- The design of α/β-peptides: Study on three-residue turn motifs and the influence of achiral glycine on helix and turn
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Novel three-residue helix-turn secondary structures, nucleated by a helix at the N terminus, were generated in peptides that have 'β-Caa-L-Ala-L-Ala, ' 'β-Caa-L-Ala-γ-Caa,' and 'β-Caa-L-Ala-γ-Caa' (in which β-Caa is C-linked carbo-β-amino acid, γ-Caa is C-linked carbo-γ-amino acid, and γ-Caa is C-linked carbo-γ-amino acid) at the C terminus. These turn structures are stabilized by 12-, 14-, and 15-membered (mr) hydrogen bonding between NH(i)/CO(i+2) (i+2 is the last residue in the peptide) along with a 7-mr hydrogen bond between CO(i)/NH(i+2). In addition, a series of α/β-peptides were designed and synthesized with alternating glycine (Gly) and (S)-β-Caa to study the influence of an achiral α-residue on the helix and helix-turn structures. In contrast to previous results, the three 'β-α-β' residues at the C terminus (α-residue being Gly) are stabilized by only a 13-mr forward hydrogen bond, which resembles an α-turn. Extensive NMR spectroscopic and molecular dynamics (MD) studies were performed to support these observations. The influence of chirality and side chain is also discussed. A turn for the better: α/β-Peptides with novel turns (12/7-, 14/7-, and 15/7-) at the C terminus were prepared. Similarly, the design with glycine gave an opportunity to study the influence of achiral α-residues on helix formation and stability. This study also resulted in a new 13-membered 'turn' in the forward direction, which resembles the α-turn (see picture). Copyright
- Sharma, Gangavaram V. M.,Chandramouli, Nagula,Basha, Shaik Jeelani,Nagendar, Pendem,Ramakrishna, Kallaganti V. S.,Sarma, Akella V. S.
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- Solvent-Directed Switch of a Left-Handed 10/12-Helix into a Right-Handed 12/10-Helix in Mixed β-Peptides
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Present study describes the synthesis and conformational analysis of β-peptides from C-linked carbo-β-amino acids [β-Caa(l)] with a d-lyxo furanoside side chain and β-hGly in 1:1 alternation. NMR and CD investigations on peptides with an (S)-β-Caa(l) monomer at the N-terminus revealed a right-handed 10/12-mixed helix. An unprecedented solvent-directed "switch" both in helical pattern and handedness was observed when the sequence begins with a β-hGly residue instead of a (S)-β-Caa(l) constituent. NMR studies on these peptides in chloroform indicated a left-handed 10/12-helix, while the CD spectrum in methanol inferred a right-handed secondary structure. The NMR data for these peptides in CD3OH showed the presence of a right-handed 12/10-helix. NMR investigations in acetonitrile indicated the coexistence of both helix types. Quantum chemical studies predicted a small energy difference of 0.3 kcal/mol between the two helix types, which may explain the possibility of solvent influence. Examples for a solvent-directed switch of both the H-bonding pattern and the handedness of foldamer helices are rare so far. A comparable solvent effect was not found in the corresponding peptides with (R)-β-Caa(l) residues, where right-handed 12/10-helices are predominating.
- Thodupunuri, Prashanth,Katukuri, Sirisha,Ramakrishna, Kallaganti V. S.,Sharma, Gangavaram V. M.,Kunwar, Ajit C.,Sarma, Akella V. S.,Hofmann, Hans-J?rg
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- Three-residue turn in β-peptides nucleated by a 12/10 helix
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A new three-residue turn in β peptides nucleated by a 12/10-mixed helix is presented. In this design, β peptides were derived from the 1:1 alternation of C-linked carbo-β-amino acid ester [BocNH-(R)-β-Caa(r)-OMe] (Boc = tert-butyloxycarbonyl), which consisted of a D-ribo furanoside side chain, and β-hGly residues. The hexapeptide with (R)-β-Caa(r) at the N terminus showed the 'turn' stabilized by a 14-membered NH(4)...CO(6) hydrogen bond at the C terminus nucleated by a robust 12/10-mixed helix, thus providing a 'helix-turn' (HT) motif. The turn and the helix were additionally stabilized by intraresidue electrostatic interaction between the furan oxygen in the carbohydrate side chain and NH in the backbone. However, the hexapeptide with a β-hGly residue at the N terminus demonstrated the presence of a 10/12 helix through its entire length, which again showed the intraresidue interaction between NH and furan oxygen. The intraresidue NH...O-Me electrostatic interactions observed in the monomer, however, were absent in the peptides.
- Sharma, Gangavaram V. M.,Yadav, Thota Anupama,Marumudi, Kanakaraju,Thodupunuri, Prashanth,Reddy, Pothula Purushotham,Kunwar, Ajit C.
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- Synthesis of an unsaturated β-alanine derivative
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A procedure was developed for preparing an acrylic derivative of β-alanine. A terpolymer of this compound with glycidyl methacrylate and ethylene glycol dimethacrylate was prepared.
- Khimich,Slabospitskaya,Korzhikov,Tennikova
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Read Online
- Aryl imidazole derivative and application thereof
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The invention relates to an aryl imidazole derivative and application thereof. The aryl imidazole derivative is a compound shown as a formula (I) in the description or pharmaceutically acceptable salt thereof. The invention also discloses application of the aryl imidazole derivative in preparation of drugs for treating cancers. The invention further discloses application of the aryl imidazole derivative in preparation of drugs for treating diseases caused by EGFR mutation.
