- A synthesis of tiruchanduramine and a reinvestigation of its glycosidase inhibitory activity
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Tiruchanduramine 1 was prepared using a convergent strategy with the longest linear sequence being eight steps. Synthetic 1, displayed a broader range of inhibition than reported previously and, in addition to α-glucosidases, 1 also inhibits almond β-gluc
- Buck, Matthew L.,Evans, Daniel M.,Evans, Victoria A.,Herkt, Dominik,Sharp, Hazel,Hollinshead, Jackie,Mitschang, Fabian,Murphy, Patrick J.,Nash, Robert J.,Wenbourne, Jack
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Read Online
- ANTIMICROBIAL VACCINE COMPOSITIONS
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This invention is directed to antimicrobial vaccine compounds and compositions comprising oligosaccharide β-(1→6)- glucosamine groups having from 3 to 12 glucosamine units linked through a linker group to tetanus toxoid wherein the toxoid is primarily in
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Paragraph 0081; 0093
(2021/03/05)
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- METHOD FOR PRODUCING (2S)-2-[(1H-PYRAZOL-1-YL)METHYL]-1,3-OXAZINANE DERIVATIVE
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Provided is a novel process for producing a (2S)-2-[(1H-pyrazol-1-yl)methyl]-1,3-oxazinane derivative. More specifically, provided is a process for producing a (2S)-2-[(1H-pyrazol-1-yl)methyl]-1,3-oxazinane derivative represented by formula (1): the process comprising reacting 3-aminopropan-1-ol with glyoxylic acid.
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Paragraph 0290-0292
(2021/05/21)
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- Phosphine-Catalyzed Synthesis of Chiral N-Heterocycles through (Asymmetric) P(III)/P(V) Redox Cycling
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Phosphine-catalyzed tandem Michael addition/intramolecular Wittig reactions have been developed for the synthesis of chiral 2,5-dihydro-1H-pyrrole and tetrahydropyridine derivatives. These processes have been rendered catalytic in phosphine, thanks to the in situ reduction of phosphine oxide by phenylsilane. Furthermore, catalytic and asymmetric P(III)/P(V) processes were implemented using enantiopure chiral phosphines.
- Lorton, Charlotte,Saleh, Nidal,Voituriez, Arnaud
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supporting information
p. 3340 - 3344
(2021/06/26)
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- LOW CONTAMINANT ANTIMICROBIAL VACCINES
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Disclosed are antimicrobial vaccines comprising oligosaccharide β-(1→6)-glucosamine groups.
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Paragraph 0081; 0093
(2021/05/21)
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- Design, synthesis and anticancer profile of new 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine-linked sulfonamide derivatives with V600EBRAF inhibitory effect
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A new series of 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine linked sulfonamide derivatives 12a–n was designed and synthesized according to the structure of well-established V600EBRAF inhibitors. The terminal sulfonamide moiety was linked to the pyrimidine ring via either ethylamine or propylamine bridge. The designed series was tested at fixed concentration (1 μM) against V600EBRAF, finding that 12e, 12i and 12l exhibited the strongest inhibitory activity among all target compounds and 12l had the lowest IC50 of 0.49 μM. They were further screened on NCI 60 cancer cell lines to reveal that 12e showed the most significant growth inhibition against multiple cancer cell lines. Therefore, cell cycle analysis of 12e was conducted to investigate the effect on cell cycle progression. Finally, virtual docking studies was performed to gain insights for the plausible binding modes of vemurafenib, 12i, 12e and 12l.
- Abdel-Maksoud, Mohammed S.,Mohamed, Ahmed A. B.,Hassan, Rasha M.,Abdelgawad, Mohamed A.,Chilingaryan, Garri,Selim, Samy,Abdel-Bakky, Mohamed S.,Al-Sanea, Mohammad M.
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- Anticancer profile and anti-inflammatory effect of new N-(2-((4-(1,3-diphenyl-1H-pyrazol-4-yl)pyridine sulfonamide derivatives
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A new series of N-(2-((4-(1,3-diphenyl-1H-pyrazol-4-yl)pyridine sulfonamide derivatives 11a-o were designed and synthesized based on our previous works. The new series was tested for its anticancer and anti-inflammatory effects. The anticancer profile of
- Abdel-Maksoud, Mohammed S.,Mohamed Hassan, Rasha,Abdel-Sattar El-Azzouny, Aida,Nabil Aboul-Enein, Mohamed,Oh, Chang-Hyun
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- METHODS FOR PROVIDING CONTINUOUS THERAPY AGAINST PNAG COMPRISING MICROBES
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Disclosed are antimicrobial vaccines comprising oligosaccharide β-(1→6)-glucosamine groups.
