- Synthesis and hyperpolarisation of eNOS substrates for quantification of NO production by 1H NMR spectroscopy
-
Hyperpolarization enhances the intensity of the NMR signals of a molecule, whose in vivo metabolic fate can be monitored by MRI with higher sensitivity. SABRE is a hyperpolarization technique that could potentially be used to image nitric oxide (NO) production in vivo. This would be very important, because NO dysregulation is involved in several pathologies, including cardiovascular ones. The nitric oxide synthase (NOS) pathway leads to NO production via conversion of L-arginine into L-citrulline. NO is a free radical gas with a short half-life in vivo (≈5?s), therefore direct NO quantification is challenging. An indirect method – based on quantifying conversion of an L-Arg- to L-Cit-derivative by 1H NMR spectroscopy – is herein proposed. A small library of pyridyl containing L-Arg derivatives was designed and synthesised. In vitro tests showed that compounds 4a–j and 11a–c were better or equivalent substrates for the eNOS enzyme (NO2? production?=?19–46?μM) than native L-Arg (NO2? production?=?25?μM). Enzymatic conversion of L-Arg to L-Cit derivatives could be monitored by 1H NMR. The maximum hyperpolarization achieved by SABRE reached 870-fold NMR signal enhancement, which opens up exciting future perspectives of using these molecules as hyperpolarized MRI tracers in vivo.
- Fernandez Diaz-Rullo, Fernando,Zamberlan, Francesco,Mewis, Ryan E.,Fekete, Marianna,Broche, Lionel,Cheyne, Lesley A.,Dall'Angelo, Sergio,Duckett, Simon B.,Dawson, Dana,Zanda, Matteo
-
-
Read Online
- Supramolecular parallel β-sheet and amyloid-like fibril forming peptides using δ-aminovaleric acid residue
-
Four terminally blocked tripeptides containing δ-aminovaleric acid residue self-assemble to form supramolecular β-sheet structures as are revealed from their FT-IR data. Single crystal X-ray diffraction studies of two representative peptides also show that they form parallel β-sheet structures. Self-aggregation of these β-sheet forming peptides leads to the formation of fibrillar structures, as is evident from scanning electron microscopic (SEM) and transmission electron microscopic (TEM) images. These peptide fibrils bind to a physiological dye, Congo red and exhibit a typical green-gold birefringence under polarized light, showing close resemblance to neurodegenerative disease causing amyloid fibrils.
- Banerjee, Arijit,Das, Apurba Kumar,Drew, Michael G.B.,Banerjee, Arindam
-
-
Read Online
- Cationic poly(2-oxazoline) hydrogels for reversible DNA binding
-
A new 2-oxazoline monomer with a Boc-protected amino group in the side chain (BocOx) was synthesized. Homopolymerization as well as copolymerization with 2-ethyl-2-oxazoline (EtOx) revealed a pseudo first order kinetic. A series of homopolymers was synthesized, deprotected and characterized regarding their structure and thermal properties. The copolymerization with EtOx yielded a series of water soluble polymers with varying amino contents. After deprotection it was shown by the ethidium bromide assay that these polymers were able to form complexes with DNA. Treatment with epichlorohydrin leads to the formation of hydrogels. The swelling properties of the gels were investigated and it could be demonstrated that also the polymeric scaffolds were able to immobilize DNA from aqueous solution. Furthermore, the release of the DNA was accomplished using heparin.
- Hartlieb, Matthias,Pretzel, David,Kempe, Kristian,Fritzsche, Carolin,Paulus, Renzo M.,Gottschaldt, Michael,Schubert, Ulrich S.
-
-
Read Online
- Selective Pseudo-irreversible Butyrylcholinesterase Inhibitors Transferring Antioxidant Moieties to the Enzyme Show Pronounced Neuroprotective Efficacy in Vitro and in Vivo in an Alzheimer's Disease Mouse Model
-
A series of multitarget-directed ligands (MTDLs) was designed by functionalizing a pseudo-irreversible butyrylcholinesterase (BChE) inhibitor. The obtained hybrids were investigated in vitro regarding their hBChE and hAChE inhibition, their enzyme kinetics, and their antioxidant physicochemical properties (DPPH, ORAC, metal chelating). In addition, in vitro assays were applied to investigate antioxidant effects using murine hippocampal HT22 cells and immunomodulatory effects on the murine microglial N9 cell line. The MTDLs retained their antioxidative properties compared to the parent antioxidant-moieties in vitro and the inhibition of hBChE was maintained in the submicromolar range. Representative compounds were tested in a pharmacological Alzheimer's disease (AD) mouse model and demonstrated very high efficacy at doses as low as 0.1 mg/kg. The most promising compound was also tested in BChE-/- mice and showed reduced efficacy. In vivo neuroprotection by BChE inhibition can be effectively enhanced by incorporation of structurally diverse antioxidant moieties.