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Paragraph 0346-0350
(2021/06/23)
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- Structure-Based Design and Development of Chemical Probes Targeting Putative MOR-CCR5 Heterodimers to Inhibit Opioid Exacerbated HIV-1 Infectivity
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Crystal structures of ligand-bound G-protein-coupled receptors provide tangible templates for rationally designing molecular probes. Herein, we report the structure-based design, chemical synthesis, and biological investigations of bivalent ligands targeting putative mu opioid receptor C-C motif chemokine ligand 5 (MOR-CCR5) heterodimers. The bivalent ligand VZMC013 possessed nanomolar level binding affinities for both the MOR and CCR5, inhibited CCL5-stimulated calcium mobilization, and remarkably improved anti-HIV-1BaL activity over previously reported bivalent ligands. VZMC013 inhibited viral infection in TZM-bl cells coexpressing CCR5 and MOR to a greater degree than cells expressing CCR5 alone. Furthermore, VZMC013 blocked human immunodeficiency virus (HIV)-1 entry in peripheral blood mononuclear cells (PBMC) cells in a concentration-dependent manner and inhibited opioid-accelerated HIV-1 entry more effectively in phytohemagglutinin-stimulated PBMC cells than in the absence of opioids. A three-dimensional molecular model of VZMC013 binding to the MOR-CCR5 heterodimer complex is constructed to elucidate its mechanism of action. VZMC013 is a potent chemical probe targeting MOR-CCR5 heterodimers and may serve as a pharmacological agent to inhibit opioid-exacerbated HIV-1 entry.
- Huang, Boshi,Wang, Huiqun,Zheng, Yi,Li, Mengchu,Kang, Guifeng,Barreto-De-Souza, Victor,Nassehi, Nima,Knapp, Pamela E.,Selley, Dana E.,Hauser, Kurt F.,Zhang, Yan
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p. 7702 - 7723
(2021/06/28)
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- Structure-activity relationship and molecular modelling studies of quinazolinedione derivatives MMV665916 as potential antimalarial agent
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A series of new quinazolinedione derivatives have been readily synthesized and evaluated for their in vitro antiplasmodial growth inhibition activity. Most of the compounds inhibited P. falciparum FcB1 strain in the low to medium micromolar concentration. The 2-ethoxy 8ag’, 2-trifluoromethoxy 8ai’ and 4-fluoro-2-methoxy 8ak’ showed the best inhibitory activity with EC50 values around 5 μM and were non-toxic to the primary human fibroblast cell line AB943. However, these compounds were less potent than the original hit MMV665916, which showed remarkable growth inhibition with EC50 value of 0.4 μM and presented the highest selectivity index (SI > 250). In addition, a novel approach for determining the docking poses of these quinazolinedione derivatives with their potential protein target, the P. falciparum farnesyltransferase PfFT, was investigated.
- Albrecht, Sébastien,Florent, Isabelle,Mouray, Elisabeth,Mourot, Laura,Schmitt, Marjorie,Spichty, Martin
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supporting information
(2021/11/22)
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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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supporting information
p. 6949 - 6957
(2020/10/02)
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- Reverse Turn Foldamers: An Expanded β-Turn Motif Reinforced by Double Hydrogen Bonds
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Hybrid tetrapeptides sharing a backbone with a central α/β-dipeptide segment flanked by aromatic ?3-amino acid residues fold into the same hairpin conformation with an expanded β-turn. This hairpin/β-turn motif is general for accommodating different α- A nd β-amino acid residues. Replacing glycine with other α-amino acid residues has an insignificant influence on or slightly decreases the stabilities of the folded conformations; substituting β-alanine with other β-amino acid residues enhances the stabilities of the folded structures.
- Tang, Quan,Zhong, Yulong,Miller, Daniel P.,Liu, Rui,Zurek, Eva,Lu, Zhong-Lin,Gong, Bing
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supporting information
p. 1003 - 1007
(2020/02/04)
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- Preparation method of beta-alanine ester compound
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The invention belongs to the technical field of chemical industry, and particularly relates to a preparation method of a beta-alanine ester compound. The method comprises the following steps of a) dissolving cyanoacetate in a solvent I, adding a basic substance and Raney nickel for a catalysis hydrogenation reaction, after the reaction is completed,filtering and concentrating a filtrate to obtaina product A; b) dissolving the product A in a solvent II, adding the solvent II solution of hydrogen chloride dropwise,when the pH of a system is 2-3, stopping the dropwise addition,and obtaining mixed liquid B; c) concentrating the mixed liquid B and drying under a reduced pressure to obtainan aimed product. The method is adopted to prepare amino acid derivatives by catalytic hydrogenation of cyanoacetate,is simple to operate, mild in condition, low in equipment requirements and low in input cost, easily obtains raw materials, is low in price, is low in operating cost, is high in conversionrate of reactants, is high in product yield and is suitable for industrial large-scale production.
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Paragraph 0008-0015
(2019/07/16)
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- Discovery of a series of selective and cell permeable beta-secretase (BACE1) inhibitors by fragment linking with the assistance of STD-NMR
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Two β-secreatase (BACE1) inhibitors from natural products (cinnamic acid and flavone) were linked to furnish potent, cell permeable BACE1 inhibitors with noncompetitive mode of inhibition, with the assistance of saturated transfer difference (STD)-NMR technique. Some of these conjugates also exhibited selective BACE1 inhibition over other aspartyl proteases such as BACE-2 and renin, as well as poor cytotoxicity. Taken together, conjugates 4 represent a new series of BACE inhibitors warrants further investigation for their potential in Alzheimier's disease therapy.
