- A Set of Highly Sensitive Sirtuin Fluorescence Probes for Screening Small-Molecular Sirtuin Defatty-Acylase Inhibitors
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Human sirtuins (SIRT1-7) regulate not only deacetylation but also deacylation of fatty acid-derived acyl moieties (defatty-acylation) at the ?-amino group of lysine residues. SIRT-subtype-specific defatty-acylase activity modulators are needed for detailed investigation of the biological roles of these enzymes, and to find suitable small molecules, we require appropriate screening systems. Here, we designed and synthesized a set of SIRT defatty-acylase activity probes with various quencher moieties and peptide sequences based on our previously developed one-step FRET-based SIRT probe SFP3, using improved methodology. Scanning of this set of probes with SIRT isozymes revealed that certain probe/isozyme combinations showed especially high responses. To illustrate the utility of the combinations thus identified, we applied compound 18/SIRT2 for inhibitor screening of a large chemical library. This enabled us to discover a new small molecule SIRT2-specific defatty-acylase inhibitor.
- Nakajima, Yuya,Kawaguchi, Mitsuyasu,Ieda, Naoya,Nakagawa, Hidehiko
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Read Online
- Positive variation of the MRI signal via intramolecular inclusion complexation of a C-2 functionalized β-cyclodextrin
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The synthesis of a new contrast agent based on a β-cyclodextrin scaffold and bearing a flexible lipophilic spacer arm on its secondary face is reported. Intermolecular host-guest inclusion complexes were known to undergo an enhancement of the contrast imaging. We extend this concept to intramolecular complexation. Inter- and intramolecular interactions are compared by NMR spectroscopy, circular dichroism and magnetic resonance imaging using hydrocinnamic acid and adamantane carboxylic acid as external guests. This positive variation of the observed relaxivity is a key element of new strategies aiming at developing smart molecular MRI probes.
- Zgani,Idriss,Barbot,Djeda?ni-Pilard,Petit,Hubert-Roux,Estour,Gouhier
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supporting information
p. 564 - 569
(2017/01/25)
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- Amine compound and process for preparation thereof, liquid crystal aligning, liquid crystal alignment film, the liquid crystal display element (by machine translation)
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The present invention relates to an amine compound, a method for preparing same, and a liquid crystal alignment agent, a liquid crystal alignment film, and a liquid crystal display device, having same. A liquid crystal alignment agent having polyamic acid or polyimide prepared using the amine compound of the present invention enables a liquid crystal alignment film and a liquid crystal display device having excellent thermal stability even after forming the liquid crystal alignment film, and expressing high alignment and stability even after an ultraviolet ray irradiation.
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Paragraph 0229; 0230
(2016/12/01)
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- Design, synthesis and biological evaluation of novel sesquiterpene mustards as potential anticancer agents
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Several novel series of sesquiterpene mustards (SMs) bearing nitrogen mustard and glutathione (GSH)-reactive α-methylene-γ-butyrolactone groups were successfully prepared for the first time and showed excellent antiproliferative activities in vitro. Among them, compounds 2e and 2g displayed the highest antiproliferative properties with IC50 values ranging from 2.5 to 8.7 μM. The selectivity of these two compounds was evaluated by SRB method against human cancer and normal hepatic cells (HepG2 and L02). The induction of apoptosis and effects on the cell cycle distribution with compounds 2e and 2g were investigated by Hoechst 33,258 staining and flow cytometry, which exhibited that they could induce selective cell apoptosis and cell cycle arrest in HepG2 and L02 cells. In addition, further investigation showed that compounds 2e and 2g could obviously inhibit the proliferation of HepG2 cells by inducing significant DNA cross-linking and depleting GSH in cell media. The good cytotoxicity and selectivity of compounds 2e and 2g pointed them as promising leads for anticancer drug design.
- Xu, Yuan-Zhen,Gu, Xue-Yan,Peng, Shou-Jiao,Fang, Jian-Guo,Zhang, Ying-Mei,Huang, De-Jun,Chen, Jian-Jun,Gao, Kun
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p. 284 - 297
(2015/03/30)
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- Two-chamber hydrogen generation and application: Access to pressurized deuterium gas
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Hydrogen and deuterium gas were produced and directly applied in a two-chamber system. These gaseous reagents were generated by the simple reaction of metallic zinc with HCl in water for H2 and DCl in deuterated water for D2. The setup proved efficient in classical Pd-catalyzed reductions of ketones, alkynes, alkenes, etc. in near-quantitative yields. The method was extended to the synthesis and isotope labeling of quinoline and 1,2,3,4-tetrahydroquinoline derivatives. Finally, CX-546 and Olaparib underwent efficient Ir-catalyzed hydrogen isotope exchange reactions.