- Scheiner, Matthias,Hoffmann, Matthias,He, Feng,Poeta, Eleonora,Chatonnet, Arnaud,Monti, Barbara,Maurice, Tangui,Decker, Michael
-
-
Read Online
- Synthesis and functional characterization of imbutamine analogs as histamine H3 and H4 receptor ligands
-
Imbutamine (4-(1H-imidazol-4-yl)butanamine) is a potent histamine H 3 (H3R) and H4 receptor (H4R) agonist (EC50 values: 3 and 66 nM, respectively). Aiming at improved selectivity for the H4R, the imidazole ring in imbutamine was methyl-substituted or replaced by various differently substituted heterocycles (1,2,3-triazoles, 1,2,4-triazoles, pyridines, pyrimidines) as potential bioisosteres. Investigations in [35S]GTPγS binding assays using membranes of Sf9 insect cells expressing the respective human histamine receptor subtype revealed only very weak activity of most of the synthesized hetarylalkylamines at both receptors. By contrast, the introduction of substituents at the 4-imidazolyl ring was most effective regarding H 4R selectivity. This holds for methyl substitution in position 2 and, especially, in position 5. 5-Methylimbutamine (H4R: EC50 = 59 nM, α = 0.8) was equipotent with imbutamine at the hH4R, but revealed about 16-fold selectivity for the hH4R compared to the hH3R (EC50 980 nM, α = 0.36), whereas imbutamine preferred the hH3R. The functional activities were in agreement with radioligand binding data. The results support the hypothesis that, by analogy with histamine, methyl substitution in histamine homologs offers a way to shift the selectivity in favor of the H4R. According to a bioisosteric approach, the imidazole ring in the dual histamine H3/H4 receptor agonist imbutamine (n = 4) was replaced by various five- and six-membered N-heterocycles. Whereas these structural modifications resulted in a reduction or loss of activity at both receptors, 5-methyl substitution at the imidazol-4-yl ring in imbutamine changed the receptor subtype selectivity in favor of the H4R.
- Geyer, Roland,Kaske, Melanie,Baumeister, Paul,Buschauer, Armin
-
-
Read Online
- Probing linker design in citric acid-ciprofloxacin conjugates
-
A series of structurally related citric acid-ciprofloxacin conjugates was synthesised to investigate the influence of the linker between citric acid and ciprofloxacin on antibacterial activities. Minimum inhibitory concentrations (MICs) were determined against a panel of reference strains and clinical isolates of bacteria associated with infection in humans and correlated with the DNA gyrase inhibitory activity. The observed trend was rationalised by computational modelling.
- Milner, Stephen J.,Snelling, Anna M.,Kerr, Kevin G.,Abd-El-Aziz, Ahmad,Thomas, Gavin H.,Hubbard, Roderick E.,Routledge, Anne,Duhme-Klair, Anne-Kathrin
-
-
Read Online
- Bisubstrate-Type Chemical Probes Identify GRP94 as a Potential Target of Cytosine-Containing Adenosine Analogs
-
We synthesized affinity-based chemical probes of cytosine-adenosine bisubstrate analogs and identified several potential targets by proteomic analysis. The validation of the proteomic analysis identified the chemical probe as a specific inhibitor of gluco
- Arimondo, Paola B.,Assemat, Fanny,Burlet-Schiltz, Odile,Chaoui, Karima,Chiosis, Gabriela,Halby, Ludovic,Lopez, Marie,Marcellin, Marlene,Pechalrieu, Dany,Sharma, Sahil,Yan, Pengrong
-
-
Read Online
- N, S-Double Labeling of N-Terminal Cysteines via an Alternative Conjugation Pathway with 2-Cyanobenzothiazole
-
Conjugation of 2-cyanobenzothiazole (CBT) with N-terminal cysteines (NCys) typically gives a luciferin product. We herein report an alternative reaction pathway leading to an N-terminal amidine rendering the side chain thiol available for further modification. Examination of peptide sequence dependence of this amidine conjugation reveals a tripeptide tag CIS that allows facile N, S-double labeling of a protein of interest with >90% yield. This alternative reaction pathway of CBT-NCys condensation presents a significant addition to the toolbox for site-specific protein modifications.