- Fang, Wei-Shuo,Sun, De-yang,Yang, Shuang,Cheng, Chen,Moschke, Katrin,Li, Tianqi,Sun, Shanshan,Lichtenthaler, Stefan F.,Huang, Jian,Wang, Yinghong
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supporting information
(2019/09/30)
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- Multitarget CFTR Modulators Endowed with Multiple Beneficial Side Effects for Cystic Fibrosis Patients: Toward a Simplified Therapeutic Approach ?
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Cystic fibrosis (CF) is a multiorgan disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR). In addition to respiratory impairment due to mucus accumulation, viruses and bacteria trigger acute pulmonary exacerbations, accelerating disease progression and mortality rate. Treatment complexity increases with patients' age, and simplifying the therapeutic regimen represents one of the key priorities in CF. We have recently reported the discovery of multitarget compounds able to "kill two birds with one stone" by targeting F508del-CFTR and PI4KIIIβ and thus acting simultaneously as CFTR correctors and broad-spectrum enterovirus (EV) inhibitors. Starting from these preliminary results, we report herein a hit-to-lead optimization and multidimensional structure-activity relationship (SAR) study that led to compound 23a. This compound showed good antiviral and F508del-CFTR correction potency, additivity/synergy with lumacaftor, and a promising in vitro absorption, distribution, metabolism, and excretion (ADME) profile. It was well tolerated in vivo with no sign of acute toxicity and histological alterations in key biodistribution organs.
- Tassini, Sabrina,Langron, Emily,Delang, Leen,Mirabelli, Carmen,Lanko, Kristina,Crespan, Emmanuele,Kissova, Miroslava,Tagliavini, Giulia,Fontò, Greta,Bertoni, Simona,Palese, Simone,Giorgio, Carmine,Ravanetti, Francesca,Ragionieri, Luisa,Zamperini, Claudio,Mancini, Arianna,Dreassi, Elena,Maga, Giovanni,Vergani, Paola,Neyts, Johan,Radi, Marco
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supporting information
p. 10833 - 10847
(2019/12/25)
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- From hit to lead: Structure-based discovery of naphthalene-1-sulfonamide derivatives as potent and selective inhibitors of fatty acid binding protein 4
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Fatty acid binding protein 4 (FABP4) plays a critical role in metabolism and inflammatory processes and therefore is a potential therapeutic target for immunometabolic diseases such as diabetes and atherosclerosis. Herein, we reported the identification of naphthalene-1-sulfonamide derivatives as novel, potent and selective FABP4 inhibitors by applying a structure-based design strategy. The binding affinities of compounds 16dk, 16do and 16du to FABP4, at the molecular level, are equivalent to or even better than that of BMS309403. The X-ray crystallography complemented by the isothermal titration calorimetry studies revealed the binding mode of this series of inhibitors and the pivotal network of ordered water molecules in the binding pocket of FABP4. Moreover, compounds 16dk and 16do showed good metabolic stabilities in liver microsomes. Further extensive in vivo study demonstrated that 16dk and 16do exhibited a dramatic improvement in glucose and lipid metabolism, by decreasing fasting blood glucose and serum lipid levels, enhancing insulin sensitivity, and ameliorating hepatic steatosis in obese diabetic (db/db) mice.
- Gao, Ding-Ding,Dou, Hui-Xia,Su, Hai-Xia,Zhang, Ming-Ming,Wang, Ting,Liu, Qiu-Feng,Cai, Hai-Yan,Ding, Hai-Peng,Yang, Zhuo,Zhu, Wei-Liang,Xu, Ye-Chun,Wang, He-Yao,Li, Ying-Xia
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- Spin-labeled derivatives of cardiotonic steroids as tools for characterization of the extracellular entrance to the binding site on Na+,K+-ATPase
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The information obtained from crystallized complexes of the Na+,K+-ATPase with cardiotonic steroids (CTS) is not sufficient to explain differences in the inhibitory properties of CTS such as stereoselectivity of CTS binding or effect of glycosylation on the preference to enzyme isoforms. The uncertainty is related to the spatial organization of the hydrophilic cavity at the entrance of the CTS-binding site. Therefore, there is a need to supplement the crystallographic description with data obtained in aqueous solution, where molecules have significant degree of flexibility. This work addresses the applicability of the electron paramagnetic resonance (EPR) method for the purpose. We have designed and synthesized spin-labeled compounds based on the cinobufagin steroid core. The length of the spacer arms between the steroid core and the nitroxide group determines the position of the reporting group (N-O) confined to the binding site. High affinity to Na+,K+-ATPase is inferred from their ability to inhibit enzymatic activity. The differences between the EPR spectra in the absence and presence of high ouabain concentrations identify the signature peaks originating from the fraction of the spin labels bound within the ouabain site. The degree of perturbations of the EPR spectra depends on the length of the spacer arm. Docking of the compounds into the CTS site suggests which elements of the protein structure might be responsible for interference with the spin label (e.g., steric clashes or immobilization). Thus, the method is suitable for gathering information on the cavity leading to the CTS-binding site in Na+,K+-ATPase in all conformations with high affinity to CTS.
- Guo, Jin-Hua,Jiang, Ren-Wang,Andersen, Jacob Lauwring,Esmann, Mikael,Fedosova, Natalya U.
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p. 2292 - 2305
(2018/05/14)
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- 6-MEMBERED URACIL ISOSTERES
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Provided herein are dUTPase inhibitors, compositions comprising such compounds and methods of using such compounds and compositions.
