- Colorimetric analysis of painting materials using polymer-supported polydiacetylene films
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Analysis of artworks and identification of their molecular components are of utmost importance for selecting proper conservation strategies and monitoring restoration. Accordingly, development of simple and readily applicable paint analysis assays is high
- Trachtenberg, Alexander,Malka, Orit,Kootery, Kaviya Parambath,Beglaryan, Stella,Malferrari, Danilo,Galletti, Paola,Prati, Silvia,Mazzeo, Rocco,Tagliavini, Emilio,Jelinek, Raz
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Read Online
- Photochemical Deracemization at sp3-Hybridized Carbon Centers via a Reversible Hydrogen Atom Transfer
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A photochemical deracemization of 5-substituted 3-phenylimidazolidine-2,4-diones (hydantoins) is reported (27 examples, 69%-quant., 80–99% ee). The reaction is catalyzed by a chiral diarylketone which displays a two-point hydrogen bonding site. Mechanistic evidence (DFT calculations, radical clock experiments, H/D labeling) suggests the reaction to occur by selective hydrogen atom transfer (HAT). Upon hydrogen binding, one substrate enantiomer displays the hydrogen atom at the stereogenic center to the photoexcited catalyst allowing for a HAT from the substrate and eventually for its conversion into the product enantiomer. The product enantiomer is not processed by the catalyst and is thus enriched in the photostationary state.
- Bach, Thorsten,Breitenlechner, Stefan,Gro?kopf, Johannes,Plaza, Manuel,Seitz, Antonia,Storch, Golo
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supporting information
p. 21241 - 21245
(2021/12/27)
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- Convenient method for the synthesis of some novel chiral methyl 2-(2-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)propanoate derivatives and biological evaluation of their antioxidant, cytotoxic, and molecular docking properties
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Ten chiral methyl 2-(2-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)propanoate derivatives 6a-6j have been synthesized from optically pure amino methyl phenol 5 and 4-nitrophenyl chloroformate. These derivatives 6a-6j are characterized by 1H NMR, 13C NMR, FT-IR, and HRMS spectral techniques. Optical purity of these derivatives was confirmed by chiral HPLC method. Ten synthesized ester derivatives 6a-6j were screened for their in vitro antioxidant activity. Among the compounds 6b-d and 6h-j have exhibited comparable antioxidant activity with ascorbic acid as a standard. Compounds 6a and 6e-g have shown moderate antioxidant activity. Further, the in vitro cytotoxicity of these compounds were studied through MTT cell proliferation assay in addition the effect on LDH leakage and NO release. Among the derivatives, 6j showed extremely best activity and the IC50 value (12.54 ± 0.71 μM) is very close to doxorubicin (7.2 ± 0.58 μM) as a standard. Compounds 6b, 6h, and 6i showed better inhibition next to compound 6j on the viability of HepG2 cells with an IC50 value (μM) of 56.02 ± 1.4, 41.76 ± 0.58, and 38.17 ± 0.34, respectively. Also, molecular docking studies have been carried out with STAT-3 (PDB ID: 1BG1) and BCL-2 (PDB ID: 4AQ3) proteins against the four active compounds 6b, 6h, 6i, and 6j. The binding energies of the tested compounds were in the range of ?7.76 to ?8.41 kcal/mol, which is very close to doxorubicin (?8.53 kcal/mol) as a standard. These molecular docking results are in good agreement with the in vitro studies.
- Matam, Sivakumar,Kaliyan, Prabakaran,Selvaraj, Loganathan,Muthu, Seenivasa Perumal,Lohanathan, Bharathi Priya,Viswanadhan, Vijaya Padma,Makala, Himesh,Venkatasubramanian, Ulaganathan
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supporting information
p. 569 - 579
(2020/12/11)
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- Cathepsin K inhibitors based on 2-amino-1,3,4-oxadiazole derivatives
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Two new series of hitherto unknown dipeptides, containing an electrophilic nitrile or a non-electrophilic 2-amino-1,3,4-oxadiazole moiety were synthesized and evaluated in vitro as Cathepsin K (Cat K) inhibitors. From 14 compounds obtained, the oxadiazole derivatives 10a, 10b, 10e, and 10g acted as enzymatic competitive inhibitors with Ki values between 2.13 and 7.33 μM. Molecular docking calculations were carried out and demonstrated that all inhibitors performed hydrogen bonds with residues from the enzyme active site, such as Asn18. The best inhibitors (10a, 10b, 10g) could also perform these bonds with Cys25, and 10a showed the most stabilizing interaction energy (?134.36 kcal mol?1) with the active cavity. For the first time, derivatives based in 2-amino-1,3,4-oxadiazole scaffolds were evaluated, and the results suggested that this core displays a remarkable potential as a building block for Cat K inhibitors.
- Gontijo, Talita B.,Lima, Patrícia S.,Icimoto, Marcelo Y.,Neves, Raquel Le?o,de Alvarenga, érika C.,Carmona, Adriana K.,de Castro, Alexandre A.,Ramalho, Teodorico C.,da Silva Júnior, Eufranio N.,de Freitas, Rossimiriam P.
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- Two-Dimensional Barriers for Probing Conformational Shifts in Macrocycles
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We describe the development and use of composite two-dimensional barriers in macrocyclic backbones. These tunable constructs derive their mode of action from heterocyclic rearrangements. The Boulton-Katritzky reaction has been identified as a particularly versatile means to effect a composite barrier, allowing the examination of the influence of heterocycle translocation on conformation. Kinetic studies using 1H NMR have revealed that the in-plane atom movement is fast in 17, 18, 19-membered rings but slows down in 16-membered rings. The analysis by NMR and MD simulation experiments is consistent with the maintenance of rare cis-amide motifs during conformational interconversion. Taken together, our investigation demonstrates that heterocyclic rearrangement reactions can be used to control macrocyclic backbones and provides fundamental insights that may be applicable to the development of a wide range of other conformational control elements.
- Kobori, Shinya,Huh, Sungjoon,Appavoo, Solomon D.,Yudin, Andrei K.
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supporting information
p. 5166 - 5171
(2021/05/04)
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- One-pot synthesis of 1,2,4-oxadiazoles from chalcogen amino acid derivatives under microwave irradiation
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A series of sulfur- and selenium-bearing, amino acid-derived 1,2,4-oxadiazoles were obtained by a simple procedure. The method consists of EDC-promoted coupling of chalcogen amino acid derivatives with arylamidoximes in acetone, followed by solvent removal and microwave irradiation in water medium. Influence of amidoxime substituents, of the chalcogen atom and of the amino acid side chain is discussed. The results showed this to be a fast, easy and effective method to obtain these compounds, with good functional-group tolerance, potentially favouring future applications in organic synthesis.