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Paragraph 0078; 0090
(2021/05/29)
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- Methods for inhibiting biofilm formation
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Disclosed are methods and kits of parts useful in inhibiting biofilm formation in vivo in subjects at risk of developing biofilms. These methods include inhibiting biofilm formation where the extracellular matrix in the biofilm includes poly-β-(1→6)glucos
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Page/Page column 20-21
(2020/11/23)
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- Design and synthesis of novel pyrrolo[2,3-b]pyridine derivatives targeting V600EBRAF
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Several pyrrolo[2,3-b]pyridine-based B-RAF inhibitors are well known and some of them are currently FDA approved as anticancer agents. Based on the structure of these FDA approved V600EB-RAF inhibitors, two series of pyrrolo[2,3-b]pyridine scaffold were designed and synthesized in attempt to develop new potent V600EB-RAF inhibitors. The 38 synthesized compounds were biologically evaluated for their V600EB-RAF inhibitory effect at single dose (10 μM). Compounds with high percent inhibition were tested to determine their IC50 over V600EB-RAF. Compounds 34e and 35 showed the highest inhibitory effect with IC50 values of 0.085 μM and 0.080 μM, respectively. Headed for excessive biological evaluation, the synthesized derivatives were tested over sixty diverse human cancer cell lines. Only compound 35 emerged as a potent cytotoxic agent against different panel of human cancer cell lines.
- Abdel-Maksoud, Mohammed S.,Ali, Eslam M. H.,Ammar, Usama M.,Mersal, Karim I.,Oh, Chang-Hyun,Yoo, Kyung Ho
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- IMIDE-BASED MODULATORS OF PROTEOLYSIS AND METHODS OF USE
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The description relates to imide-based compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.
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Page/Page column 158; 161; 181-182
(2019/08/12)
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- Photo-organocatalytic synthesis of acetals from aldehydes
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A mild and green photo-organocatalytic protocol for the highly efficient acetalization of aldehydes has been developed. Utilizing thioxanthenone as the photocatalyst and inexpensive household lamps as the light source, a variety of aromatic and aliphatic aldehydes have been converted into acyclic and cyclic acetals in high yields. The reaction mechanism was extensively studied.
- Nikitas, Nikolaos F.,Triandafillidi, Ierasia,Kokotos, Christoforos G.
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supporting information
p. 669 - 674
(2019/02/14)
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- Acyclic nucleoside phosphonates containing the amide bond: hydroxy derivatives
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Abstract: To study the influence of a linker rigidity and changes in donor–acceptor properties, three series of nucleotide analogs containing a P–X–HN–C(O)– residue (X=CH(OH)CH2, CH(OH)CH2CH2, CH2CH(OH)CH2
- G?owacka, Iwona E.,Piotrowska, Dorota G.,Andrei, Graciela,Schols, Dominique,Snoeck, Robert,Wróblewski, Andrzej E.
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p. 733 - 745
(2019/03/14)
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- Staudinger/aza-Wittig reaction to access Nβ-protected amino alkyl isothiocyanates
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A unified approach to access Nβ-protected amino alkyl isothiocyanates using Nβ-protected amino alkyl azides through a general strategy of Staudinger/aza-Wittig reaction is described. The type of protocol used to access isothiocyanates depends on the availability of precursors and also, especially in the amino acid chemistry, on the behavior of other labile groups towards the reagents used in the protocols; fortunately, we were not concerned about both these factors as precursor-azides were prepared easily by standard protocols, and the present protocol can pave the way for accessing title compounds without affecting Boc, Cbz and Fmoc protecting groups, and benzyl and tertiary butyl groups in the side chains. The present strategy eliminates the need for the use of amines to obtain title compounds and thus, this method is step-economical; additional advantages include retention of chirality, convenient handling and easy purification. A few hitherto unreported compounds were also prepared, and all final compounds were completely characterized by IR, mass, optical rotation, and 1H and 13C NMR studies.
- Santhosh,Durgamma,Shekharappa,Sureshbabu, Vommina V.
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p. 4874 - 4880
(2018/07/15)
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- Efficient Water Reduction with sp3-sp3 Diboron(4) Compounds: Application to Hydrogenations, H–D Exchange Reactions, and Carbonyl Reductions
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A series of crystalline sp3-sp3 diboron(4) compounds were synthesized and shown to promote the facile reduction of water with dihydrogen formation. The application of these diborons as simple and effective dihydrogen and dideuterium sources was demonstrated by conducting a series of selective reductions of alkynes and alkenes, and hydrogen–deuterium exchange reactions using two-chamber reactors. Finally, as the water reduction reaction generates an intermediate borohydride species, a range of aldehydes and ketones were reduced by using water as the hydride source.