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Paragraph 0836
(2018/06/12)
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- Fluoroquinolone amino derivatives and use thereof in prevention and control of citrus diseases
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Citrus canker and brown spot are common diseases of citrus. At present, few drugs are available to prevent and control the two diseases and have certain defects. Amino groups at the 7th positions of fluoroquinolone drugs are linked with an active fragment by means of a connecting structure so as to obtain compounds shown in a formula I or a formula II. Experiments prove that the compounds providedby the invention have effects of preventing and controlling the citrus canker and the brown spot and have very good application prospect.
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Paragraph 0113-0114; 0134
(2018/07/30)
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- Deciphering the potentiometric properties of (porphinato)zinc(ii)-derived supramolecular polymers and related superstructures
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Because modulating the structure-function relationships of π-conjugated superstructures opens fresh opportunities to tune the electronic structures of semiconducting materials, self-assembled architectures have emerged as pivotal candidates to engineer optoelectronic devices. While the photophysical and electrical properties of 1-dimensional supramolecular polymers have been extensively explored, establishing their fundamental potentiometric properties using reliable electrochemical measurements has been less scrutinized and would benefit the engineering of semiconducting materials. In this regard, elucidating the energy level of valence and conduction bands that delineate the electronic structure of self-assemblies is critical to unveiling the parameters that regulate their structure-function properties. In the present contribution, design principles to engineer 2-dimensional nanosheets, nanowires, fibers and amorphous solids from (porphinato)zinc(ii) (PZn) building blocks have been elucidated by modifying the structural properties of the side chains that flank PZn-based cores. As these self-assemblies feature identical redox-active building blocks but evidence different solid-state morphologies, the elucidation of their potentiometric properties reveals important structural parameters that regulate the potentials at which holes and electrons are injected into the valence and conduction bands of these hierarchical materials. While self-assembly conformations modestly impact valence band energies, superstructures built from H-type aggregates feature a conduction band energy stabilized by more than 350 meV with respect to those constructed from J-type aggregates.
- Liu, Chuan,Liu, Kaixuan,Klutke, Jared,Ashcraft, Adam,Steefel, Samantha,Olivier, Jean-Hubert
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supporting information
p. 11980 - 11991
(2018/11/26)
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- Silver comes into play: Henry reaction and domino cycloisomerisation sequence catalysed by [Ag(i)(Pc-L)] complexes
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We report herein the synthesis of new pyridine-containing macrocyclic ligands (Pc-L) bearing a non-innocent pendant arm, by exploiting both chiral and functional properties of natural amino acids. The obtained macrocyclic ligands were employed to synthesize well-defined cationic silver(i) complexes that were shown to be competent catalysts for the Henry (nitroaldol) reaction. Good to excellent yields and full selectivity in the β-nitroalcohol product were obtained starting from electron-poor aromatic aldehydes or other activated aldehydes such as furfural under mild reaction conditions. The straightforward synthesis of the macrocyclic ligands starting from cheap commercially available starting materials allowed the introduction of a suitable basic functionality into the ligand pendant arm, thus providing a bifunctional catalyst. Based on our previous experience in the [Ag(i)(Pc-L)] catalysed domino addition/cycloisomerisation reaction of o-alkynylbenzaldehydes and nucleophiles, the synthesis of isochromenes coupling the Henry reaction and the cycloisomerisation in a single step was subsequently explored. Although with low selectivity, [Ag(i)(Pc-L)] cationic complexes were able to promote such a cascade reaction and a possible mechanism based on experimental evidence has been proposed.
- Tseberlidis, Giorgio,Dell'Acqua, Monica,Valcarenghi, Daniele,Gallo, Emma,Rossi, Elisabetta,Abbiati, Giorgio,Caselli, Alessandro
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p. 97404 - 97419
(2016/10/25)
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- Design, synthesis, and biological characterization of tamibarotene analogs as anticancer agents
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In our efforts of developing novel compounds as potential anticancer agents, a series of tamibarotene analogs containing Zn2+-binding moieties were designed and developed. Biological characterization identified compound 7b as the most potent one with improved antiproliferative activities against multiple cancer cell lines, compared to parent compound tamibarotene. Further characterization also demonstrated that compound 7b exhibited moderate activities as a histone deacetylase inhibitor with IC50 of 1.8?±?0.1?μm, thus suggesting that this could contribute to the improved antiproliferative activities of 7b. Pharmacokinetic studies revealed that compound 7b could release tamibarotene after administration and prolong the circulation time of tamibarotene, and this may also potentially contribute to the improved antiproliferative activities. Collectively, the results demonstrated that compound 7b could serve as a new lead for further development of more potent analogs as potential anticancer agents.
- Jiang, Yuqi,Li, Xiaoyang,Wang, Xue,Wang, Zhonglan,Zhang, Jian,Wu, Jingde,Xu, Wenfang
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p. 542 - 555
(2016/10/06)
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- Catalysts and temperature driven melt polycondensation reaction for helical poly(ester-urethane)s based on natural L-amino acids
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Catalyst and temperature driven melt polycondensation reaction was developed for natural L-amino acid monomers to produce new classes of poly(ester-urethane)s. Wide ranges of catalysts from alkali, alkali earth metal, transition metal and lanthanides were developed for the condensation of amino acid monomers with diols to yield poly(ester-urethane)s. A-B Diblock and A-B-A triblock species were obtained by carefully choosing mono- or diols in model reactions. More than two dozens of transition metal and lanthanide catalysts were identified for the polycondensation to yield high molecular weight poly(ester-urethane)s. Theoretical studies revealed that the carbonyl carbon in ester possessed low electron density compared to the carbonyl carbon in urethane which driven the thermo-selective polymerization process. Optical purity of the L-amino acid residues in the melt polycondensation process was investigated using D- and L-isomers and the resultant products were analyzed by chiral-HPLC and CD spectroscopy. CD analysis revealed that the amino acid based polymers were self-assembled as β-sheet and polyproline type II secondary structures. Electron and atomic force microscopic analysis confirmed the formation of helical nano-fibrous morphology in poly(ester-urethane)s. The newly developed melt polycondensation process is very efficient and optimized for wide range of catalysts to produce diverse polymer structures from natural L-amino acids.