- Wolf, Lucas,Mayer, Jo?o C.P.,Quoos, Natália,Sauer, André C.,Schwab, Ricardo S.,Rodrigues, Oscar E.D.,Dornelles, Luciano
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supporting information
(2021/06/06)
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- Optimization of N-Phenylpropenoyl- l -amino Acids as Potent and Selective Inducible Nitric Oxide Synthase Inhibitors for Parkinson's Disease
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N-Phenylpropenoyl-l-amino acids (NPAs) are inducible nitric oxide synthase (iNOS) inhibitors possessing preventive effects for Parkinson's disease (PD). Here, structural modifications for improving the iNOS inhibitory activity and blood-brain barrier (BBB) permeability of NPAs were conducted, leading to 20 optimized NPA derivatives (1-20). Compound 18, with the most potent activity (IC50 = 74 nM), high BBB permeability (Pe = 19.1 × 10-6 cm/s), and high selectivity over other NOS isoforms, was selected as the lead compound. Further studies demonstrated that 18 directly binds to iNOS. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced acute PD model, the oral administration of 18 (1 and 2 mg/kg) exerted preventive effects by alleviating the loss of dopaminergic (DAergic) neurons. Notably, in the MPTP-/probenecid-induced chronic PD model, the same dose of 18 also displayed a therapeutic effect by repairing the damaged DAergic neurons. Finally, good pharmacokinetic properties and low toxicity made 18 a promising candidate for the treatment of PD.
- Hu, Xiao-Long,Lv, Xian-Yu,Wang, Rong,Long, Huan,Feng, Jia-Hao,Wang, Bao-Lin,Shen, Wei,Liu, Hao,Xiong, Fei,Zhang, Xiao-Qi,Ye, Wen-Cai,Wang, Hao
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p. 7760 - 7777
(2021/06/28)
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- Eco-friendly synthesis of peptides using fmoc-amino acid chlorides as coupling agent under biphasic condition
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Background: Agro-waste derived solvent media act as a greener process for the peptide bond formation using Nα-Fmoc-amino acid chloride and amino acid ester salt with in situ neutralization and coupling under biphasic condition. The Fmoc-amino acid chlorides are prepared by the reported procedure of freshly distilled SOCl2 with dry CH2Cl2. The protocol found many added ad-vantages such as neutralization of amino acid ester salt and not required additional base for the neu-tralization, and directly coupling take place with Fmoc-amino acid chloride gave final product dipeptide ester in good to excellent yields. The protocol occurs with complete stereo chemical integrity of the configuration of substrates. Here, we revisited Schotten-Baumann condition, instead of using inorganic base. Objective: To develop green protocol for the synthesis of peptide bond using Fmoc-amino acid chloride with amino acid esters salt. Methods: The final product isolated is analyzed in several spectroscopic and analytical techniques such as FT-IR,1H-,13C-NMR, Mass spectrometry and RP-HPLC to check stereo integrity and puri-ty of the product. Conclusion: The present method developed greener using natural agro-waste (lemon fruit shell ash) derived solvent medium for the reaction and not required chemical entity.
- Kantharaju, Kamanna,Khatavi, Santosh Y.
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p. 699 - 707
(2021/08/23)
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- Ribose conversion with amino acids into pyrraline platform chemicals-expeditious synthesis of diverse pyrrole-fused alkaloid compounds
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One-pot conversion of sustainable d-ribose with l-amino acid, methyl esters produced pyrrole-2-carbaldehydes 5 in reasonable yields (32-63%) under pressurized conditions of 2.5 atm at 80 °C. The value-added pyrraline compounds 5 as platform chemicals were utilized for quick installation of poly-heterocyclic cores for the development of pyrrole-motif natural and artificial therapeutic agents. A pyrrole-fused piperazin-2-one scaffold 6 was prepared by reductive amination of pyrralines 5 with benzylamine. While further cyclization of pyrralines 5 with ethane-1,2-diamine produced pyrrolo-piperazin-2-ones 7 with an extra imidazolidine ring, the reaction with 2-amino alcohols derived from natural l-amino acids, alanine, valine, and phenylalanine, respectively provided pyrrolo-piperazin-2-ones 8, 9, and 10 with oxazolidine as the third structural core. Cell viability and an anti-inflammatory effect of the synthesized compounds were briefly tested by the MTT method and the Griess assay, among which 8h and 10g exhibited significant anti-inflammatory effects with negligible cell toxicity.
- Cho, Soohyeon,Gu, Lina,In, Ik Joon,Kim, Hakwon,Koo, Sangho,Lee, Taehoon,Wu, Bo
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p. 31511 - 31525
(2021/11/30)
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- Application of proteasome inhibitor in inhibition of novel coronavirus
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The invention provides application of a proteasome inhibitor in inhibition of a novel coronavirus or preparation of novel coronavirus inhibitors. The proteasome inhibitor has a structure represented by a formula (I) or isomers, pharmaceutically acceptable salts thereof and prodrugs thereof. According to the application, by applying the proteasome inhibitor to inhibition of the novel coronavirus, good inhibiting activity is obtained, and a novel treatment way of think is provided for diseases such as pneumonia caused by the novel coronavirus.
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Paragraph 0130-0133
(2021/06/22)
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- N-1 BRANCHED ALKYL SUBSTITUTED IMIDAZO[4,5-C]QUINOLINE COMPOUNDS, COMPOSITIONS, AND METHODS
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Imidazo[4,5-c]quinoline compounds having a substituent that is attached at the N-1 position by a branched group, single enantiomers of the compounds, pharmaceutical compositions containing the compounds, and methods of making the compounds are disclosed. Methods of use of the compounds as immune response modifiers, for inducing (or inhibiting) cytokine biosynthesis in humans and animals, and in the treatment of diseases including infectious and neoplastic diseases are also disclosed.
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Page/Page column 65
(2020/12/29)
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- Amino acid conjugates of 2-mercaptobenzimidazole provide better anti-inflammatory pharmacology and improved toxicity profile
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Benzimidazole is an important pharmacophore for clinically active drugs against inflammation and treatment of pain, however, it is associated with gastrointestinal side effects. Here we synthesized benzimidazole based agents with significant analgesic/anti-inflammatory potential but with less gastrointestinal adverse effects. In this study, we synthesized novel, orally bioavailable 2-mercaptobenzimidazole amino acid conjugates (4a–4o) and screened them for analgesic, anti-inflammatory and gastro-protective effects. The synthesized 2-mercaptbenzimidazole derivatives were characterized for their structure using FTIR, 1H NMR and 13C NMR spectroscopic techniques. The 2-mercaptobenzimidazole amino acid conjugates have found to possess potent analgesic, anti-inflammatory and gastroprotective activities, particularly with compound 4j and 4k. Most of the compounds exhibited remarkable anti-ulcer and antisecretory effects. Molecular docking studies were carried out to study the binding affinities and interactions of the synthesized compounds with target proteins COX-2 (PDB ID: 3LN1) and H+/K+-ATPase (PDB ID: 5Y0B). Our results support the clinical promise of these newly synthesized 2-mercaptobezimidazol conjugates as a component of therapeutic strategies for inflammation and analgesia, for which the gastric side effects are always a major limitation.