- Modvig, Amalie,Andersen, Thomas L.,Taaning, Rolf H.,Lindhardt, Anders T.,Skrydstrup, Troels
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p. 5861 - 5868
(2014/07/08)
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- Synthesis and hydrolytic evaluation of acid-labile imine-linked cytotoxic isatin model systems
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In this study a series of isatin-based, pH-sensitive aryl imine derivatives with differing aromatic substituents and substitution patterns were synthesised and their acid-catalysed hydrolysis evaluated. These derivatives were functionalised at the C3 carbonyl group of a potent N-substituted isatin cytotoxin and were stable at physiological pH but readily cleaved at pH 4.5. Observed rates of hydrolysis for the embedded imine-acid moiety were in the order para-phenylpropionic acid > phenylacetic acid (para > meta) > benzoic acid (meta > para). The ability to fine-tune hydrolysis rates in this way has potential implications for optimising imine linked, tumour targeting cytotoxin-protein conjugates.
- Matesic, Lidia,Locke, Julie M.,Vine, Kara L.,Ranson, Marie,Bremner, John B.,Skropeta, Danielle
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experimental part
p. 1771 - 1778
(2011/04/17)
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- HKGreen-3: A rhodol-based fluorescent probe for peroxynitrite
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A novel fluorescent probe, HKGreen-3, for sensing peroxynitrite is designed on the basis of the rhodol scaffold and a peroxynitrite-specific oxidation reaction. The probe turns out to be highly sensitive and selective for detecting peroxynitrite in both chemical and biological systems.
- Peng, Tao,Yang, Dan
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supporting information; scheme or table
p. 4932 - 4935
(2010/12/25)
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- NOVEL MULTIMERIC MOLECULES, A PROCESS FOR PREPARING THE SAME AND THE USE THEREOF FOR MANUFACTURING MEDICINAL DRUGS
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The invention relates to a compound of the formula (I): in which k and j are independently 0 or 1, Y is a macrocycle in which the cycle includes 9 to 36 carbon atoms and is functionalised by three amino functions and by a chain for attaching the spacer arm Z via an X bond, Rc is a binding pattern with a receptor of the TNF superfamily, X is a chemical function for binding the Y group to the space arm, and Z is a bi-, tri- or tetra-functional spacer arm.
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- NOVEL MULTIMERIC CD40 LIGANDS, METHOD FOR PREPARING SAME AND USE THEREOF FOR PREPARING DRUGS
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The invention concerns a compound of formula (I), wherein Y represents a macrocycle whereof the cycle comprises 9 to 36 atoms, and is functionalized by three amine or COOH functions; Rc represents a group of formula H—Xa—Xb—Xc—Xd—Xe—(Xf)i—, wherein i represents 0 or 1, Xn is in particular selected among lysine, arginine, ornithine residues, Xb is in particular selected among glycine, asparagine, L-proline or D-proline residues, Xc et Xd are in particular selected among tyrosine, phenylalanine or 3-nitrotyrosine residues, Xe et Xf are in particular selected among the following amino acid residues: NH2—(CH2)n—COOH, n ranging from 1 to 10 or NH2—(CH2—CH2—O)m—CH2CH2COOH, m ranging from 3 to 6, provided that one at least of the amino acid residues Xa, Xb, Xc and Xd is different from the corresponding amino acid in the sequence of the natural CD40 143Lys-Gly-Tyr-Tyr146 fragment
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- Novel palladium-on-carbon/diphenyl sulfide complex for chemoselective hydrogenation: Preparation, characterization, and application
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A diphenyl sulfide immobilized on palladium-on-carbon system, Pd/C[Ph 2S], was developed to achieve the highly chemoselective hydrogenation of alkenes, acetylenes, azides, and nitro groups in the presence of aromatic ketones, halides, benzyl esters, and N-Cbz protective groups. Instrumental analyses of the heterogeneous catalyst demonstrated that diphenylsul fide was embedded on Pd/C via coordination of its sulfur atom to palladium metal or physical interaction with graphite layers of the activated carbon. The catalyst could be recovered and reused at least five times without any significant loss of the reactivity.