- Anantharaj, Santhanaraj,Jayakannan, Manickam
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p. 1065 - 1077
(2016/03/12)
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- Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins
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A series of gossypol Schiff bases that were derived from unnatural linear amino acid methyl esters were identified and found to be much more potent than gossypol and ABT-199 in terms of anticancer activity. This is the first example of gossypol Schiff bases with increased activity. The investigation of the Schiff base side chain of gossypol revealed that the unique anticancer effect was achieved by the introduction of hydrophobic ester groups. The optimized products showed low micromolar pan antitumor activities against NCI-60 tumor cell lines, which is promising for further drug development. Studies on the preliminary mechanism of action for their cellular activities was also carried out with antiapoptotic protein (Bcl-2 and Mcl-1) inhibition FP assays. The molecular modeling analysis demonstrated a possible binding mode for these compounds with Bcl-2, which could explain the binding affinity of the novel gossypol Schiff bases with these proteins.
- Lu, Yuzhi,Wu, Shuangchan,Yue, Yuan,He, Si,Li, Jun,Tang, Jun,Wang, Wei,Zhou, Hai-Bing
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supporting information
p. 1185 - 1190
(2016/12/18)
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- A multifaceted secondary structure mimic based on piperidine-piperidinones
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Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus dld-1-faf crystallized in a conformation that is estimated to be 0.91 kcal-mol-1 above the minimum energy solution state. Do we know, when designing a new peptidomimetic scaffold like the one shown, how it can resemble secondary structures? Design and modular synthesis of this elongated mimic is reported, and the structure is related to ideal and real structures at PPI interfaces.
- Xin, Dongyue,Perez, Lisa M.,Ioerger, Thomas R.,Burgess, Kevin
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supporting information
p. 3594 - 3598
(2014/04/17)
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- N-SUBSTITUTED ISOPROPYLDIMETHYL AZULENE SULFONAMIDE DERIVATIVES, AND PREPARATION METHOD AND USE THEREOF
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The present invention provides an N-substituted isopropyldimethyl azulene sulfonamide derivative as represented by formula (I), and preparation method and uses thereof, wherein R1 is an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, amino, or a substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and amino. The N-substituted isopropyldimethyl azulene sulfonamide derivative can be used in treating gastric ulcer.
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Paragraph 0016
(2014/08/06)
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- OxymaPure/DIC: An efficient reagent for the synthesis of a novel series of 4-[2-(2-acetylaminophenyl)-2-oxo-acetylamino] benzoyl amino acid ester derivatives
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OxymaPure (ethyl 2-cyano-2-(hydroxyimino)acetate) was tested as an additive for use in the carbodiimide (DIC) approach for the synthesis of a novel series of α-ketoamide derivatives (4-[2-(2-acetylaminophenyl)-2-oxo-acetylamino] benzoyl amino acid ester derivatives). OxymaPure showed clear superiority to HOBt/DIC or carbodiimide alone in terms of purity and yield. The title compounds were synthesized via the ring opening of N-acylisatin. First, N-acetylisatin was reacted with 4-aminobenzoic acid under conventional heating as well as microwave irradiation to afford 4-(2-(2-acetamidophenyl)-2-oxoacetamido)benzoic acid. This α-ketoamide was coupled to different amino acid esters using OxymaPure/DIC as a coupling reagent to afford 4-[2-(2-acetylaminophenyl)-2- oxoacetylamino] benzoyl amino acid ester derivatives in excellent yield and purity. The synthesized compounds were characterized using FT-IR, NMR, and elemental analysis.
- El-Faham, Ayman,Al Marhoon, Zainab,Abdel-Megeed, Ahmed,Albericio, Fernando
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p. 14747 - 14759
(2014/01/17)
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- Optical activity 1,5-substituted-1,3,5-hexahydrotriazine-2-N-nitroimines: Synthesis and insecticidal activity
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Twelve novel neonicotinoid analogues 1-(2-furfuryl)-5-substituted-1,3,5- hexahydrotriazine-2-N-nitroimines 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l were synthesized. Their structures were characterized by 1H NMR, IR, and elemental analysis. The preliminary bioassay tests showed that all the title compounds gave ≥90% mortality against Nilaparvata lugen 500 mg/L.
- Xue, Si-Jia,Bu, Hong-Fei,Liu, Li,Xu, Xiao,Ma, Xubo,Zhu, Jun
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p. 1067 - 1070
(2013/10/21)
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- Direct C-H alkylation of naphthoquinones with amino acids through a revisited Kochi-Anderson radical decarboxylation: Trends in reactivity and applications
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In our ongoing research program into the discovery of new anticancer drugs, we were interested in the preparation of naphthoquinone scaffolds bearing aminoalkyl side-chains. Following this aim, we revisited the Kochi-Anderson radical decarboxylation of amino acids in order to set up a versatile route to the direct functionalization of naphthoquinones. The best reaction conditions were applied to a selected series of compounds in a systematic methodological study which allowed us to establish important trends in reactivity. We found that α-substituted β-amino acids were the most suitable substrates for the radical addition. In contrast, α-amino acids gave modest results. The influence of the amine protecting groups on the reaction outcome has also been studied. This practical procedure allows the introduction of various unsymmetrical moieties, including orthogonally protected linear aminoalkyl chains or chiral dipeptidic chains, and opens the door to a wide scope of easily accessible chemical diversity.