- Flinker, Mathias,Yin, Hongfei,Juhl, René W.,Eikeland, Espen Z.,Overgaard, Jacob,Nielsen, Dennis U.,Skrydstrup, Troels
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supporting information
p. 15910 - 15915
(2017/11/23)
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- Synthesis and evaluation of chirally defined side chain variants of 7-chloro-4-aminoquinoline to overcome drug resistance in malaria chemotherapy
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A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methyl-piperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.
- Dola, Vasantha Rao,Soni, Awakash,Agarwal, Pooja,Ahmad, Hafsa,Raju, Kanumuri Siva Rama,Rashid, Mamunur,Wahajuddin, Muhammad,Srivastava, Kumkum,Haq,Dwivedi,Puri,Katti
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- Polymer-Supported Chiral-at-Metal Lewis Acid Catalysts
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The covalent immobilization of a chiral-at-metal bis-cyclometalated iridium(III) catalyst on a solid support is reported, and its catalytic activity has been investigated. As a catalyst immobilization strategy, a catalyst precursor was tethered to polystyrene macrobeads through an ester or amide linkage and subsequently converted to the immobilized active chiral Lewis acid by treatment with a Br?nsted acid. The amide-linked catalyst displays high robustness and can be recycled multiple times without deterioration of enantioselectivity and only a gradual loss of catalytic activity. Chiral Lewis acid activity was demonstrated as an example for the enantioselective Friedel-Crafts alkylation of indole with an α,β-unsaturated 2-acyl imidazole and for the enantioselective Diels-Alder reactions of an α,β-unsaturated 2-acyl imidazole with 2,3-dihydrofuran or isoprene.
- Larionov, Vladimir A.,Cruchter, Thomas,Mietke, Thomas,Meggers, Eric
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supporting information
p. 1457 - 1460
(2017/04/28)
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- CYCLIC KETO-AMIDE COMPOUNDS AS CALPAIN MODULATORS AND METHODS OF PRODUCTION AND USE THEREOF
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The present technology relates to cyclic keto-amide compounds of general formulae I to XXXII, compositions and kits thereof as calpain modulators and methods useful for the treatment of various diseases or disorders such as fibrotic disease or cancer whic
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Paragraph 00396
(2017/09/27)
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- Synthesis of Substituted Quinolizidines via a Gold-Catalyzed Double Cyclization Cascade
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A novel synthesis of quinolizidines by a cationic gold-catalyzed double cyclization cascade has been developed. The reaction was initiated by the gold-catalyzed 6-exo-dig cyclization of ynamides, which was followed by a second cyclization of an enamide intermediate to provide the corresponding quinolizidine derivatives. The utility of this reaction was demonstrated by application to the synthesis of multi-substituted quinolizidines and by the total synthesis of a quinolizidine alkaloid, (±)-lupinine.
- Nonaka, Shiori,Sugimoto, Kenji,Ueda, Hirofumi,Tokuyama, Hidetoshi
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supporting information
p. 380 - 385
(2016/02/12)
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- FUNCTIONALIZED LINEAR LIGANDS AND COMPLEXES THEREOF
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The invention relates to chemical compounds and complexes that can be used in therapeutic and diagnostic applications.
- -
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Paragraph 00181; 00189; 00190
(2016/07/27)
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- Design, synthesis, and in vitro antiproliferative and kinase inhibitory effects of pyrimidinylpyrazole derivatives terminating with arylsulfonamido or cyclic sulfamide substituents
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A novel series of substituted pyrimidine compounds bearing N-phenylpyrazole and terminating with aryl and cyclic sulfonamido moiety were designed, synthesized, and evaluated in vitro as antiproliferative agents against a panel of 53 cell lines of differen
- Gamal El-Din, Mahmoud M.,El-Gamal, Mohammed I.,Abdel-Maksoud, Mohammed S.,Yoo, Kyung Ho,Baek, Daejin,Choi, Jungseung,Lee, Huiseong,Oh, Chang-Hyun
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p. 111 - 122
(2016/12/14)
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- Mild deprotection of PMB ethers using tert-butyl bromide
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A convenient and high yielding method for the cleavage and scavenging of p-methoxybenzyl protecting group of several alcohols using tert-butyl bromide in refluxing acetonitrile is described. Under these mild conditions other protecting groups such as acid sensitive allyl, benzyl, and Me3CPh2Si ethers, or isopropylidene acetals were unchanged. Interestingly, a selective alkoxy-PMB cleavage was observed in the presence of a PMB phenoxy ether.
- Rival, Nicolas,Albornoz Grados, Arantxa,Schiavo, Lucie,Colobert, Fran?oise,Hanquet, Gilles
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p. 6823 - 6826
(2015/11/27)
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- A polyamine-modified near-infrared fluorescent probe for selective staining of live cancer cells
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We report the synthesis of novel polyamine-modified near-infrared (NIR) probes, which show excellent water-solubility and good optical properties. One probe was taken up efficiently by living cancer cell lines whereas no staining of the non-cancer cells was observed.