- Gao, Jianmin,Wang, Wenjian
-
-
Read Online
- Design, synthesis and biological evaluation of novel o-aminobenzamide derivatives as potential anti-gastric cancer agents in vitro and in vivo
-
Although gastric cancer has become a major public health problem, oral agents applied in clinics for gastric cancer therapy are scarce. Therefore, to explore new oral chemical entities with high efficiency and low toxicity, 41 o-aminobenzamide derivatives based on the scaffolds of MS-275 and SAHA were designed, synthesized, and evaluated for their anti-gastric cancer abilities in vitro and in vivo. Structure-activity relationships were discussed, leading to the identification of compounds F8 (IC50 = 0.28 μM against HGC-27 cell) and T9 (IC50 = 1.84 μM against HGC-27 cell) with improved cytotoxicity, anti-gastric cancer proliferation potency, induction of cell apoptosis and cell cycle arrest ability, inhibition of cell migration and invasion. What is worth mentioning is that compound F8 was more efficient and less toxic than the positive drug capecitabine in vivo on the HGC-27-xenograft model. Meanwhile, compound F8 exhibited suitable pharmacokinetic properties and less acute toxicity (LD50 > 1000 mg/kg). Besides, western blotting analysis, IHC analysis, differentially expressed proteins analysis and ABPP experiment indicated that compound F8 could modulate molecular pathways involved in apoptosis and cell cycle progression. Consequently, compound F8 is a strong candidate for the development of human gastric cancer therapy.
- Deng, Xuemei,Feng, Hanzhong,Feng, Yiyue,He, Yongxing,Jiang, Weifan,Li, Junfang,Li, Zhao,Liu, Dan,Lu, Yingmei,Shi, Tao,Wang, Zhen,Zhang, Honghua,Zhang, Jian
-
-
- Remote Amino Acid Recognition Enables Effective Hydrogen Peroxide Activation at a Manganese Oxidation Catalyst
-
Precise delivery of a proton plays a key role in O2 activation at iron oxygenases, enabling the crucial O?O cleavage step that generates the oxidizing high-valent metal–oxo species. Such a proton is delivered by acidic residues that may either
- Costas, Miquel,Olivo, Giorgio,Vicens, Laia
-
supporting information
(2021/12/27)
-
- An Integrated Cofactor/Co-Product Recycling Cascade for the Biosynthesis of Nylon Monomers from Cycloalkylamines
-
We report a highly atom-efficient integrated cofactor/co-product recycling cascade employing cycloalkylamines as multifaceted starting materials for the synthesis of nylon building blocks. Reactions using E. coli whole cells as well as purified enzymes produced excellent conversions ranging from >80 and 95 % into desired ω-amino acids, respectively with varying substrate concentrations. The applicability of this tandem biocatalytic cascade was demonstrated to produce the corresponding lactams by employing engineered biocatalysts. For instance, ?-caprolactam, a valuable polymer building block was synthesized with 75 % conversion from 10 mM cyclohexylamine by employing whole-cell biocatalysts. This cascade could be an alternative for bio-based production of ω-amino acids and corresponding lactam compounds.
- Sarak, Sharad,Sung, Sihyong,Jeon, Hyunwoo,Patil, Mahesh D.,Khobragade, Taresh P.,Pagar, Amol D.,Dawson, Philip E.,Yun, Hyungdon
-
p. 3481 - 3486
(2020/12/17)
-
- Two-way homologation of aliphatic aldehydes: Both one-carbon shortening and lengthening via the same intermediate
-
Aliphatic aldehydes can be homologated to both one-carbon shorter and one-carbon longer homologous carbonyl compounds through the 2–4 steps of reactions via the same intermediates, β,γ-unsaturated α-nitrosulfones, prepared from the proline-catalyzed sequential reactions of several aliphatic aldehydes with phenylsulfonylnitromethane. While the oxidative cleavage of the key intermediates gave one-carbon less homologous carbonyl compounds, the reduction of the same key intermediates followed by an oxidation produced one-carbon more homologous carbonyl compounds.