- Naturale, Guillaume,Lamblin, Marc,Commandeur, Claude,Dessolin, Jean,Felpin, Francois-Xavier
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supporting information
p. 5774 - 5788,15
(2020/09/15)
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- Synthesis, characterization and pharmacological evaluation of amino acid conjugates of ketoprofen
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Ketoprofen is used for its antipyretic, analgesic and antiinflammatory properties by inhibiting cyclooxygenase-1 and cyclooxygenase-2 enzymes reversibly, which decreases production of proinflammatory prostaglandin precursors. Ketoprofen suffers from the general side effects of nonsteroidal antiinflammatory drugs, owing to presence of free carboxylic acid group. The study aimed to retard the adverse effects of gastrointestinal origin. Different conjugates of ketoprofen have been synthesized by amidation with methyl esters of amino acids namely, phenylalanine, lysine, arginine, glycine, cysteine, valine, glutamine, serine, proline and alanine. Synthesized conjugates were characterized and evaluated for analgesic and antiinflammatory activities.
- Dubey,Jain,Bhadoria,Sinha
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experimental part
p. 1170 - 1174
(2012/08/28)
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- Polymers from amino acids: Development of dual ester-urethane melt condensation approach and mechanistic aspects
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A new dual ester-urethane melt condensation methodology for biological monomers-amino acids was developed to synthesize new classes of thermoplastic polymers under eco-friendly and solvent-free polymerization approach. Naturally abundant l-amino acids were converted into dual functional ester-urethane monomers by tailor-made synthetic approach. Direct polycondensation of these amino acid monomers with commercial diols under melt condition produced high molecular weight poly(ester-urethane)s. The occurrence of the dual ester-urethane process and the structure of the new poly(ester-urethane)s were confirmed by 1H and 13C NMR. The new dual ester-urethane condensation approach was demonstrated for variety of amino acids: glycine, β-alanine, l-alanine, l-leucine, l-valine, and l-phenylalanine. MALDI-TOF-MS end group analysis confirmed that the amino acid monomers were thermally stable under the melt polymerization condition. The mechanism of melt process and the kinetics of the polycondensation were studied by model reactions and it was found that the amino acid monomer was very special in the sense that their ester and urethane functionality could be selectively reacted by polymerization temperature or catalyst. The new polymers were self-organized as β-sheet in aqueous or organic solvents and their thermal properties such as glass transition temperature and crystallinity could be readily varied using different l-amino acid monomers or diols in the feed. Thus, the current investigation opens up new platform of research activates for making thermally stable and renewable engineering thermoplastics from natural resource amino acids.
- Anantharaj,Jayakannan
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experimental part
p. 2446 - 2455
(2012/10/08)
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- Structure-activity relationship studies of 1-(4-chloro-2,5-dimethoxyphenyl) -3-(3-propoxypropyl)thiourea, a non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type-1
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The reverse transcriptase (RT) of the human immunodeficiency virus type-1 (HIV-1) is still a prime target for drug development due to the continuing need to block drug-resistant RT mutants by new inhibitors. We have previously identified 1-(4-chloro-2,5-dimethoxyphenyl)-3-(3-propoxypropyl)thiourea, compound 1, as a potent RT inhibitor from an available chemical library. Here, we further modified this compound to study structure-activity relationships when replacing various groups in the molecule. Different functional groups were systematically introduced on the aromatic ring and the aliphatic chain of the compound was modified. The effect of these modifications on viral infectivity was then evaluated. The most potent compound found was propyl 4-(amino-N-(4-chloro-2,5-dimethoxyphenyl)methanethioamino)butanoate, 45c, which inhibited infectivity with a calculated IC50 of about 1.1 μM. Docking studies identified potential important interactions between the top scoring ligands and HIV-1 RT, and the predicted relative affinity of the ligands was found to be in agreement with the experimental results.
- Weitman, Michal,Lerman, Keti,Nudelman, Abraham,Major, Dan Thomas,Hizi, Amnon,Herschhorn, Alon
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scheme or table
p. 447 - 467
(2011/03/20)
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- Total synthesis of asperlicin C, circumdatin F, demethylbenzomalvin A, demethoxycircumdatin H, sclerotigenin, and other fused quinazolinones
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Using scandium triflate and microwaves, the direct double dehydrocyclization of anthranilate-containing tripeptides was achieved, affording the total syntheses of (i) quinazolino[3,2-a]benzodiazepinediones (1a-f), (ii) diazepino[2,1-b]quinazolinediones (2a-e), and (iii) pyrazino[2,1-b]quinazolinediones (3a-e) with good overall isolated yields (23-43%, 37-47% and 31-56%, respectively). Among the quinazolino[3,2-a] benzodiazepinediones synthesized, 1a (sclerotigenin), 1b (circumdatin F), and 1f (asperlicin C) are natural products.
- Tseng, Ming-Chung,Yang, Huei-Yun,Chu, Yen-Ho
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experimental part
p. 419 - 427
(2010/02/16)
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- Supramolecular gelation of alcohol and water by synthetic amphiphilic gallic acid derivatives
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The supramolecular organogelation of alcohols was observed in relatively hydrophobic amphiphiles with a short oligo(ethylene glycol) unit and three long alkyl chains at room temperature, while the hydrogelation occurred in more hydrophilic gelators with a longer poly(ethylene glycol) unit and two long alkyl chains at various temperatures. When a hot aqueous solution of some of the synthetic hydrogelators was cooled down, the supramolecular hydrogel was formed at room temperature. In some other amphiphiles with less intermolecular interactivity in water at room temperature, a reverse phase transition of sol to gel was observed by elevating the temperature of their aqueous systems, especially below a physiological temperature, 37 °C. The supramolecular hydrogelation at a low or high temperature was dependent on a slight molecular modification of the synthetic amphiphiles.