- Mori, Akinori,Mizusaki, Tomoteru,Kawase, Masami,Maegawa, Tomohiro,Monguchi, Yasunari,Takao, Shinobu,Takagi, Yukio,Sajikia, Hironao
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experimental part
p. 406 - 410
(2009/04/06)
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- Development of a highly sensitive and specific enzyme-linked immunosorbent assay for detection of sudan I in food samples
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A highly selective and sensitive indirect competitive enzyme-linked immunosorbent assay (ELISA) for Sudan I was developed. Two hapten derivatives with different lengths of carboxylic spacer at the azo-bound para-position were synthesized and coupled to carrier proteins. The hapten-bovine serum albumin (BSA) conjugates were used as immunogens, while the hapten-ovalbumin (OA) conjugates were applied as coating antigens. The antisera which were obtained from four immunized rabbits were characterized in terms of sensitivity and specificity. At optimal experimental conditions it was found that IC 50 and LOD values of seven pairs based on four antisera and two coating antigens were in the range of 0.3-2 ng/mL and 0.02-0.1 ng/mL, respectively. The most sensitive ELISA could be established with Sudan I-propionic acid-OA coating antigen and the antiserum which was obtained with the corresponding immunogen. The cross-reactivity values of the four antisera with Sudan II, III, and IV was estimated with 0.1-14.3%. No cross-reactivity was found with six edible colorants Sunset yellow, Amarant, Kermes, Indigotin, Bright blue and Lemon yellow, indicating high specificity for Sudan I. Six food samples were fortified with Sudan I and extracted by simple sample preparation. The methanolic extracts after dilution with methanol:water (5:95, v/v) were analyzed by the developed ELISA. Assay precision and accuracy was estimated by determination of three replicates. Acceptable recovery rates of 92.5-114% and intra-assay coefficients of variation of 5.9-24.8% were obtained. The data were validated by conventional HPLC method. As revealed, both methods were highly correlated (r= 0.9851, n = 7), demonstrating the applicability of the developed ELISA for Sudan I analysis in food samples.
- Han, Dan,Yu, Meng,Knopp, Dietmar,Niessner, Reinhard,Wu, Mei,Deng, Anping
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p. 6424 - 6430
(2008/09/17)
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- INDANYLAMINO URACILS AND THEIR USE AS ANTIOXIDANTS AND NEUROPROTECTANTS
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Disclosed are compounds having the structure (I) wherein, R1 is H, NH2, NH-(C1-C4) alkyl, or N-[(C1-C4)alkyl]2; R2 and R3 are each independently H, (C1-C4) alkyl, or structure (II), wherein R4 is H, (C1-C4) alkyl, halogen, hydroxy, (C1-C10)alkoxy, cyano, nitro, -NR5R6, or -OCONR7R8; wherein R5 and R6 are each independently H, or a substituted or unsubstituted (C1-C4) alkyl; and wherein R7 and R8 are each independently H, or substituted or unsubstituted (C1-C4) alkyl or (C1-C10)aryl; and wherein only one of R2 and R3 is H, enantiomers, tautomers, and pharmaceutically acceptable salts of the compounds, pharmaceutical compositions containing such compounds or salts, and processes for their preparation. The subject invention also provides methods of alleviating symptoms of neurologic and inflammatory disorders, methods of preventing oxidation of lipids, proteins, or deoxyribonucleic acids on a cellular level, and methods of protecting human red blood cells from lysis by O2 radicals.
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Page/Page column 50
(2008/06/13)
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- Design, synthesis, and pharmacological evaluation of thapsigargin analogues for targeting apoptosis to prostatic cancer cells
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A series of thapsigargin (TG) analogues, containing an amino acid applicable for conjugation to a peptide specifically cleaved by prostate-specific antigen (PSA), has been prepared to develop the drug-moiety of prodrugs for treatment of prostatic cancer. The analogues were synthesized by converting TG into O-8-debutanoylthapsigargin (DBTG) and esterifying O-8 of DBTG with various amino acid linkers. The compounds were evaluated for their ability to elevate the cytosolic Ca2+ concentration ([Ca2+]i) in TSU-Pr1 cells, their ability to inhibit the rabbit skeletal muscle SERCA pump, and their ability to induce apoptosis in TSU-Pr1 human prostatic cancer cells. The activity of analogues, in which DBTG were esterified with ω-amino acids [HOOC(CH2)nNH2, n = 5-7, 10, 11], increased with the linker length. Analogues with 3-[4-(L-leucinoylamino)phenyl]propanoyl, 6-(L-leucinoylamino)hexanoyl, and 12-(L -serinoylamino)dodecanoyl were considerably less active than TG, and analogues with 12-(L-alaninoylamino)dodecanoyl and 12-(L-phenylalaninoylamino)dodecanoyl were almost as active as TG. The 12-(L-leucinoylamino)dodecanoyl gave an analogue equipotent with TG, making this compound promising as the drug-moiety of a PSA sensitive prodrug of TG.