- Yoo, Jae Won,Seo, Youngran,Park, Jong Beom,Kim, Young Gyu
-
-
- Oxidative damage of proline residues by nitrate radicals (NO3): A kinetic and product study
-
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
-
supporting information
p. 6949 - 6957
(2020/10/02)
-
- Synthetic studies towards N-substituted 3-vinyl-4-piperidineacetic acid derivatives
-
The synthesis and full characterization of two new (E)-2-butenyl)-5-amino-2-pentenoates, (Z)-4-[N-(3-buten-1-yl)benzamido]-2-buten-1-ol, and (Z)-1-chloro-4-[N-(3-buten-l-yl)benzamido]-2-butene are reported. These were designed as substrates for a projected thermal ene cyclization leading to the N-substituted 3-vinyl-4-piperidineacetic acid scaffold. Although conditions for this ene-cyclization have not yet been uncovered, the ease of preparation of these ene-cyclization substrates gives promise for their future use.
- Johnson, David A.,Gribble, Gordon W.
-
p. 178 - 195
(2019/05/15)
-
- INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE AND METHODS OF THEIR USE
-
The present invention provides a compound of formula (II): an inhibitor of indoleamine 2,3-dioxygenase (IDO), which may be used as medicaments for the treatment of proliferative disorders, such as cancer, viral infections and/or autoimmune diseases. Its prodrugs are disclosed.
- -
-
Page/Page column 163; 164; 165
(2019/07/20)
-
- Design, synthesis and preliminary bioactivity evaluations of 8-hydroxyquinoline derivatives as matrix metalloproteinase (MMP) inhibitors
-
Matrix metalloproteinases (MMPs) play important roles in many diseases including cancer. With moderate metal-binding affinity, 8-hydroxyquinoline has gained much interest in current drug design and development. Specially, it has been reported that 8-hydroxyquinoline derivatives serve as MMP-2 inhibitors with micromolar IC50 values. In the current study, a series of 8-hydroxyquinoline derivatives were designed and synthesized as new MMP-2 and MMP-9 inhibitors. The most active compounds 5e and 5h not only displayed good inhibitory activities against MMP-2/9 with IC50 at submicromolar level, but also possessed potent anti-proliferative, anti-invasive and anti-angiogenesis activity in A549 cell line. Western blot also revealed that 5e and 5h down-regulate the expression of MMP-2 and MMP-9 in A549 cell line. Moreover, flow cytometry analysis indicated that compound 5e could promote apoptosis of A549 cells in vitro. Molecular docking analysis also revealed favorable binding modes of 5e in the active sites of MMP-2 and MMP-9.
- Chen, Chen,Yang, Xinying,Fang, Hao,Hou
-
-
- Genetic Incorporation of Olefin Cross-Metathesis Reaction Tags for Protein Modification
-
Olefin cross-metathesis (CM) is a viable reaction for the modification of alkene-containing proteins. Although allyl sulfide or selenide side-chain motifs in proteins can critically enhance the rate of CM reactions, no efficient method for their site-selective genetic incorporation into proteins has been reported to date. Here, through the systematic evaluation of olefin-bearing unnatural amino acids for their metabolic incorporation, we have discovered S-allylhomocysteine (Ahc) as a genetically encodable Met analogue that is not only processed by translational cellular machinery but also a privileged CM substrate residue in proteins. In this way, Ahc was used for efficient Met codon reassignment in a Met-auxotrophic strain of E. coli (B834 (DE3)) as well as metabolic labeling of protein in human cells and was reactive toward CM in several representative proteins. This expands the use of CM in the toolkit for "tag-and-modify" functionalization of proteins.
- Bhushan, Bhaskar,Lin, Yuya A.,Bak, Martin,Phanumartwiwath, Anuchit,Yang, Nan,Bilyard, Matthew K.,Tanaka, Tomonari,Hudson, Kieran L.,Lercher, Lukas,Stegmann, Monika,Mohammed, Shabaz,Davis, Benjamin G.
-
supporting information
p. 14599 - 14603
(2018/11/21)
-
- NOVEL TETRAHYDROPYRIDOPYRIMIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HBV INFECTION
-
The present invention provides novel compounds having general formula (I), wherein R1 to R4, A, W, Q and Y are as described herein, compositions including the compounds and methods of using the compounds.
- -
-
Page/Page column 153
(2018/09/25)
-
- Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures
-
Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t1/2 > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 ? resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-Aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel.