- K?nig, Sandra G.,?z, Simin,Kr?mer, Roland
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supporting information
p. 7360 - 7363
(2015/06/03)
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- Functionalizing αvβ3- or α5β1-selective integrin antagonists for surface coating: A method to discriminate integrin subtypes in vitro
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Stuck with the right choice: αvβ3- or α5β1-selective integrin ligands were functionalized for surface coating without losing activity and selectivity. The coating of nanostructured gold surfaces with these compounds stimulated subtype-selective cell adhesion of genetically modified αvβ3- or α5β1-expressing fibroblasts in vitro. Copyright
- Rechenmacher, Florian,Neubauer, Stefanie,Polleux, Julien,Mas-Moruno, Carlos,De Simone, Mariarosaria,Cavalcanti-Adam, Elisabetta Ada,Spatz, Joachim P.,F?ssler, Reinhard,Kessler, Horst
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supporting information
p. 1572 - 1575
(2013/04/10)
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- ARYLPIPERAZINE-CONTAINING PURINE DERIVATIVES AND USES THEREOF
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A novel arylpiperazine-containing purine derivatives and a pharmaceutical composition comprising the same as an active ingredient, which are useful for preventing or treating depressive disorders, are provided.
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Page/Page column 16
(2012/09/22)
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- Virtual screening, selection and development of a benzindolone structural scaffold for inhibition of lumazine synthase
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Virtual screening of a library of commercially available compounds versus the structure of Mycobacterium tuberculosis lumazine synthase identified 2-(2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)acetic acid (9) as a possible lead compound. Compound 9 proved to be an effective inhibitor of M. tuberculosis lumazine synthase with a Ki of 70 μM. Lead optimization through replacement of the carboxymethylsulfonamide sidechain with sulfonamides substituted with alkyl phosphates led to a four-carbon phosphate 38 that displayed a moderate increase in enzyme inhibitory activity (Ki 38 μM). Molecular modeling based on known lumazine synthase/inhibitor crystal structures suggests that the main forces stabilizing the present benzindolone/enzyme complexes involve π-π stacking interactions with Trp27 and hydrogen bonding of the phosphates with Arg128, the backbone nitrogens of Gly85 and Gln86, and the side chain hydroxyl of Thr87.
- Talukdar, Arindam,Morgunova, Ekaterina,Duan, Jianxin,Meining, Winfried,Foloppe, Nicolas,Nilsson, Lennart,Bacher, Adelbert,Illarionov, Boris,Fischer, Markus,Ladenstein, Rudolf,Cushman, Mark
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experimental part
p. 3518 - 3534
(2010/08/05)
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- ARYLPIPERAZINE-CONTAINING PYRROLE 3-CARBOXAMIDE DERIVATIVES FOR TREATING DEPRESSIVE DISORDERS
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The present invention relates to novel arylpiperazine-containing pyrrole 3-carboxamide derivatives of formula (I) or a pharmaceutically acceptable salt thereof which is useful for preventing or treating depressive disorders. The present invention also provides a method for preparing the arylpiperazine-containing pyrrole 3-carboxamide derivatives or the pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, and a method for preventing or treating depressive disorders.
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Page/Page column 50
(2010/04/27)
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- FATTY ACID ACETYLATED SALICYLATES AND THEIR USES
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The invention relates to Fatty Acid Acetylated Salicylate Derivatives; compositions comprising an effective amount of a Fatty Acid Acetylated Salicylate Derivative; and methods for treating or preventing an inflammatory disorder comprising the administration of an effective amount of a Fatty Acid Acetylated Salicylate Derivative.
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Page/Page column 114-115
(2010/03/04)
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- A mild and efficient chemoselective: N-benzyloxycarbonylation of amines using TBAB a catalyst under solvent-free conditions
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We describe a mild and efficient method for the chemoselective N-benzyloxycarbonylation of amines by treatment amines and aminoesters with benzyloxycarbonyl chloride (Cbz-Cl) in the presence of TBAB under solvent-free in excellent yields. The method is ge
- Babu, Kothamasu Suresh,Rao, Vidadala Rama Subba,Rao, Ravu Ranga,Babu, Sakhamuri Sivaram,Rao, Janaswami Madhusudana
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experimental part
p. 393 - 396
(2009/10/17)
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- COMPOUNDS FOR INHIBITING WIP1, PRODRUGS AND COMPOSITIONS THEREOF, AND RELATED METHODS
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The invention provides compounds useful in inhibiting the activity of a Wip1 protein in a cell as well as prodrugs thereof, related methods of use and compositions which include the aforesaid compounds and prodrugs thereof. The compounds comprise a ring structure having at least five functional groups bonded thereto, wherein each functional group is bonded to a different ring atom, and wherein the at least five functional groups comprise: (a) first (R1) and second (R3) moieties each comprising a phosphate group wherein these first and second moieties are separated by at least one ring atom; (b) first (R2) and second (R4) hydrophobic groups, wherein the first and second hydrophobic groups are separated by at least one ring atom, and wherein the first hydrophobic group is bonded to a ring atom located between the ring atoms to which the first (R1) and second (R2) moieties are bonded; and an amide or carboxylic acid (R5).