- Jakobsen,Denmeade,Isaacs,Gady,Olsen,Christensen
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p. 4696 - 4703
(2007/10/03)
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- Novel tropane-based irreversible ligands for the dopamine transporter
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3α-(Diphenylmethoxy)tropane (benztropine) and its analogues are tropane ring-containing dopamine uptake inhibitors that display binding and behavioral profiles that are distinct from cocaine. We previously prepared a benztropine-based photoaffinity label [125I]-(N-[4-(4′-azido-3′-iodophenyl)butyl]- 3α-[bis(4′-fluorophenyl)methoxy]tropane, [125I]1, that covalently attached to the 1-2 transmembrane spanning region of the dopamine transporter (DAT). This was in contrast to the 4-7 transmembrane spanning region labeled by a cocaine-based photoaffinity label, [125I] 2 (RTI 82). To characterize further these different binding domains, photoaffinity ligands that had the 4′-azido-3′-iodophenyl substituent extended from the same position on the tropane ring were desirable. Thus, identification of the optimal alkyl linker between this substituent and the tropane nitrogen in the benztropine series was investigated to ultimately prepare the identical N-substituted analogue of 2. In this pursuit, the N-[4-(4′-azido-3′-iodophenyl)propyl] analogue of 3α-[bis(4′-fluorophenyl)methoxy]tropane (9a) was synthesized as well as two isothiocyanate analogues that do not require photoactivation (10a,b) for irreversible binding. The synthesis of these target compounds was achieved using a modification of the strategy developed for 1. Evaluation of these compounds for displacing [3H]WIN 35 428 binding at DAT in rat caudate putamen revealed that the 4′-azido-3′-iodophenylbutyl substituent, found in 1, provided optimal binding affinity and was chosen to replace the N-CH3 group on 2. Both the 4′-azido-3′-iodophenyl- and the 4′-isothiocyanatophenylbutyl analogues of 2 (25 and 26, respectively) were synthesized. Both products bound to DAT with comparable potency (IC50 = 30 nM) to RTI 82 (2). In addition, compound 26 demonstrated wash-resistant displacement of [3H]WIN 35 428 in HEK 293 cells stably transfected with hDAT. These ligands will provide important tools for further characterizing the binding domains for tropane-based dopamine uptake inhibitors at the DAT.
- Zou,Kopajtic,Katz,Wirtz,Justice Jr.,Newman
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p. 4453 - 4461
(2007/10/03)
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- Pyrimido?5,4-D!pyrimidines, medicaments comprising these compounds, their use and processes for their preparation
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The present invention relates to pyrimido?5,4-d!pyrimidines of the general formula STR1 in which Ra to Rc are as defined herein, their tautomers, their stereoisomers and their salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases which have valuable pharmacological properties, in particular an inhibiting action on signal transduction mediated by tyrosine kinases, their use for the treatment of diseases, in particular tumor diseases.
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- Pyrimido[5,4]-dipyrimidines, pharmaceuticals containing them, their use and processes for the preparation thereof
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Pyrimido[5,4-d]pyrimidines of the general formula [Figure] which have an inhibitory effect on signal transduction mediated by tyrosine kinases, their use for the treatment of disorders, in particular of oncoses, and their preparation. Exemplary compounds are: 4-[(3-Chloro-4-fluorophenyl)amino]-6-[1-methyl-4-piperidinylamino]pyrimido[5,4-d]pyrimidine, and 4-[(3-Chloro-4-fluorophenyl)amino]-6-[trans-4-dimethyl-aminocycohexylamino]pyrimido[5,4-d]pyrimidine.