- Schwertz, Geoffrey,Witschel, Matthias C.,Rottmann, Matthias,Bonnert, Roger,Leartsakulpanich, Ubolsree,Chitnumsub, Penchit,Jaruwat, Aritsara,Ittarat, Wanwipa,Sch?fer, Anja,Aponte, Raphael A.,Charman, Susan A.,White, Karen L.,Kundu, Abhijit,Sadhukhan, Surajit,Lloyd, Mel,Freiberg, Gail M.,Srikumaran, Myron,Siggel, Marc,Zwyssig, Adrian,Chaiyen, Pimchai,Diederich, Fran?ois
-
supporting information
p. 4840 - 4860
(2017/06/28)
-
- Enhanced Spacer Length between Mannose Mimicking Shikimoyl and Quinoyl Headgroups and Hydrophobic Region of Cationic Amphiphile Increases Efficiency of Dendritic Cell Based DNA Vaccination: A Structure-Activity Investigation
-
In the field of dendritic cell based genetic immunization, previously we showed that liposomes of cationic amphiphiles containing mannose-mimicking shikimoyl headgroup are promising DNA vaccine carriers for dendritic cell (DC) transfection. The present structure-activity study reports on the influence of spacer length (between mannose-mimicking headgroups and quaternary nitrogen centers) in modulating the DC-transfection efficiencies. Further, we report on the anti-melanoma immune response inducing properties of the promising cationic amphiphiles in syngeneic C57BL/6J mice under prophylactic settings.
- Voshavar, Chandrashekhar,Meka, Rakesh C. R.,Samanta, Sanjoy,Marepally, Srujan,Chaudhuri, Arabinda
-
p. 1605 - 1610
(2017/03/08)
-
- Isoxazole-Based-Scaffold Inhibitors Targeting Cyclooxygenases (COXs)
-
A new set of cyclooxygenase (COX) inhibitors endowed with an additional functionality was explored. These new compounds also contained either rhodamine 6G or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, two moieties typical of efflux pump substrates and
- Perrone, Maria Grazia,Vitale, Paola,Panella, Andrea,Ferorelli, Savina,Contino, Marialessandra,Scilimati, Antonio,Lavecchia, Antonio
-
p. 1172 - 1187
(2016/07/13)
-
- Isoxazole-based-scaffold inhibitors targeting cyclooxygenases (COXs)
-
DMA new set of cyclooxygenase (COX) inhibitors endowed with an additional functionality was explored. These new compounds also contained either rhodamine 6G or 6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoline, two moieties typical of efflux pump substrates a
- Perrone, Maria Grazia,Vitale, Paola,Panella, Andrea,Ferorelli, Savina,Contino, Marialessandra,Lavecchia, Antonio,Scilimati, Antonio
-
p. 1172 - 1187
(2017/10/13)
-
- Synthesis and structure-activity relationship studies of small molecule disruptors of EWS-FLI1 interactions in Ewing's sarcoma
-
EWS-FLI1 is an oncogenic fusion protein implicated in the development of Ewing's sarcoma family tumors (ESFT). Using our previously reported lead compound 2 (YK-4-279), we designed and synthesized a focused library of analogues. The functional inhibition of the analogues was measured by an EWS-FLI1/NR0B1 reporter luciferase assay and a paired cell screening approach measuring effects on growth inhibition for human cells containing EWS-FLI1 (TC32 and TC71) and control PANC1 cell lines devoid of the oncoprotein. Our data revealed that substitution of electron donating groups at the para-position on the phenyl ring was the most favorable for inhibition of EWS-FLI1 by analogs of 2. Compound 9u (with a dimethylamino substitution) was the most active inhibitor with GI50 = 0.26 ± 0.1 μM. Further, a correlation of growth inhibition (EWS-FLI1 expressing TC32 cells) and the luciferase reporter activity was established (R2 = 0.84). Finally, we designed and synthesized a biotinylated analogue and determined the binding affinity for recombinant EWS-FLI1 (Kd = 4.8 ± 2.6 μM).
- Tosso, Perrer N.,Kong, Yali,Scher, Lauren,Cummins, Ryan,Schneider, Jeffrey,Rahim, Said,Holman, K. Travis,Toretsky, Jeffrey,Wang, Kan,üren, Aykut,Brown, Milton L.