- Tamiaki, Hitoshi,Ogawa, Keishiro,Enomoto, Keisuke,Taki, Kazutaka,Hotta, Atsushi,Toma, Kazunori
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supporting information; experimental part
p. 1661 - 1666
(2010/04/24)
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- Discovery of inhibitors of aberrant gene transcription from libraries ofdna binding molecules: Inhibition of LEF-1-mediated gene transcription and oncogenic transformation
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The screening of a >9000 compound library of synthetic DNA binding molecules for selective binding to the consensus sequence of the transcription factor LEF-1 followed by assessment of the candidate compounds in a series of assays that characterized functional activity (disruption of DNA-LEF-1 binding) at the intended target and site (inhibition of intracellular LEF-1-mediated gene transcription) resulting in a desired phenotypic cellular change (inhibit LEF-1-driven cell transformation) provided two lead compounds: lefmycin-1 and lefmycin-2. The sequence of screens defining the approach assures that activity in the final functional assay may be directly related to the inhibition of gene transcription and DNA binding properties of the identified molecules. Central to the implementation of this generalized approach to the discovery of DNA binding small molecule inhibitors of gene transcription was (1) the use of a technically nondemanding fluorescent intercalator displacement (FID) assay for initial assessment of the DNA binding affinity and selectivity of a library of compounds for any sequence of interest, and (2) the technology usedto prepare a sufficiently large library of DNA binding compounds.
- Stover, James S.,Shi, Jin,Jin, Wei,Vogt, Peter K.,Boger, Dale L.
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supporting information; experimental part
p. 3342 - 3348
(2009/07/30)
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- A convenient synthesis of amino acid methyl esters
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A series of amino acid methyl ester hydrochlorides were prepared in good to excellent yields by the room temperature reaction of amino acids with methanol in the presence of trimethylchlorosilane. This method is not only compatible with natural amino acids, but also with other aromatic and aliphatic amino acids.
- Li, Jiabo,Sha, Yaowu
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p. 1111 - 1119
(2008/09/21)
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- The synthesis of novel methotrexate-like compounds
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Methotrexate (MTX) is a folate antagonist used in treatment of several chronic inflammatory and neoplastic conditions. In this study, new MTX-like compounds that may-be potential anticancer agents were synthesized and their structures were determined by IR, UV, GC-MS, 1H NMR, and 13C NMR spectra. Also, in this study, a series structurally related to MTX or folate analogous compounds were evaluated whether they have inhibitory properties on the dihydrofolate reductase activity (DHFR).
- Colak, Naki,Yildirir, Yilmaz,Kavutcu, Mustafa,Nurlu, Nilhan
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p. 1283 - 1287
(2008/03/27)
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- Evaluation of azasterols as anti-parasitics
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In this article, the design and synthesis of some novel azasterols is described, followed by their evaluation against Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum, the causative agents of human African trypanosomiasis, Chagas disease, leishmaniasis, and malaria, respectively. Some of the compounds showed anti-parasitic activity. In particular, a number of compounds appeared to very potently inhibit the growth of the blood stream form T. b. rhodesiense, with one compound giving an IC 50 value of 12 nM. Clear structure activity relationships could be discerned. These compounds represent important leads for further optimization. Azasterols have previously been shown to inhibit sterol biosynthesis in T. cruzi and L. donovani by the inhibition of the enzyme sterol 24-methyltransferase. However, in this case, none of the compounds showed inhibition of the enzyme. Therefore, these compounds have an unknown mode of action.
- Gros, Ludovic,Lorente, Silvia Orenes,Jimenez, Carmen,Yardley, Vanessa,Rattray, Lauren,Wharton, Hayley,Little, Susan,Croft, Simon L.,Ruiz-Perez, Luis M.,Gonzalez-Pacanowska, Dolores,Gilbert, Ian H.
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p. 6094 - 6103
(2007/10/03)
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- Enantioselective alkylation and protonation of prochiral enolates in the asymmetric synthesis of β-amino acids
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Achiral 1-benzoyl-3-methylperhydropyrimidin-4-one (1) was deemed a useful, potential precursor for the enantioselective synthesis of α-substituted β-amino acids. Pyrimidinone 1 was prepared from inexpensive β-aminopropanoic acid in 62% overall yield. Prochiral enolate derivative 1 -Li was alkylated in good yield and moderate enantioselectivity in the presence of chiral amines (S)-8, (S,S)-9, (S,S)-10, or (-)-sparteine. The enantioselectivity of the alkylation process is highest in toluene as the solvent and in the presence of lithium bromide as additive. The racemic alkylated derivatives 2 and 3 were readily metallated with LDA to give prochiral enolates 2-Li and 3-Li, that were reprotonated with novel chiral phenolic acids (S)-11, (S,S)-12, (S)-13, and (S,S)-14 in moderate enantioselectivity in the case of 2-Li and good enantioselectivity in the case of 3-Li. The acid (6N HCl) hydrolysis of enantioenriched 2 and 3 proceeded in good yield and without racemization to afford α-alkyl-β-amino acids 4 and 5, respectively.
- Mu?oz-Mu?iz, Omar,Juaristi, Eusebio
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p. 4223 - 4229
(2007/10/03)
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- New 2-(2'-phenyl-9'-benzyl-8'-azapurin-6'-ylamino)-carboxylic acid methylesters as ligands for A1 adenosine receptors.