- Khan, Muhammad T.,Nadeem, Humaira,Khan, Arif-ullah,Abbas, Muzaffar,Arif, Muazzam,Malik, Nadia Shamshad,Malik, Zulkifal,Javed, Ibrahim
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p. 1057 - 1072
(2020/08/13)
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- Re-Engineering Organocatalysts for Asymmetric Friedel-Crafts Alkylation of Indoles through Computational Studies
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The discovery of efficient organocatalysts is generally carried out by thorough experimental screening of different candidates. We recently reported an efficient organocatalyst for iminium-ion-based asymmetric Diels-Alder reactions following a rational design approach. This result encouraged us to test this optimal catalyst in the mechanistically related Friedel-Crafts alkylation of indoles, but to our surprise, almost null enantioselectivity was observed. The results did not significantly improve with structurally related catalysts, and a totally unexpected facial selectivity inversion was also noticed. Using DFT calculations by modeling the competing transition structures with ONIOM, we could unravel the origins of those findings, further employed to predict the most efficient catalyst for this new transformation. The computational results were validated experimentally (up to 92:8 er), providing another successful example of a general strategy to accelerate catalyst development which still remains underexplored.
- Gerosa, Gabriela G.,Marcarino, Maribel O.,Spanevello, Rolando A.,Suárez, Alejandra G.,Sarotti, Ariel M.
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p. 9969 - 9978
(2020/09/03)
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- Synthesis and antimalarial activity of (S)-methyl-(7-chloroquinolin-4-ylthio)acetamidoalquilate derivatives
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The synthesis of five new (S)-methyl-(7-chloroquinolin-4-ylthio)acetamidoalquilate derivatives is carried out under a modified version of the Steglich esterification reaction between different l-amino acid methyl esters and 2-(7-chloroquinolin-4-ylthio)acetic acid. Two of the compounds showed significant inhibition (>50%) of β-hematin formation. The two active structures were tested in vivo as potential antimalarials in mice infected with Plasmodium berghei ANKA, a chloroquine susceptible strain. Compounds 6b and 6e exhibited antimalarial activity comparable to that of chloroquine.
- Colmenarez, Custodiana,Acosta, María,Rodríguez, Miguel,Charris, Jaime
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p. 161 - 166
(2020/01/09)
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- Peptide-Catalyzed Fragment Couplings that Form Axially Chiral Non-C2-Symmetric Biaryls
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We have demonstrated that small, modular, tetrameric peptides featuring the Lewis-basic residue β-dimethylaminoalanine (Dmaa) are capable of atroposelectively coupling naphthols and ester-bearing quinones to yield non-C2-symmetric BINOL-type scaffolds with good yields and enantioselectivity. The study culminates in the asymmetric synthesis of backbone-substituted scaffolds similar to 3,3′-disubstituted BINOLs, such as (R)-TRIP, with good (94:6 e.r.) to excellent (>99.9:0.1 e.r.) enantioselectivity after recrystallization, and a diastereoselective net arylation of the minimally modified nonsteroidal anti-inflammatory drug (NSAID) naproxen.
- Coombs, Gavin,Sak, Marcus H.,Miller, Scott J.
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supporting information
p. 2875 - 2880
(2020/01/24)
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- Synthesis of a novel category of pseudo-peptides using an Ugi three-component reaction of levulinic acid as bifunctional substrate, amines, and amino acid-based isocyanides
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The synthesis of a novel category of pseudo-peptides via intramolecular Ugi reaction of levulinic acid (4-oxopentanoic acid), aromatic and aliphatic amines, and amino acid-based isocyanides is reported. Levulinic acid was applied as a bifunctional substrate containing both carbonyl and acid moieties suitable for the Ugi reaction. This article provides a facile and convenient one-pot procedure for the synthesis of peptide-like heterocyclic molecules containing 2-pyrrolidone (γ-lactam), amide and ester functional groups with good to excellent yields.
- Khalesi, Maryam,Halimehjani, Azim Ziyaei,Martens, Jürgen
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supporting information
p. 852 - 857
(2019/04/17)
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- Cocrystallization of Chiral N7,N16-bis (S-1-Phenylethyl)-1,4,10,13-Tetraoxo-7,16-Diazacyclooctadecane-7,16-Dicarboxamide with Hydrochlorides of Methyl Ethers of Leucine and Valine Enantiomers
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An attempt to co-crystallize N7,N16-bis(S-1-phenylethyl)-1,4,10,13-tetraoxo-7,16-diazacyclooctadecane-7,16-dicarboxamide (1) with hydrochlorides of methyl ethers (HCMEs) of L- and D-valine and also L- and D-leucine results in separate crystallization of diazacrown-ether 1 (or its monohydrate 1·H2O) and HCMEs of respective α-amino acids. Crystal structures of D-leucine 1·H2O (1) and HCME (2) compounds, which were not described previously, are solved by single crystal X-ray diffraction.
- Fonari,Pluzhnik-Gladyr,Kamalov,Kravtsov, V. Kh.
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p. 143 - 150
(2019/04/30)
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- Rhodium-Catalyzed Enantioselective Synthesis of Oxazinones via an Asymmetric Ring Opening-Lactonization Cascade of Oxabicyclic Alkenes
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The rhodium-catalyzed asymmetric ring opening reaction of oxabicyclic alkenes is shown to be an efficient method for synthesizing chiral heterocycles. We demonstrate that the pairwise combination of chiral catalyst with chiral amino-acid-derived pronucleophiles results in a stereodivergent synthesis of diastereomeric hydroxyesters. A favorable conformational preference induces the subsequent lactonization of one diastereomer leading to the highly enantioselective synthesis of oxazinones.
- Yen, Andy,Pham, Anh Hoang,Larin, Egor M.,Lautens, Mark
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supporting information
p. 7549 - 7553
(2019/10/02)
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- Hydroxyphosphinylacetic acid as a chiral auxiliary compound
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The aim of the presented research was to check whether 2-hydroxy-2-(ethoxyphenylphosphinyl)acetic acid is a versatile chiral phosphonic auxiliary (readily seen in 31P NMR). The preliminary studies indicate that this compound may be used as chiral derivatizing agents for amines and alcohols, since the separation of selected examples of diastereomeric alcohols and amines in 31P NMR spectra was found to be satisfactory. The preliminary research about using this compound as a CSA are also promising.