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Page/Page column 23
(2009/04/25)
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- N-Benzyloxycarbonylation of amines in the ionic liquid [TPA][l-Pro] as an efficient reaction medium
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An efficient method for the N-benzyloxycarbonylation of amines is described. The reaction of amines with Cbz-Cl in the ionic liquid [TPA][l-Pro] afforded the corresponding N-Cbz derivatives in excellent yields. The method is versatile for the preparation
- Suryakiran,Chinni Mahesh,Ramesh,Jon Paul Selvam,Venkateswarlu
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p. 2607 - 2610
(2008/09/18)
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- Convenient method for the preparation of carbamates, carbonates, and thiocarbonates
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(Chemical Equation Presented) A convenient, rapid, and efficient method for the preparation of carbamates from amines with 1-alkoxycarbonyl-3-nitro-1,2,4- triazole transfer reagents is reported. Reactions of newly synthesized stable crystalline reagents with alkyl amines were completed in a few minutes without any additional base, and highly pure carbamates were obtained without chromatographic purification. These highly active reagents are also useful for the selective protection of nucleobases and preparation of carbonates and thiocarbonates.
- Shimizu, Mamoru,Sodeoka, Mikiko
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p. 5231 - 5234
(2008/09/17)
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- A mild and efficient chemoselective protection of amines as N-benzyloxycarbonyl derivatives in the presence of La(NO3)3·6H2O under solvent-free conditions
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A facile and versatile method for the chemoselective N-benzyloxycarbonylation of amines has been developed by treatment with benzyloxycarbonyl chloride (Cbz-Cl) in the presence of lanthanum(III) nitrate hexahydrate under solvent-free conditions. The metho
- Chinni Mahesh,Narasimhulu,Srikanth Reddy,Suryakiran,Venkateswarlu
-
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- An efficient and chemoselective Cbz-protection of amines using silica-sulfuric acid at room temperature
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A simple, facile, and chemoselective N-benzyloxycarbonylation of amines using silica-sulfuric acid that proceeds under solvent-free conditions at room temperature has been achieved. These reactions are applicable to a wide variety of primary (aliphatic and cyclic) secondary amines, amino alcohols, and heterocyclic amines.
- Gawande, Manoj B.,Polshettiwar, Vivek,Varma, Rajender S.,Jayaram, Radha V.
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p. 8170 - 8173
(2008/03/13)
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- The study of the reaction of terminated oligomerization in the synthesis of oligo-(β1-6)-glucosamines
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The applicability of terminated oligomerization to the synthesis of oligo-(β1-6)-glucosamines, fragments of the intercellular polysaccharide adhesin of staphylococci, was studied. The reactions of terminated oligomerization were carried out with mono-, di-, and trisaccharide monomers and N-protected aminopropanol; and spacered mono-and disaccharides as terminating molecules were also attempted. The primary formation of cyclic products of monomer intramolecular glycosylation was observed in almost all the reactions. Only the experiments with the monomer based on the disaccharide bromide under the conditions of the Helferich reaction led to reduced yields (30%) of the cyclic products. However, even in this case, the desired terminated oligosaccharides were generated in approximately 10% yield and mainly were the products of single glycosylation of the terminator by the monomer. These experiments allow the conclusion that, under the examined conditions, the reaction of terminated oligomerization could not result in the synthesis of oligoglucosamines with a high molecular mass. Pleiades Publishing, Inc., 2006.
- Gening,Tsvetkov,Pier,Nifantiev
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p. 389 - 399
(2008/02/09)
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- Kinase-mediated trapping of bi-functional conjugates of paclitaxel or vinblastine with thymidine in cancer cells
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In the present work, we explore the possibility of introducing selectivity to existing chemotherapeutics via the design of non-pro-drug, bi-functional molecules comprising a microtubule-binding agent and a substrate for a disease-associated kinase. The design, synthesis, and in vitro biological evaluation of paclitaxel-thymidine and vinblastine-thymidine bi-functional conjugates are reported here. This work provides the first account of 'kinase-mediated trapping' of cancer therapeutics.
- Aspland, Simon E.,Ballatore, Carlo,Castillo, Rosario,Desharnais, Joel,Eustaquio, Trisha,Goelet, Philip,Guo, Zijian,Li, Qing,Nelson, David,Sun, Chengzao,Castellino, Angelo J.,Newman, Michael J.