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Synthesis of a series of new 2-phenyl-9-benzyl-8-azaadenines bearing on N6 an alkyl or aralkyl chain having a carbonyloxymethyl group on the carbon bound to N6 were reported. The ester group could assure to the molecule a better water-solubility than the 8-azaadenines 2, 6 and 9 substituted with lipophilic groups synthesised in the past. Compounds synthesised demonstrated only little capability of binding A1 adenosine receptors.
- Biagi,Giorgi,Pacchini,Livi,Scartoni
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p. 929 - 931
(2007/10/03)
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- Catalyse intramoleculaire de l'aminolyse d'heterocycles phosphores derives des α aminoamides. I: Synthese de (thio) phosphor(N)diamides incorporant un residu de ss aminoacide
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A general scheme of intramolecular nucleophilic catalysis of aminolysis of the heterocycles B is proposed (Figure 2). The requisite heterocycle D, when built with a β aminoamide residue, allows also a repetitive β peptide synthesis, as with α aminoacids (Figure 1). In order to evaluate the feasibility of both schemes, fifteen phosphor(n)diamides (table III) incorporating one residue of β aminoacid, in form of esters 3, acids 5 (models of E, Figure 2), nitrile 11, or hydrazides 12 have been synthesized starting from P(IV) dichlorides 1 (Figure 3). Unexpectedly hydrolysis of nitriles 6 b c leads to β diacids 9 b c with the regular acids 8 b c.
- Dujols, Frederic,Jollet, Philippe,Mulliez, Michel
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p. 231 - 254
(2007/10/03)
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- Asymmetric Synthesis of β-Amino Acids. 1. Highly Diastereoselctive Addition of a Racemic β-Alanine Enolate Derivative to Electrophiles
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β-Alanine, an inexpensive β-amino acid, was converted into the 2-tert-butylperhydropyrimidin-4-one derivative 2, which can be alkylated with high stereoselectivity via the corresponding enolate.The high diastereoselectivity observed for the reaction of 2-Li with electrophiles seems to be due to steric hindrance generated by an axial disposition of the tert-butyl group at C(2), which directs addition from the enolate face opposite to this group.The hydrolysis of the resulting adducts proceeds with 6N hydrochloric acid to affford α-substituted β-amino acids in good yields.These results pave the road to the development of a new asymmetric synthesis of enantiomerically pure α-substituted β-amino acids.
- Juaristi, Eusebio,Quintana, Delia,Lamatsch, Bernd,Seebach, Dieter
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p. 2553 - 2557
(2007/10/02)
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- Antihypertensive dihydropyridines with 1,4,4-trisubstitution
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Dihydropyridines with 1,4,4-trisubstitution were synthesized and tested for antihypertensive activity in a spontaneously hypertensive rat model. This substitution pattern on the dihydropyridine nucleus differs markedly from that found most active in the structure-activity relationship established for nifedipine-like compounds. However, some were found to significantly lower blood pressure at testing doses (30 mg/kg, ip and 100 mg/kg, po) for up to 24 h. Methyl 1,4-dihydro-4,4-dimethyl-1-pyridinepropanoate (2-1), for example, lowered blood pressure 71 mmHg at 30 mg/kg, ip and the effect endured for greater than 24 h. Unlike prototypical dihydropyridines such as nifedipine, these compounds did not seem to have any effect on calcium channels.
- Kukla,Breslin,Gill
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p. 223 - 228
(2007/10/02)
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- PHOSPHONATE AND PHOSPHONAMIDE ENDOPEPTIDASE INHIBITORS
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Compounds of the formula STR1 wherein Y is O or NH and X is STR2 will inhibit the action of neutral endopeptidase. As a result, such compounds produce diuresis, natriuresis, and lower blood pressure as well as being useful in the treatment of congestive heart failure, relieving pain, and diarrhea when administered to a mammalian host.
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- Dihydropyridine compounds having 1,4,4-trisubstitution useful as antihypertensive agents
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Dihydropyridine compounds having 1,4,4-trisubstitution of the following formula (I): STR1 wherein R is one of --COR3, R3 being a group such as phenyl or benzyl; R4 where R4 is a heterocycle; --(CH2)n NR5 R6, with R5 and R6 being alkyl or joined to define a ring; or --(CH2)n COOR7, with R7 being alkyl or benzyl. R1 and R2 are alkyl, phenyl or substituted phenyl. The compounds are useful for the treatment of hypertension in mammals, e.g., in humans.
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- ATTOGRAM-LEVEL DETECTION AND RELATIVE RESPONSE OF STRONG ELECTROPHORES BY GAS CHROMATOGRAPHY WITH ELECTRON CAPTURE DETECTION.
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The responses as peak areas of some divergent compounds, most of which are strong electron absorbers, are measured by gas chromatography with electron capture detection (GC-ECD). The most sensitive compounds are derivatized lodothyronines, which are essentially 20-fold more sensitive than lindane. N,N-Dipentafluorobenzoylpentafluoroaniline, a somewhat less sensitive but more volatile substance, was selected for determination of a detection limit. The value was 90 ag(1. 6 multiplied by 10** minus **1**9 mol), largely due to an anomalous increase in its response at the trace level. This increases the reported sensitivity of GC-ECD by 100-fold.
- Corkill,Joppich,Kuttab,Giese
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p. 481 - 485
(2007/10/02)
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- L-Pyroglutamyl-L-histidyl-L-prolyl-beta-alaninamide and salts
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This disclosure relates to L-pyroglutamyl-L-histidyl-L-prolyl-beta-alaninamide and acid addition salts thereof as anti-depressant agents.
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