- Majewska, Paulina
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p. 585 - 590
(2019/01/04)
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- The synthesis and characterization of tetramic acid derivatives as Mdm2-p53 inhibitors
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We present syntheses, prediction of tautomer forms and activities of the second generation of the Mdm2-p53 inhibitors that are based on the tetramic acid scaffold. The inhibitors do not contain 6-chloroindole. Binding of these compounds to Mdm2 was checked by two orthogonal methods: the fluorescence polarization and the 1H-15N HSQC NMR titration experiments. We discovered that the 3-phenylthio-substituted tetramic acid derivatives exist in solution solely in their enol forms which is in contrast to the similar 3-aliphatic substituted derivatives. The inhibitory (Ki) and dissociation (KD) constants are in low micromolar ranges with the best binding compound 9a having KD = 2.9 μM. Furthermore, our data show that the compounds indeed bind to the p53-binding pocket of Mdm2 and do not cause dimerization of Mdm2. The current work provides solid base for further rational design of the Mdm2/p53 inhibitors.
- Muszak, Damian,?abuzek, Beata,Brela, Mateusz Z.,Twarda-Clapa, Aleksandra,Czub, Miroslawa,Musielak, Bogdan,Surmiak, Ewa,Holak, Tad A.
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p. 161 - 174
(2019/04/26)
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- Synthesis and structure-activity relationship of nitrile-based cruzain inhibitors incorporating a trifluoroethylamine-based P2 amide replacement
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The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly nonadditive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the nonadditivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity.
- Gomes, Juliana C.,Cianni, Lorenzo,Ribeiro, Jean,dos Reis Rocho, Fernanda,da Costa Martins Silva, Samelyn,Batista, Pedro Henrique Jatai,Moraes, Carolina Borsoi,Franco, Caio Haddad,Freitas-Junior, Lucio H.G.,Kenny, Peter W.,Leit?o, Andrei,Burtoloso, Antonio C.B.,de Vita, Daniela,Montanari, Carlos A.
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- N-Heterocyclic Carbene Iron(III) Porphyrin-Catalyzed Intramolecular C(sp3)–H Amination of Alkyl Azides
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Metal-catalyzed intramolecular C?H amination of alkyl azides constitutes an appealing approach to alicyclic amines; challenges remain in broadening substrate scope, enhancing regioselectivity, and applying the method to natural product synthesis. Herein we report an iron(III) porphyrin bearing axial N-heterocyclic carbene ligands which catalyzes the intramolecular C(sp3)–H amination of a wide variety of alkyl azides under microwave-assisted and thermal conditions, resulting in selective amination of tertiary, benzylic, allylic, secondary, and primary C?H bonds with up to 95 % yield. 14 out of 17 substrates were cyclized selectively at C4 to give pyrrolidines. The regioselectivity at C4 or C5 could be tuned by modifying the reactivity of the C5–H bond. Mechanistic studies revealed a concerted or a fast re-bound mechanism for the amination reaction. The reaction has been applied to the syntheses of tropane, nicotine, cis-octahydroindole, and leelamine derivatives.
- Shing, Ka-Pan,Liu, Yungen,Cao, Bei,Chang, Xiao-Yong,You, Tingjie,Che, Chi-Ming
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supporting information
p. 11947 - 11951
(2018/09/11)
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- A valsartan synthesis method of alkylation impurity (by machine translation)
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A valsartan synthesis method of alkylation impurities, is to L - valine that may exist in the impurity D - valine, alanine, leucine isoleucine amino acid as the raw material and the like, in thionyl chloride under the conditions of the esterification reaction with methanol, after the reaction by reducing pressure methanol, then with 2 - cyano - 4' - bromomethyl biphenyl in the reaction under alkaline conditions, after completion of the reaction, saturated salt water washing, adding hydrochloric acid to adjust the pH=1 - 2, the temperature of the crystallization, filtering to obtain the target product valsartan alkylation impurity. The present invention is to provide high-purity impurity, will its known impurity used for alkylation of valsartan in mass analysis, the position of the clear of impurities in the sample, the degree of impurity of the sample inspection, optimizes the analytical method, contribute to improving the quality of valsartan research, for the production of valsartan reducing impurity, improve the quality of the valsartan; at the same time, this invention has mild condition, the reaction yield is higher, convenient operation and the like. (by machine translation)
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Paragraph 0019-0020
(2018/10/19)
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- Novel Fubinaca/Rimonabant hybrids as endocannabinoid system modulators
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The discovery of novel modulators of the cannabinoid system is a current topic in medicinal chemistry. In this paper, we report nine novel carboxamides designed as hybrids of Fubinaca family compounds and Rimonabant. These hybrids were obtained by linking the 1-benzyl-2,5-dichloroindazole-3-carboxylic acid to different amino acids bearing a hydrophobic side chain and three different C-terminus. The new chemical entities were tested in vitro to evaluate their bioactivity by means of receptor binding assays and [35S]GTPγS stimulation assays to reveal their affinity and potency. We found that all compounds were able to bind to the cannabinoid receptors in the low nanomolar range with a marked selectivity towards the CB1 cannabinoid receptor. Some of them are full agonists, whereas the others act as partial agonists. These molecules could be potentially used as anti-obesity agents, antiemetic and analgesics.
- Stefanucci, Azzurra,Macedonio, Giorgia,Dvorácskó, Szabolcs,T?mb?ly, Csaba,Mollica, Adriano
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p. 1595 - 1605
(2018/09/14)
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- 3, 5-disubstituted hydantoin compound as well as preparation method and application thereof
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The invention provides a 3, 5-disubstituted hydantoin compound as well as a preparation method and an application thereof. The structure of the compound is shown in formula I in the description. The application of the 3, 5-disubstituted hydantoin compound shown in the formula I or solvates, hydrates or salts of the compound in preparation of medicines for treating Alzheimer's disease, vascular dementia and other dementia diseases with memory impairment also belongs to the protection scope. Animal experiments prove that the compound has the effect of saving memory of animal models, has high safety, does not have mutagenicity, can stay in blood for several hours after oral administration and intravenous injection, and can enter the brain.