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p. 5194 - 5198
(2008/02/02)
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- Synthesis of a αMan(1→3)αMan(1→2)αMan glycocluster presented on a β-cyclodextrin scaffold
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Application of 6-thio-α- and β-cyclodextrins as the core component for the construction of multivalent carbohydrate structures is described. The method employed for the attachment of monomeric glycosides to a cyclodextrin core is based on the efficient nu
- Carpenter, Clare,Nepogodiev, Sergey A.
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p. 3286 - 3296
(2007/10/03)
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- Peptide-cleaving catalyst selective for peptide deformylase
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A peptide-cleaving catalyst selective for peptide deformylase (PDF) was obtained from a library containing about 15000 catalyst candidates. The catalyst cleaved the polypeptide backbone of PDF at Gln(152)-Arg(153). Docking simulations suggested multiple m
- Chae, Pil Seok,Kim, Myoung-Soon,Jeung, Chul-Seung,Lee, Seong Du,Park, Hwangseo,Lee, Sangyoub,Suh, Junghun
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p. 2396 - 2397
(2007/10/03)
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- Removal of the phosphate group in mechanism-based inhibitors of inositol monophosphatase leads to unusual inhibitory activity.
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Inositol monophosphatase is widely held to be the therapeutic target for inhibition by lithium ion in the treatment of bipolar disorder. In a continued effort to improve the bioavailability of alternative inhibitors, we have designed and tested two new se
- Miller, David J,Bashir-Uddin Surfraz,Akhtar, Mahmoud,Gani, David,Allemann, Rudolf K
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p. 671 - 688
(2007/10/03)
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- Stereoselective Aldol Additions Catalyzed by Dihydroxyacetone Phosphate-Dependent Aldolases in Emulsion Systems: Preparation and Structural Characterization of Linear and Cyclic Iminopolyols from Aminoaldehydes
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The potential of dihydroxyacetone phosphate (DHAP)-dependent aldolases to catalyze stereoselective aldol additions is, in many instances, limited by the solubility of the acceptor aldehyde in aqueous/co-solvent mixtures. Herein, we demonstrate the efficiency of emulsion systems as reaction media for the class I fructose-1,6-b isphosphate aldolase (RAMA) and class II recombinant rhamnulose-1-phosphate aldolase from E. coli (RhuA)catalyzed aldol addition between DHAP and N-benzyloxycarbonyl (N-Cbz) aminoaldehydes. The use of emulsions improved the RAMA-catalyzed aldol conversions by three to tenfold relative to those in conventional DMF/ water mixtures. RhuA was more reactive than RAMA towards the N-Cbz aminoaldehydes regardless of the reaction medium. With (S)- or (R)-Cbz-alaninal, RAMA exhibited preference for the R enantiomer, while RhuA had no enantiomeric discrimination. The linear N-Cbz aminopolyols thus obtained were submitted to catalytic intramolecular reductive amination to afford the corresponding iminocyclitols. This reaction was diastereoselective in all cases examined; the face selectivity was controlled by the stereochemistry of the newly formed hydroxyl group originating from the aldehyde. Characterization of the resulting iminocyclitols allowed the assessment of the diastereoselectivity of the enzymatic aldol reactions with respect to the N-protected aminoaldehyde. RAMA formed single diastereoisomers from N-Cbz-glycinal and from both enantiomers of N-Cbz-alaninal, while 14% of the epimeric product was observed from N-Cbz-3-aminopropanal. Diastereoselectivity from RhuA was lower than that observed from RAMA. Interestingly, a single diastereoisomer was formed from (S)-Cbz-alaninal, whereas only a 34% diastereomeric excess was observed from its enantiomer (i.e., (R)-Cbz-alaninal).
- Espelt, Laia,Parella, Teodor,Bujons, Jordi,Solans, Conxita,Joglar, Jesus,Delgado, Antonio,Clapes, Pere
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p. 4887 - 4899
(2007/10/03)
-
- Studies on the synthesis of (2S,3R)-3-hydroxy-3-methylproline via C 2-N bond formation
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A new efficient synthesis of (2S,3R)-3-hydroxy-3-methylproline (3) is reported. During the course of a recent study on the Lewis acid promoted intramolecular opening of an epoxide by a carbamate NH, a highly concerted rearrangement was unexpectedly observed. Further investigations of substrate generality show that δ-carbamate-α,β-epoxide esters commonly underwent similar rearrangements with the aid of Lewis acids. Retrosynthetic analysis of such a C2 - N disconnection can lead to an efficient synthesis of (2S,3R)-3-hydroxy-3-methylproline (3) in high enantio purity. Stereochemistries were established by a Sharpless asymmetric dihydroxylation and a diastereo-selective reductive amination.