-
p. 10290 - 10303
(2015/02/19)
-
- Design, synthesis, and pharmacological evaluation of fluorescent and biotinylated antagonists of ρ1 GABAC receptors
-
The ρ1 GABAC receptor is a ligand-gated chloride ion channel that shows promise as a therapeutic target for myopia, sleep disorders, memory and learning facilitation, and anxiety-related disorders. As such, there is a need for molecular probes to understand the role GABA C receptors play in physiological and pathological processes. To date, no labeled (either radioactive or fluorescent) GABAC selective ligand has been developed that can act as a marker for GABAC receptor visualization and localization studies. Herein, we report a series of fluorescent ligands containing different-sized linkers and fluorophores based around (S)-4-ACPBPA [(4-aminocyclopenten-1-yl)-butylphosphinic acid], a selective GABAC antagonist. One of these conjugates, (S)-4-ACPBPA-C5-BODIPY (13), displayed moderate potency (IC50 = 58.61 μM) and selectivity (>100 times) for ρ1 over α1β2γ2L GABAA receptors. These conjugates are novel lead agents for the development of more potent and selective fluorescent probes for studying the localization and function of GABAC receptors in living cells.
- Gavande, Navnath,Kim, Hye-Lim,Doddareddy, Munikumar R.,Johnston, Graham A. R.,Chebib, Mary,Hanrahan, Jane R.
-
supporting information
p. 402 - 407
(2013/06/05)
-
- DIBENZOTHIAZEPINE DERIVATIVES AND THEIR USE IN THE TREATMENT OF CNS DISORDERS
-
A compound of formula (I): or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, wherein: R1, R2, R3, R4, R5, R6, X and m are as defined herein.
- -
-
Page/Page column 37
(2012/11/07)
-
- Synthesis and cytotoxic activity of methyl glycyrrhetinate esterified with amino acids
-
Methyl glycyrrhetinate was esterified at position C3 of ring A using different amino acids. A short, unbranched chain of four carbon atoms with two amino groups in positions 2 and 4 was shown to be the most active compound of this series (IC50 = 0:8 M on liposarcoma Lipo cells). These compounds trigger apoptosis as shown by an acridine orange/ethidium bromide assay, trypan blue tests and DNAladdering experiments.
- Csuk, Rene,Schwarz, Stefan,Siewert, Bianka,Kluge, Ralph,Stroehl, Dieter
-
p. 731 - 746
(2012/11/13)
-
- COMPOUND, SYNTHESIS, COMPOSITION AND USES THEREOF
-
The instant application provides the disclosure for a compound of formula I, synthesis of compound of formula I and its pharmaceutical acceptable salts, as well as its polymorphs, solvates, and hydrates thereof. The pharmaceutically acceptable salt may be
- -
-
Page/Page column 13-14
(2011/11/30)
-
- Synthesis of poly(aspartimide)-based bio-glycoconjugates
-
The purpose of this programme was to synthesize and analyze new bioconjugates of interest for the potential inhibition of the influenza virus, using poly(aspartimide) as a polymer support. The macromolecular targets were obtained by attaching various sial
- Carlescu, Irina,Osborn, Helen M.I.,Desbrieres, Jacques,Scutaru, Dan,Popa, Marcel
-
experimental part
p. 33 - 40
(2011/02/28)
-
- Incorporation of fluorescent-labeled non-α-amino carboxylic acids into the N-terminus of proteins in response to amber initiation codon
-
Incorporation of non-natural amino acid derivatives containing fluorescent groups into proteins is a useful method for protein analyses. Here, we investigated the incorporation of fluorescent-labeled non-α-amino carboxylic acids into the N-terminus of proteins in response to the UAG initiation codon. A series of TAMRA-labeled amino carboxylic acids were synthesized and attached to an amber suppressor initiator tRNA derived from Escherichia coli initiator tRNA. Fluorescent-labeled amino carboxylic acids were successfully incorporated into the N-terminus of streptavidin by adding TAMRA-acylated initiator tRNAs to an E. coli cell-free translation system, although the incorporation efficiency differed depending on the amino carboxylic acid chain length. Based on this observation, 3-aminopropionic acid derivatives labeled with BODIPY, rhodamine, and cyanine fluorophores were designed and synthesized. The fluorescent-labeled 3-aminopropionic acid derivatives developed using BODIPY and rhodamine dyes could be incorporated with good efficiency. On the other hand, 6-aminohexanoic acid was effectively incorporated when labeled with cyanine dyes. The present study demonstrates that translation initiation can accept a wide variety of non-natural substrates and provides a useful method for N-terminal-specific labeling of proteins with various fluorophores.