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Paragraph 0041; 0049; 0050; 0061; 0062
(2018/10/19)
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- Synthesis and antiproteasomal activity of novel O-benzyl salicylamide-based inhibitors built from leucine and phenylalanine
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Inhibition of protein degradation is one of strategies for suppression of uncontrolled proliferation of cancer cells. Proteolytic degradation in cells is mainly ensured by proteasome and its inhibition by bortezomib showed benefit in clinical use for the treatment of multiple myeloma. We report here the library of antiproteasomal O-benzyl salicylamides built from leucine and phenylalanine. Prepared compounds displayed antiproliferative activity on K562, CEM and U266 cancer cell lines, ranging from high micromolar to submicromolar GI50 values. The most potent compounds (series 4 and 6) were further assayed for their inhibition of chymotrypsin-like protease activity of the 26S proteasome in U266 cells. The majority of compounds inhibited the proteasome in mid-nanomolar concentrations (IC50 ranging from 57 to 197 nM) and it correlated with cellular potency. In a cell based assay involving green fluorescence protein (GFP) fused to a short degron that is rapidly degraded by a proteasome the compounds induced accumulation of GFP, visualised and quantified by live-cell imaging. Levels of polyubiquitinated proteins in U266 cells treated by compound 4m were also analyzed by immunoblotting, revealing a typical high molecular mass smear of ubiquitin conjugates. Finally, apoptotic cell death in treated U266 cells was detected biochemically by measuring the activity of caspases 3 and 7 in lysates and by immunoblotting of caspase 7, its substrate poly(ADP-ribose)polymerase, and Mcl-1, which all together showed changes typical for apoptosis. All these observations were in agreement with expected cellular mechanism of action and confirmed proteasome targeting by prepared O-benzyl salicylamides.
- Jorda, Radek,Du?ek, Jan,?ezní?ková, Eva,Pauk, Karel,Magar, Pratibha P.,Imramovsky, Ale?,Kry?tof, Vladimír
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supporting information
p. 142 - 158
(2017/04/26)
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- Synthesis and antiviral activity of novel glycyrrhizic acid conjugates with D-amino acid esters
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Glycyrrhizic acid (GA) conjugates with methyl and ethyl esters of D-amino acids (D-Trp, D-Phe, D-Tyr, D-Val, D-Leu) have been synthesized by the activated esters method using mixtures of N-hydroxybenzotriazole or N-hydroxysuccinimide with N,N′-dicyclohexylcarbodiimide. GA conjugate with D-Trp ethyl ester exhibited antiviral activity against influenza viruses A/H3N2, A/H1N1/pdm09, A/H5N1, B (SI > 10–29), and HRSV (SI > 25). GA conjugate with D-Trp methyl ester inhibited influenza virus A/H1N1/pdm09 (SI > 30).
- Fayrushina,Baltina,Baltina,Konovalova,Petrova,Eropkin, M. Yu.
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p. 456 - 462
(2017/08/08)
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- Synthesis and Deployment of an Elusive Fluorovinyl Cation Equivalent: Access to Quaternary α-(1′-Fluoro)vinyl Amino Acids as Potential PLP Enzyme Inactivators
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Developing specific chemical functionalities to deploy in biological environments for targeted enzyme inactivation lies at the heart of mechanism-based inhibitor development but also is central to other protein-tagging methods in modern chemical biology including activity-based protein profiling and proteolysis-targeting chimeras. We describe here a previously unknown class of potential PLP enzyme inactivators; namely, a family of quaternary, α-(1′-fluoro)vinyl amino acids, bearing the side chains of the cognate amino acids. These are obtained by the capture of suitably protected amino acid enolates with β,β-difluorovinyl phenyl sulfone, a new (1′-fluoro)vinyl cation equivalent, and an electrophile that previously eluded synthesis, capture and characterization. A significant variety of biologically relevant AA side chains are tolerated including those for alanine, valine, leucine, methionine, lysine, phenylalanine, tyrosine, and tryptophan. Following addition/elimination, the resulting transoid α-(1′-fluoro)-β-(phenylsulfonyl)vinyl AA-esters undergo smooth sulfone-stannane interchange to stereoselectively give the corresponding transoid α-(1′-fluoro)-β-(tributylstannyl)vinyl AA-esters. Protodestannylation and global deprotection then yield these sterically encumbered and densely functionalized quaternary amino acids. The α-(1′-fluoro)vinyl trigger, a potential allene-generating functionality originally proposed by Abeles, is now available in a quaternary AA context for the first time. In an initial test of this new inhibitor class, α-(1′-fluoro)vinyllysine is seen to act as a time-dependent, irreversible inactivator of lysine decarboxylase from Hafnia alvei. The enantiomers of the inhibitor could be resolved, and each is seen to give time-dependent inactivation with this enzyme. Kitz-Wilson analysis reveals similar inactivation parameters for the two antipodes, L-α-(1′-fluoro)vinyllysine (Ki = 630 ± 20 μM; t1/2 = 2.8 min) and D-α-(1′-fluoro)vinyllysine (Ki = 470 ± 30 μM; t1/2 = 3.6 min). The stage is now set for exploration of the efficacy of this trigger in other PLP-enzyme active sites.
- McCune, Christopher D.,Beio, Matthew L.,Sturdivant, Jill M.,De La Salud-Bea, Roberto,Darnell, Brendan M.,Berkowitz, David B.
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supporting information
p. 14077 - 14089
(2017/10/17)
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- Novel thiazolidinedione-5-acetic-acid-peptide hybrid derivatives as potent antidiabetic and cardioprotective agents
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Thiazolidinediones (TZDs) are one of the important clinically established antidiabetic agents. Amino-acid and peptides have an advantage of better target selectivity and specificity. As hybrids, they also improved absorption and showed better bioavailability, which in turn makes them safer. Hence, here an effort has been made to synthesize hybrids of thiazolidinedione with amino-acids and peptides and evaluate their antidiabetic and cardioprotective effect in streptozotocin-nicotinamide (STZ-NA) induced Type 2 diabetes mellitus (T2DM) rat models. A series of 14 thiazolidinedione-5-acetic acid hybrids with of different amino-acids and peptide combinations were synthesized, characterized and further screened for antidiabetic and cardioprotective activity. Among all, six compounds T1 (SSDMA1), T4 (SSDMA4), T5 (SSDMA5), T7 (SDMA13), T9 (SSDMA15) and T13 (SSDMA49) showed better antioxidant activity and comparable % glucose uptake by yeast cells. Hence, the in vivo antidiabetic screening was done for these six compounds. Among all six T1, T7, T13 showed significant blood glucose level decrease compared to standard pioglitazone HCl. Also T1, T7 and T13 showed better antioxidant activity with lower IC50 value than standard ascorbic acid, and hence in vivo cardioprotective studies were done for these. The ECG studies showed that T1 (SSDMA1) and T7 (SSDMA13) were better effective than SDMA49 (T13) in restoring the normal functioning of the heart, thus may help in preventing the development of diabetic cardiomyopathy (DCM) and controlling T2DM.