- Shen, Jun-Wei,Qin, Dong-Guang,Zhang, Hong-Wang,Yao, Zhu-Jun
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p. 7479 - 7484
(2007/10/03)
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- Nonpeptide bradykinin B2 receptor antagonists: Conversion of rodent-selective bradyzide analogues into potent, orally-active human bradykinin B2 receptor antagonists
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The 1-(2-nitrophenyl)thiosemicarbazide (TSC) derivative, (S)-l-[4-(4-benzhydrylthiosemicarbazido)-3-nitrobenzenesulfonyl] pyrrolidine-2-carboxylic acid {2-[(2-dimethylaminoethyl)methylamino]ethyl} amide (bradyzide; (S)-4), was recently disclosed as a novel, potent, orally active nonpeptide bradykinin (BK) B2 receptor antagonist. The compound inhibited the specific binding of [3H]BK to NG108-15 cell membrane preparations (rodent neuroblastoma-glioma) expressing B2 receptors with a Ki of 0.5 ± 0.2 nM. Compound (S)-4 also demonstrated oral efficacy against Freund's complete adjuvant (FCA)-induced mechanical hyperalgesia in rats with an ED50 value of 0.84 μmol/kg. After we optimized the terminal binding determinants projecting from the TSC framework, we found that it was possible to replace the potentially toxicophoric nitro and divalent sulfur moieties with only a 15-fold loss in binding affinity ((S)-14a). However, bradyzide and its congeners were found to have much lower affinities for cloned human B2 receptors, expressed in Cos-7 cells. The hitherto synthesized TSC series was screened against the human B2 receptor, and the dibenzosuberane (DBS) pharmacophore emerged as the key structural requirement for potency. Incorporation of this group resulted in a series of derivatives ((S)-14d,e and 19b-d) with Ki ranges of 10.7-176 nM in NG108-15 cells (expressing the rodent B2 receptor) and 0.79-253 nM in Cos-7 cells (expressing the human B2 receptor). There was no evidence of agonist activity with any of the nonpeptides in any of the cell lines tested. In vivo, oral administration of compound 19c reversed FCA-induced and turpentine-induced mechanical hyperalgesia in rodents with ED50 values of 0.027 and 0.32 μmol/kg, respectively. The selectivity profiles of compounds (S)-14f and (S)-14g were also assessed to determine the conformational and/or steric preferences of the double-ring arrangement. The affinity of (S)-14g for the human B2 receptor suggested that it may be a hydrophobic interaction with the ethane bridge of the DBS moiety that accounts for the increased potency of compounds (S)-14d,e and 19b,c at this receptor, by favoring a binding mode inaccessible to the unsubstituted diphenylmethyl derivative, (S)-4.
- Dziadulewicz, Edward K.,Ritchie, Timothy J.,Hallett, Allan,Snell, Christopher R.,Davies, John W.,Wrigglesworth, Roger,Dunstan, Andrew R.,Bloomfield, Graham C.,Drake, Gillian S.,McIntyre, Peter,Brown, Michael C.,Burgess, Gillian M.,Lee, Wai,Davis, Clare,Yaqoob, Mohammed,Phagoo, Steve B.,Phillips, Elsa,Perkins, Martin N.,Campbell, Elizabeth A.,Davis, Andrew J.,Rang, Humphrey P.
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p. 2160 - 2172
(2007/10/03)
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- Effect of spermine conjugation on the cytotoxicity and cellular transport of acridine
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Polyamines are believed to be potent vectors for the selective delivery of chemotherapeutic agents into cancer cells. In this paper, we report the effect of spermine conjugation on the cytotoxic and transport properties of acridine. Six derivatives, composed of a spermine chain attached at its N1 position to an acridine via an aliphatic chain, were synthesized. The aliphatic linker, comprised of 3-5 methylene units, was connected to the position-9 of the heterocycle through either an amide (amidoacridines 8-10) or an amine (aminoacridines 11-13) linkage. Independently of their architecture, all ligands showed a high affinity for DNA binding but a limited DNA sequence selectivity. In a whole cell assay with L1210 and Chinese hamster ovary (CHO) cells, the aminoacridines (IC50 values around 2 μM) were more potent than the amidoacridines (IC50 values between 20 and 40 μM). This was related to a less efficient transport for the latter. As determined from competitive uptake studies with [14C] spermidine, all conjugates had a high affinity for the polyamine transport system (PTS). However, on the basis of competitive studies with an excess of spermidine and on the differential effect on cell growth and accumulation in CHO and in the mutant PTS deficient CHO-MG cells, the accumulation of the conjugates through the PTS was found to be poor but still more efficient for the aminoacridines. α-Difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, which induces an up-regulation of the activity of the PTS, enhanced accumulation of all acridine conjugates through the PTS and had a synergistic effect on the potency of the acridine conjugates to inhibit cell growth. Despite their high affinity for the PTS, the low amount of derivatives transiting through the PTS is likely to be related to their ability to repress rapidly and efficiently the activity of the PTS and, consequently, to inhibit their own uptake via this system.