- Miura, Masanori,Muranaka, Norihito,Abe, Ryoji,Hohsaka, Takahiro
-
experimental part
p. 546 - 553
(2010/08/21)
-
- Basic techniques of working on a solid phase: From ABC of the peptide synthesis to libraries of non-natural amino acids
-
Libraries of hardly available amino acids bearing a heteroaromatic ring (2-pyrimidyl, substituted 2-pyridyl or 2-thiazolyl) at the amino group were prepared using solid-phase synthesis on various resins. The synthesized compounds are structurally similar to some known antidiabetic drugs. The paper combines features of a review (elementary introduction to the solid-phase synthesis methodology and technique for beginners and selected methods from peptide chemistry) and step-by-step experimental protocols (tested by the authors) useful as a methodic tool. The presented protocols (immobilization and modification of amino acids, placing and removal of common protective groups) require no sophisticated equipment and may be useful as pictorial introductory tasks for students education. Pleiades Publishing, Ltd., 2010.
- Babaev,Ermolat'ev
-
experimental part
p. 2572 - 2589
(2011/04/15)
-
- Decomposition of 1-(ω-aminoalkanoyl)guanidines under alkaline conditions
-
The decomposition of some NG-(ω-aminoalkanoyl)argininamides, which are key intermediates for the preparation of radiolabeled and fluorescent neuropeptide Y receptor ligands, prompted us to synthesize a small series of simple 1-(ω-aminoalkanoyl)guanidines, and to investigate these model compounds for stability in alkaline buffers. The degradation of acylguanidines was monitored by time resolved UV spectroscopy. The most labile compound, 1-(5-aminopentanoyl)guanidine, decomposed with a half life of 19 s to yield piperidin-2-one (pH 10.4 at 25 °C). In contrast the half life of 1-(6-aminohexanoyl)guanidine is 7.7 h, which is comparable to the hydrolysis of acetylguanidine (t1/2 = 9.6 h) in alkaline solution.
- Brennauer, Albert,Keller, Max,Freund, Matthias,Bernhardt, Günther,Buschauer, Armin
-
p. 6996 - 6999
(2008/03/12)
-
- Mercaptoamide-based non-hydroxamic acid type histone deacetylase inhibitors
-
Inhibitors of histone deacetylases (HDAC) are emerging as a promising class of anti-cancer agents. A mercaptoamide functionality was designed as a bidentate zinc chelator and incorporated into the hydroxamic acid based SAHA (1) scaffold in order to identify non-hydroxamate compounds as potential inhibitors of histone deacetylases. Two sets of mercaptoamides 2 and 3 with varying spacer length were synthesized and their HDAC inhibitory activity was evaluated. Low micromolar inhibition was observed for mercaptoamides 2e, 3b, and 3d.
- Anandan, Sampath-Kumar,Ward, John S.,Brokx, Richard D.,Bray, Mark R.,Patel, Dinesh V.,Xiao, Xiao-Xi
-
p. 1969 - 1972
(2007/10/03)
-
- Coordination complexes having tethered therapeutic agents and/or targeting moieties, and methods of making and using the same
-
In part, the present invention is directed to coordination complexes comprising a therapeutic agent. In one aspect, the subject compositions comprise a platinum metal center and a covalently attached therapeutic agent.