- Maji,Samanta
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p. 1163 - 1172
(2017/02/23)
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- Supramolecular self-assembly of chiral polyimides driven by repeat units and end groups
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Pyromellitic diimides (PMDIs) are effective building blocks for the construction of supramolecular systems but are infrequently used in comparison with other electron-deficient aromatic systems. We report PMDI-based chiral polyimides that form polymeric supramolecular systems with unique self-assembly features that show time-dependent spectroscopic behaviour. Extensive investigations revealed the driving forces for the self-assembly of the polyimides. One is the complementary aromatic π-π stacking between electron-accepting PMDI and electron-donating phenyl ring in the polymer backbones, and another is the hydrogen bonding interactions of the end groups. The self-assembly is readily disrupted by guest molecules with strong associations with the PMDI and the end groups. The introduction of flexible arylether diimides into the PMDI-based copolymer backbones and the sequence of PMDIs and arylether diimides in the copolymer backbones significantly influence the self-assembly of the polyimides. The results elucidate the mechanisms of polymeric self-assembly of chiral polyimides, providing important information for the development of materials based on polymeric supramolecular systems with properties and functions regulated by composition, sequence and end groups.
- Yan, Jijun,Kang, Chuanqing,Bian, Zheng,Jin, Rizhe,Ma, Xiaoye,Gao, Lianxun
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supporting information
p. 14723 - 14729
(2017/11/28)
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- Three new amino acid derivatives from edible mushroom Pleurotus ostreatus
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Three new amino acid derivatives, oxalamido-L-phenylalanine methyl ester (1), oxalamido-L-leucine methyl ester (2), and lumichrome hydrolyzate (3), together with nine known compounds (4–12), were isolated from the solid culture of edible mushroom Pleurotu
- Lu, Xiao-Jie,Feng, Bao-Min,Chen, Shao-Fei,Zhao, Dan,Chen, Gang,Wang, Hai-Feng,Pei, Yue-Hu
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p. 1160 - 1171
(2017/09/30)
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- Quantitative Modeling of Bis(pyridine)silver(I) Permanganate Oxidation of Hydantoin Derivatives: Guidelines for Predicting the Site of Oxidation in Complex Substrates
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The bis(pyridine)silver(I) permanganate promoted hydroxylation of diketopiperazines has served as a pivotal transformation in the synthesis of complex epipolythiodiketopiperazine alkaloids. This late-stage C-H oxidation chemistry is strategically critical to access N-acyl iminium ion intermediates necessary for nucleophilic thiolation of advanced diketopiperazines en route to potent epipolythiodiketopiperazine anticancer compounds. In this study, we develop an informative mathematical model using hydantoin derivatives as a training set of substrates by relating the relative rates of oxidation to various calculated molecular descriptors. The model prioritizes Hammett values and percent buried volume as key contributing factors in the hydantoin series while correctly predicting the experimentally observed oxidation sites in various complex diketopiperazine case studies. Thus, a method is presented by which to use simplified training molecules and resulting correlations to explain and predict reaction behavior for more complex substrates.
- Bischoff, Amanda J.,Nelson, Brandon M.,Niemeyer, Zachary L.,Sigman, Matthew S.,Movassaghi, Mohammad
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supporting information
p. 15539 - 15547
(2017/11/06)
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- Regiodivergent Enantioselective γ-Additions of Oxazolones to 2,3-Butadienoates Catalyzed by Phosphines: Synthesis of α,α-Disubstituted α-Amino Acids and N,O-Acetal Derivatives
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Phosphine-catalyzed regiodivergent enantioselective C-2- and C-4-selective γ-additions of oxazolones to 2,3-butadienoates have been developed. The C-4-selective γ-addition of oxazolones occurred in a highly enantioselective manner when 2-aryl-4-alkyloxazol-5-(4H)-ones were employed as pronucleophiles. With the employment of 2-alkyl-4-aryloxazol-5-(4H)-ones as the donor, C-2-selective γ-addition of oxazolones took place in a highly enantioselective manner. The C-4-selective adducts provided rapid access to optically enriched α,α-disubstituted α-amino acid derivatives, and the C-2-selective products led to facile synthesis of chiral N,O-acetals and γ-lactols. Theoretical studies via DFT calculations suggested that the origin of the observed regioselectivity was due to the distortion energy that resulted from the interaction between the nucleophilic oxazolide and the electrophilic phosphonium intermediate.
- Wang, Tianli,Yu, Zhaoyuan,Hoon, Ding Long,Phee, Claire Yan,Lan, Yu,Lu, Yixin
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supporting information
p. 265 - 271
(2016/01/25)
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- A new type of chiral-pyridoxamines for catalytic asymmetric transamination of α-keto acids
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A new type of chiral pyridoxamines bearing an adjacent chiral stereocenter has been developed via multi-step synthesis. The pyridoxamines displayed catalytic activity in asymmetric transamination of α-keto acids to give a variety of optically active amino acids in 27–78% yields with 34–62% ee's under very mild conditions. This work provides a synthetic strategy to construct new chiral pyridoxamines using bromopyridine 7 as a key synthon and also represents an early example of the applications of chiral pyridoxamines in asymmetric catalysis.
- Chen, Jianfeng,Zhao, Junyu,Gong, Xing,Xu, Dongfang,Zhao, Baoguo
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supporting information
p. 4612 - 4615
(2016/09/23)
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- Isolation, Structure Elucidation, and (Bio)Synthesis of Haprolid, a Cell-Type-Specific Myxobacterial Cytotoxin
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Myxobacteria are well-established sources for novel natural products exhibiting intriguing bioactivities. We here report on haprolid (1) isolated from Byssovorax cruenta Har1. The compound exhibits an unprecedented macrolactone comprising four modified amino acids and a polyketide fragment. As configurational assignment proved difficult, a bioinformatic analysis of the biosynthetic gene cluster was chosen to predict the configuration of each stereocenter. In-depth analysis of the corresponding biosynthetic proteins established a hybrid polyketide synthase/nonribosomal peptide synthetase origin of haprolid and allowed for stereochemical assignments. A subsequent total synthesis yielded haprolid and corroborated all predictions made. Intriguingly, haprolid showed cytotoxicity against several cell lines in the nanomolar range whereas other cells were almost unaffected by treatment with the compound.
- Steinmetz, Heinrich,Li, Jun,Fu, Chengzhang,Zaburannyi, Nestor,Kunze, Birgitte,Harmrolfs, Kirsten,Schmitt, Viktoria,Herrmann, Jennifer,Reichenbach, Hans,H?fle, Gerhard,Kalesse, Markus,Müller, Rolf
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supporting information
p. 10113 - 10117
(2016/08/16)
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- γ-Glutamyl-dipeptides: Easy tools to rapidly probe the stereoelectronic properties of the ionotropic glutamate receptor binding pocket
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γ-Glutamyl-dipeptides, built by condensing the distal carboxylate of L-Glu (or D-Glu) onto a series of differently functionalized amino acids, were prepared and used as tools for rapidly probing the stereo-electronic properties of iGluRs, searching for subtype-selective ligands.