- Delcros, Jean-Guy,Tomasi, Sophie,Carrington, Simon,Martin, Bénédicte,Renault, Jacques,Blagbrough, Ian S.,Uriac, Philippe
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p. 5098 - 5111
(2007/10/03)
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- Amino acid amidinohydrazones, alkoxyguanidines and aminoguanidines as protease inhibitors
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The present invention is directed to aminoguanidine and alkoxyguanidine compounds, including compounds of Formula I: wherein X is O or NR19and A1, A2, R7-R10, R18, Ra, Rb/s
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- Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors
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Aminoguanidine and alkoxyguanidine compounds are described, including compounds of the Formula VII: wherein X is O or NR9and Het, R1, R7, R8, R12-R15, Ra, Rb, Rc, Z, and n are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin. Also described are methods for preparing such compounds. The compounds of the invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin. The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. Additionally, the compounds can be detectably labeled and employed for in vivo imaging of thrombi.
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Page column 41
(2010/02/05)
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- Derivatives of cyclodepsipeptide PF1022 substance
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Novel derivatives of PF1022 substance, which are cyclodepsipeptides represented by the general formula (I) shown below or their salts are useful as anthelmintic agent for prevention or treatment of parasitic infections.
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- An efficient asymmetric synthesis of (2S,3S)- and (2R,3R)-β-hydroxyornithine
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Asymmetric syntheses of (2S,3S)- and (2R,3R)-β-hydroxyornithine have been achieved in four steps and 46% overall yield. The key step in this synthesis involved an aldol reaction between a chiral glycine boron enolate and (3-oxo-propyl)-carbamic acid benzy
- DeMong, Duane E.,Williams, Robert M.
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p. 183 - 185
(2007/10/03)
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- Homologation of polyamines in the rapid synthesis of lipospermine conjugates and related lipoplexes
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Lipopolyamine amides are useful cationic lipids, synthetic vectors for non-viral gene delivery. Desymmetrisation of readily available symmetrical polyamines is an important first step in the synthesis of such compounds. The application of trifluoroacetyl
- Geall, Andrew J.,Blagbrough, Ian S.
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p. 2449 - 2460
(2007/10/03)
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- Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors
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Aminoguanidine and alkoxyguanidine compounds are described, including compounds of the Formula VII: wherein X is O or NR9 and Het, R1, R7, R8, R12-R15, Ra, Rb, Rc, Z, and n are set forth in the specification, as well as hydrates, solvates or pharmaceutica
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- β-Secondary Kinetic Isotope Effects in the Clavaminate Synthase-Catalyzed Oxidative Cyclization of Proclavaminic Acid and in Related Azetidinone Model Reactions
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Clavaminate synthase is an Fe(II)/α-ketoglutarate-dependent oxygenase that catalyzes three mechanistically distinct reactions in the course of clavulanic acid biosynthesis. Clavulanic acid is of significant chemical importance as a potent inhibitor/inactivator of β-lactamase enzymes, a prominent means of bacterial resistance to, for example, penicillin. Primary and α-secondary T(V/K) kinetic isotope effects have been determined in earlier work for the clavaminate synthase-catalyzed oxidative cyclization of proclavaminic acid, one of the three reactions mediated by this enzyme. In this paper the β-secondary deuterium kinetic isotope effect for this reaction has been determined using remote 3H and 14C labels in an attempt to distinguish between radical or cationic intermediates in the reaction as suggested by the magnitudes of the primary and secondary α-effects. The presence of the adjacent azetidinone nitrogen and the intervention of an azetinone intermediate, formally antiaromatic in the resonance form of the amide, make interpretation of the low β-secondary effect (1.056 ± 0.002 for dideuteriation at C-3′) problematic. To assist interpretation of this result, a 4-chloroazetidinone model system has been constructed dideuteriated at C-3 identically to proclavaminic acid and bearing remote radiolabels. Reaction of this substrate at 25°C under both radical and solvolysis conditions afforded β-secondary kinetic isotope effect data for direct comparison to the enzymic reaction. The measured effects are similarly small but strongly dependent on the polarity/acidity of the reaction medium. These results are discussed in terms of the commitment to catalysis and the extent to which amide resonance may be favored in the transition state of the oxidative cyclization.
- Iwata-Reuyl, Dirk,Basak, Amit,Townsend, Craig A.
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p. 11356 - 11368
(2007/10/03)
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