- -
-
Page/Page column 34
(2010/02/09)
-
- Depsipeptides containing non-natural amino acids
-
A depsipeptide containing a non-natural amino acid(s) having the formula (1) wherein R1represents a C5-C20alkyl group and others; R2represents —O—CO—CH(R5)—X—CH(R6)—NH— (wherein X represent
- -
-
-
- 2- and 3-substituted 1,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: Synthesis and correlation between redox cycling activities and in vitro cytotoxicity
-
Trypanothione reductase (TR) is both a valid and an attractive target for the design of new trypanocidal drugs. Starting from menadione, plumbagin, and juglone, three distinct series of 1,4-naphthoquinones (NQ) were synthesized as potential inhibitors of TR from Trypanosoma cruzi (TcTR). The three parent molecules were functionalized at carbons 2 and/or 3 by various polyamine chains. Optimization of TcTR inhibition and TcTR specificity versus human disulfide reductases was achieved with the 3,3′-[polyaminobis(carbonylalkyl)]bis(1,4-NQ) series 19-20, in which an optimum chain length was determined for inhibition of the trypanothione disulfide reduction. The most active derivatives against trypanosomes in cultures were also studied as subversive substrates of TcTR and lipoamide dehydrogenase (TcLipDH). The activities were measured by following NAD(P)H oxidation as well as coupling the reactions to the reduction of cytochrome c which permits the detection of one-electron transfer. For TcTR, 204-c proved to be a potent subversive substrate and an effective uncompetitive inhibitor versus trypanothione disulfide and NADPH. Molecular modeling studies based on the known X-ray structures of TcTR and hGR were conducted in order to compare the structural features, dimensions, and accessibility of the cavity at the dimer interface of TcTR with that of hGR, as one of the putative NQ binding sites. TcLipDH reduced the plumbagin derivatives by an order of magnitude faster than the corresponding menadione derivatives. Such differences were not observed with the pig heart enzyme. The most efficient and specific subversive substrates of TcTR and TcLipDH exhibited potent antitrypanosomal activity in in vitro T. brucei and T. cruzi cultures. The results obtained here confirm that reduction of NQs by parasitic flavoenzymes is a promising strategy for the development of new trypanocidal drugs.
- Salmon-Chemin,Buisine,Yardley,Kohler,Debreu,Landry,Sergheraert,Croft,Krauth-Siegel,Davioud-Charvet
-
p. 548 - 565
(2007/10/03)
-
- Asymmetric catalysis of intramolecular N-H insertion reactions of α-diazocarbonyls
-
Intramolecular N-H insertion reactions of α-diazocarbonyl substrates are catalysed by rhodium(II) carboxylates with catalyst-dependent competition with C-H insertion and β-elimination; asymmetric N-H insertion leading to a pipecolic acid derivative with ee up to 45% is achieved using chiral catalysts.
- Garcia, Concepcion Fernandez,McKervey, M. Anthony,Ye, Tao
-
p. 1465 - 1466
(2007/10/03)
-
- Chemical combination of 6-deoxy-6-mycoloylamino-α,α-trehalose and N-acetyl-6-O-(aminoacyl)muramoyl dipeptide
-
6-Deoxy-6-mycoloylamino-α,α-trehalose, a biologically active derivative of 6,6′-di-O-mycoloyl-α,α-trehalose (TDM), and N-acetyl-6-O-(aminoacyl)-muramoyl dipeptide (MDP) were joined chemically by a succinic acid unit. The compounds synthesized showed activ
- Ishida, Hideharu,Ogawa, Yuji,Imai, Yasuyuki,Kiso, Makoto,Hasegawa, Akira,Sakurai, Takuma,Azuma, Ichiro
-
p. 199 - 208
(2007/10/02)
-
- A Convenient and General Method for the Preparation of tert-Butoxycarbonylaminoalkanenitriles and Their Conversion to Mono-tert-butoxycarbonylalkanediamines
-
A new method is described for the synthesis of tert-butoxycarbonylaminoalkanenitriles 3 by dehydration of the corresponding carboxamides 2 (prepared in two steps from aminoalkanoic acids) in the presence of trifluoroacetic anhydride and triethylamine.N-Boc-aminoalkanenitriles 3 are easily converted to mono-N-Boc-alkanediamines 4 under mild conditions avoiding the cleavage of the N-protective group.The monoprotected alkanediamines 4 are useful tools in affinity chromatography.
- Houssin, Raymond,Bernier, Jean-Luc,Henichart, Jean-Pierre
-
p. 259 - 261
(2007/10/02)
-
- Enkephalinase inhibitors
-
Mercaptoalkanoyl and acylmercaptoalkanoyl compounds of the formula STR1 wherein n is an integer from one to fifteen possess enkephalinase inhibition activity and are useful as analgesic agents.
- -
-
-
- Determination of unsaturated thyroxine binding protein sites using fluorescence polarization techniques
-
This invention encompasses a method for measuring unsaturated thyroxine binding protein sites in a sample comprising intermixing with the sample an effective amount of fluorescent labeled tracer having binding affinity for thyroxine binding proteins and t
- -
-
-
- Substituted carboxyfluoresceins
-
This disclosure relates to a method and reagents for determining ligands in biological fluids such as serum, plasma, spinal fluid, amnionic fluid and urine. This disclosure also relates to a novel class of tracer compounds employed as reagents in fluorescence polarization immunoassays.
- -
-
-