- Tamborini, Lucia,Nicosia, Veronica,Conti, Paola,Dall'Oglio, Federica,De Micheli, Carlo,Nielsen, Birgitte,Jensen, Anders A.,Pickering, Darryl S.,Pinto, Andrea
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p. 8486 - 8492
(2016/11/28)
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- Amino acid ester bromination salt chiral ionic liquid and its preparation method
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The invention discloses amino-acid ester bromide type chiral ionic liquid and a preparation method thereof. The general formula of the amino-acid ester bromide type chiral ionic liquid is ABr, wherein A is an amino-acid ester positive ion. The preparation method comprises the following steps: performing reaction on amino acid, methyl alcohol and thionyl chloride under low temperature to obtain amino-acid ester hydrochloride; performing mannich reaction on amino-acid ester hydrochloride, paraformaldehyde and acetone to obtain amino-acid ester mannich base; performing reaction on amino-acid ester mannich base and bromo-hydrocarbon to obtain the amino-acid ester chiral ionic liquid. The chiral amino-acid ester ionic liquid prepared through the preparation method disclosed by the invention has the advantages of high selectivity and chiral induction effect of a chiral substance, and non-volatilization, non-toxicity and no pollution of ionic liquid and is suitable for scale production of the fine chemical industry.
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Paragraph 0034; 0039-0041
(2018/02/04)
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- Phosphoramidate protides of five flavones and their antiproliferative activity against HepG2 and L-O2 cell lines
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A series of flavone-7-phosphoramidate derivatives were synthesized and tested for their antiproliferative activity in vitro against human hepatoma cell line HepG2 and human normal hepatic cell line L-O2. Compound 8d, 16d and 17d, incorporating the amino acid alanine, exhibited high inhibitory activity on HepG2 cell line with IC50 values of 9.0 μmol/L, 5.5 μmol/L and 6.6 μmol/L. The introduction of acyl groups played a pivotal role in the selective inhibition toward human hepatoma HepG2 cells, except for compound 8a, 9a and 16b. Compound 8d, 16d and 17d could significantly induce G2/M arrest in HepG2 cells. Specially, Compound 16d could lead early apoptosis in HepG2 cells.
- Li, Yue-Qing,Yang, Fei,Wang, Liu,Cao, Zhi,Han, Tian-Jiao,Duan, Zhe-Ang,Li, Zhen,Zhao, Wei-Jie
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p. 196 - 208
(2016/05/02)
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- LAT1 activity of carboxylic acid bioisosteres: Evaluation of hydroxamic acids as substrates
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Large neutral amino acid transporter 1 (LAT1) is a solute carrier protein located primarily in the blood–brain barrier (BBB) that offers the potential to deliver drugs to the brain. It is also up-regulated in cancer cells, as part of a tumor's increased metabolic demands. Previously, amino acid prodrugs have been shown to be transported by LAT1. Carboxylic acid bioisosteres may afford prodrugs with an altered physicochemical and pharmacokinetic profile than those derived from natural amino acids, allowing for higher brain or tumor levels of drug and/or lower toxicity. The effect of replacing phenylalanine's carboxylic acid with a tetrazole, acylsulfonamide and hydroxamic acid (HA) bioisostere was examined. Compounds were tested for their ability to be LAT1 substrates using both cis-inhibition and trans-stimulation cell assays. As HA-Phe demonstrated weak substrate activity, its structure–activity relationship (SAR) was further explored by synthesis and testing of HA derivatives of other LAT1 amino acid substrates (i.e., Tyr, Leu, Ile, and Met). The potential for a false positive in the trans-stimulation assay caused by parent amino acid was evaluated by conducting compound stability experiments for both HA-Leu and the corresponding methyl ester derivative. We concluded that HA's are transported by LAT1. In addition, our results lend support to a recent account that amino acid esters are LAT1 substrates, and that hydrogen bonding may be as important as charge for interaction with the transporter binding site.
- Zur, Arik A.,Chien, Huan-Chieh,Augustyn, Evan,Flint, Andrew,Heeren, Nathan,Finke, Karissa,Hernandez, Christopher,Hansen, Logan,Miller, Sydney,Lin, Lawrence,Giacomini, Kathleen M.,Colas, Claire,Schlessinger, Avner,Thomas, Allen A.
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supporting information
p. 5000 - 5006
(2016/10/05)
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- Novel leucine ureido derivatives as aminopeptidase N inhibitors. Design, synthesis and activity evaluation
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Aminopeptidase N (APN/CD13) over-expressed on tumor cells and tumor microenvironment, plays critical roles in tumor invasion, metastasis and angiogenesis. Here we described the design, synthesis and preliminary activity studies of novel leucine ureido derivatives as aminopeptidase N (APN/CD13) inhibitors. The results showed that compound 7a had the most potent inhibitory activity against APN with the IC50 value of 20 nM, which could be used for further anticancer agent research.
- Ma, Chunhua,Cao, Jiangying,Liang, Xuewu,Huang, Yongxue,Wu, Ping,Li, Yingxia,Xu, Wenfang,Zhang, Yingjie
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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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- Parietic acid derivative and its synthesis and use
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The invention relates to rheinic acid derivatives, and a synthetic method and applications thereof. The invention specifically discloses a compound with a general formula represented by formula (I), pharmaceutically acceptable salts and pharmaceutical compositions of the novel compound, and applications of the novel compound, the pharmaceutically acceptable salts and the pharmaceutical compositions in preparation of antitumor drugs, wherein R is used for representing L-amino acid amino C1-C6 alkyl, amino C2-C6 alkenyl, amino C3-C6 alkynyl, nitrogen-containing heterocyclic radical, or nitrogen-containing heterocyclic aryl group.
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Paragraph 0019-0021
(2017/04/03)
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- TRIPEPTIDE BORONIC ACID OR BORONIC ESTER, PREPARATIVE METHOD AND USE THEREOF
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The present invention discloses proteasome inhibitors of tripeptide boronic acids or boronic esters represented by Formula (I), preparative method and use thereof. The proteasome inhibitors are therapeutical agents for treating malignant tumor, various nervous system degenerative diseases, muscle cachexia or diabetes, wherein the malignant tumor is leukemia, gastric cancer, hepatocarcinoma or nasopharyngeal carcinoma.
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Paragraph 0035; 0048
(2016/11/07)
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- Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies
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Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.
- Galasiti Kankanamalage, Anushka C.,Kim, Yunjeong,Weerawarna, Pathum M.,Uy, Roxanne Adeline Z.,Damalanka, Vishnu C.,Mandadapu, Sivakoteswara Rao,Alliston, Kevin R.,Mehzabeen, Nurjahan,Battaile, Kevin P.,Lovell, Scott,Chang, Kyeong-Ok,Groutas, William C.