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- A new series of photoactivatable and iodinatable linear vasopressin antagonists
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A series of new linear photoactivatable and iodinatable antagonists of the neuropeptidic hormone vasopressin was designed and synthesized by a combination of PyBOP-mediated Boc/solid-phase peptide synthesis and solution synthesis approaches. These were based on modifications of a previously reported potent and selective antagonist of the vasopressor response (V(1a) receptor) to [arginine]vasopressin, phenylacetyl-D-Tyr(Me)-Phe-Gln-Asn-Arg- Pro-Arg-Tyr-NH2. (Azidophenyl)alkyl substitutions, of the general structure N3-C6H4(CH2)(n)CO (n = 0, 1, 2, or 3), were employed in position 1. The seven new analogues are 4-N3-C6H4CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg- Tyr-NH2 (3), 3-N3-C6H4CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (12), 4-N3-C6H4CH2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (13), 3-N3- C6H4CH2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (14), 4-N3- C6H4(CH2)2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (15) 3-N3- C6H4(CH2)2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (16), 4-N3- C6H4(CH2)3CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (17). All analogues were tested for their affinity of the rat hepatic V(1a) receptor. Analogues 3 and 12 have a low affinity (K(i) ? 20 nM) and analogues 13-17 show a high affinity (K(i) between 0.04 and 0.3 nM). The affinity values appear to be mainly a function of the alkyl chain length and to a lesser extent of the meta or para position of the azido group on the aromatic ring. Analogues 13-17 were iodinated on the Tyr-9 residue, giving compounds 18-22. All these five iodinated derivatives exhibited K(i) values of 0.2-1 nM for rat liver membranes. Their affinities for oxytocin and renal V2 vasopressin receptors were much lower. Moreover, all analogues completely antagonized the vasopressin-stimulated inositol phosphates production in WRK1 cells and were devoided of any agonistic potency. Preliminary covalent binding studies showed improved covalent yields as compared to any previously reported results. They are very promising candidates as potential high-affinity, highly selective, photosensitive ligands for the V(1a) receptor. They could serve as useful pharmacological tools for studies on the vasopressin binding site.
- Carnazzi,Aumelas,Barberis,Guillon,Seyer
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p. 1841 - 1849
(2007/10/02)
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- UTILIZATION OF A NITRENIUM ION CYCLIZATION IN A SYNTHESIS OF A PHOTOACTIVE PROSTAGLANDIN, 17-(4-AZIDO-2-HYDROXYPHENYL)-18,19,20-TRINORPROSTAGLANDIN F2α
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A nitrenium ion cyclization provided access to a suitably substituted arylpropionic ester needed in the synthesis of a potential prostaglandin photoaffinity probe, 17-(4-azido-2-hydroxyphenyl)-18,19,20-trinorprostaglandin F2α using the Corey synthesis.
- Dolence, E. Kurt,Morita, Hiroyuki,Watt, David S.,Fitz, Tony
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- Iodide Reduction of Sulfilimines. Evidence for the Partitioning of Sulfurane Intermediates
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The iodide reduction of N-(substituted phenyl)-S,S-dimethylsulfilimmonium salts (aqueous solution, 25 deg C, μ = 1.0 with KCl) is firts order in proton activity in the pH range 0.5-3.0.The reduction of N-phenyl-S,S-dimethylsulfilimmonium chloride is also catalyzed by general acids with a Broensted α of 0.7.Electron-donating groups on the aniline leaving group accelerate the rate of the reduction with a βlg = 0.54.Rate constants for the reduction of sulfilimines derived from higher pKa amines are also linear with proton activity.For N-benzyl-S,S-dimethylsulfilimmonium chloride, no general catalysis is observed.For sulfilimines with unhindered primary amines as leaving group, a small βlg of about -0.1 is observed.For sulfilimines with benzamide and sulfonamide leaving groups the proton-catalyzed reaction contains both first- and second-order terms in proton activity.The rate of the reduction of the sulfilimine ylide is accelerated by electron-withdrawing substituents with βlg = -0.5.These data are interpreted in terms of a mechanism involving rate-limiting partitioning of a common tetracoordinate sulfurane intermediate.For aniline leaving groups, proton transfer to the neutral sulfurane is suggested to be rate limiting.For higher pKa leaving groups, the protonated sulfurane is solvent equilibrated and breakdown of this intermediate becomes rate limiting.For sulfilimines with very low pKa leaving groups, the predominant pathway is suggested to involve uncatalyzed breakdown of the neutral sulfurane intermediate with expulsion of sulfonamide anion.A parallel pathway involving the general catalyzed breakdown of the neutral sulfurane is also suggested to account for the greater than first-order proton dependence.
- Young, Paul R.,McMahon, Patrick E.
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p. 7572 - 7577
(2007/10/02)
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- The Transmission of Substituent-Induced 13C NMR Chemical Shifts in para-Substituted 3-Phenyl Propanoic Acid Methyl Esters
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Carbon-13 chemical shifts have been measured of para-substituted 3-phenyl propanoic acid methyl esters.The substituent-induced 13C shifts of the side chain were related to Hammett substituent effects by the dual substituent parameter method.The transmission of substituent effects and the factors that influence 13C shifts are discussed. - Keywords: Dual Substituent Parameters, Polar and Steric Interactions, Conformational Energy, 13C NMR Spectra
- Radeglia, R.,Spassov, S. L.,Stefanova, R.,Simova, S. D.
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p. 934 - 936
(2007/10/02)
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