or alkylaryl, R2 denotes hydrogen, chlorine, bromine or a group of the formula --SO3 M, --CO2 M, CO3 M or OSO3 M. M denotes hydrogen, an alkali metal or ammonium ion or the equivalent of an alkaline earth metal ion and X denotes C3 -C19 -alkylene or arylene, preferably phenylene. These compounds are suitable as stable peroxide compounds in bleaching, oxidizing and cleaning agents.
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