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p. 3144 - 3155
(2015/04/27)
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- Synthesis, characterization and antimicrobial activity of protected dipeptides and their deprotected analogs
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Peptides are the chemical compounds which consist of amino acids coupled together by peptide linkage. Peptide derivatives are synthesized by coupling the carboxyl group of one amino acid with amino group of other. Due to the possibilities of fortuitous and unintentional reactions, various protecting groups are used to protect the carboxylic acid as well as amino groups of both the amino acids. These peptide derivatives are associated with a variety of pharmacological activities including antibacterial and antifungal activities. While doing our analysis some of the dipeptides were synthesized in a reasonable yield and purity which were fully characterised by FTIR and H1 NMR. The antimicrobial activity of these derivatives was studied and these were found to be active against two strains of fungi (Aspergillus fumigatus & Pencillium chrysogenum) and two strains of bacteria (E. coli and Salmonella typhimurium). This provides for a future insight to work on the synthesis of these dipeptide derivatives to achieve their stability.
- Gill, Jatinder Pal Kaur,Singh, Simranjeet,Sethi, Nidhi
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p. 417 - 421
(2015/06/30)
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- Synthesis, toxicity and chemo-sensitization of HeLa cells to etoposide, of some 2-methyl amino acid ester-substituted-1,3-benzoxazines
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A number of new L- or LD-2-amino acid ester-(substituted)-benz[1,3]oxazines 12-17 were synthesized from the reaction of free L- or LD-amino acid ester 9a-d with 2-methylthio-1,3-benzoxazines 11a-g. The structures of the new products 12-17 were confirmed from their 1H, 13CNMR and IR spectra and CHN microanalysis. Some of these compounds weakly inhibited DNA-PK and platelet aggregation. Studies of the toxicity for some of the new compounds showed mostly no inhibitory effects on HeLa cell growth at 1 and 10 μM and some up to 40 μM. The chemo-sensitization to etoposide by some of the compounds revealed that the most effective chemo-sensitizers at 10 μM were 14c (1.83 fold), 12e (1.42 fold), 15a (0.8 fold), 16d (0.76 fold) and 1c (0.74). However, at 1 μM in the presence of etoposide, some compounds were shown to be more effective. No direct link was observed between the type of the L-amino acid methyl ester as well as the 7-, 8-, or 7, 8-substitution on the aromatic ring on the effectiveness of the chemo-sensitizers; however, the 7-hydroxy group did lower the effective chemo-sensitizers values.
- Ihmaid, Saleh K.,Fitzgibbon, Cheree,Al-Rawi, Jasim M. A.
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p. 2825 - 2837
(2015/02/19)
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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 0121
(2014/08/06)
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- Design, synthesis, and evaluation, derivatives of the fat-accumulation inhibitor ternatin: Toward ternatin molecular probes
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Ternatin, a cyclic heptapeptide derived from mushroom, strongly inhibits fat accumulation in 3T3-L1 adipocytes. However, its mechanism of action remains unclear. In this Letter, we designed, synthesized, and evaluated its derivatives for use as molecular probes to isolate its target protein. Finally, we successfully established a pair of ternatin molecular probes.
- Kawazoe, Yoshinori,Tanaka, Yoko,Omura, Sachikazu,Uemura, Daisuke
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supporting information
p. 4445 - 4447
(2014/08/05)
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- Synthesis of two biofriendly anionic surfactants (N-n-decanoyl-L-valine and N-n-decanoyl-L-leucine) and their mixed micellization with nonionic surfactant Mega-10 in Tris-buffer medium at pH 9
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Two biofriendly anionic amino acid surfactants (AAS), N-n-decanoyl-l-valine (C10-val) and N-n-decanoyl-l-leucine (C10-leu) were synthesized and mixed micellization of them with nonionic surfactant N-decanoyl-N-methyl-glucamine (Mega-10) was investigated by tensiometry and fluorimetry in 50 mM Tris-buffer (pH = 9) medium at 298 K. The critical micelle concentration (cmc), surface properties, e.g., Gibbs surface excess (Γmax), area of exclusion per surfactant monomer (A min) and surface pressure at cmc (Πcmc) were determined. Gibbs free energy of micellization (ΔG0m) and Gibbs free energy of adsorption (ΔG0ads) were also determined. Both the free energy values are negative indicating the spontaneity and stability of the mixed micelles. The size of the micelles was determined by dynamic light scattering (DLS) measurements. The deviation of mixed micelles from the ideal behavior was discussed on the basis of Clint, Motomura, Rubingh (regular solution theory), Rosen and Maeda's theory. Rubingh-Holland theory was applied on the ternary systems made by these three surfactants. The compositions of mixed micelle, the activity coefficients and the corresponding interaction parameters were evaluated from these theories. The interaction parameters (β) are negative, indicating attractive interaction between the ionic and nonionic surfactants. The micellar aggregation number (Nagg) and micropolarity were evaluated using steady state fluorescence measurements and the packing parameter (P) was determined on the basis of Israelachvili's theory. The standard free energy changes associated with the transfer of surfactant tail due to micellization of pure, binary and ternary combinations of surfactants were determined from Nagarajan's model. We report for the first time in detail the binary and ternary combinations using amino acid based surfactants.
- Das, Sibani,Maiti, Susmita,Ghosh, Soumen
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p. 12275 - 12286
(2014/03/21)
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- Efficient asymmetric addition of diethylzinc to aldehydes using C 2-novel chiral pyridine β-amino alcohols as chiral ligands
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A series of novel C2-symmetric chiral pyridine β-amino alcohol ligands have been synthesized from 2,6-pyridine dicarboxaldehyde, m-phthalaldehyde and chiral β-amino alcohols through a two-step reaction. All their structures were characterized by 1H NMR, 13C NMR and IR. Their enantioselective induction behaviors were examined under different conditions such as the structure of the ligands, reaction temperature, solvent, reaction time and catalytic amount. The results show that the corresponding chiral secondary alcohols can be obtained with high yields and moderate to good enantiomeric excess. The best result, up to 89% ee, was obtained when the ligand 3c (2S,2R)-2,2-((pyridine-2,6-diylbis(methylene)) bisazanediyl))bis(4-methyl-1,1-diphenylpentan-1-ol) was used in toluene at room temperature. The ligand 3g (2S,2R)-2,2-((1,3-phenylenebis(methylene)) bis(azanediyl))bis(4-methyl-1,1-diphenylpentan-1-ol) was prepared in which the pyridine ring was replaced by the benzene ring compared to 3c in order to illustrate the unique role of the N atom in the pyridine ring in the inductive reaction. The results indicate that the coordination of the N atom of the pyridine ring is essential in the asymmetric induction reaction. Copyright
- Zhang, Weijie,Tang, Ruiren,Yu, Huirong,Gao, Shu
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p. 545 - 551
(2014/07/07)
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