- The Importance of Phosphates for DNA G-Quadruplex Formation: Evaluation of Zwitterionic G-Rich Oligodeoxynucleotides
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A quaternary ammonium butylsulfonyl phosphoramidate group (N+) was designed to replace all the phosphates in a G-rich oligodeoxynucleotide d(TG4T), resulting in a formally charge-neutral zwitterionic N+TG4T sequence. We evaluated the effects of N+phosphate modifications on the structural, thermodynamic and kinetic properties of the parallel G-quadruplexes (G4) formed by TG4T and compared them to the properties of the recently published phosphoryl guanidine d(TG4T) (PG-TG4T). Using size-exclusion chromatography, we established that, unlike PG-TG4T, which exists as a mixture of complexes of different molecularity in solution, N+TG4T forms an individual tetramolecular complex. In contrast to PG modifications that destabilized G4s, the presence of N+ modifications increased thermal stability relative to unmodified [d(TG4T)]4. The initial stage of assembly of N+TG4T proceeded faster in the presence of Na+ than K+ions and, similarly to PG-TG4T, was independent of the salt concentration. However, after complex formation exceeded 75 percent, N+TG4T in solution with Na+showed slower association than with K+. N+TG4T could also form G4s in solution with Li+ions at a very low strand concentration (10 μM); something that has never been reported for the native d(TG4T). Charge-neutral PG-G4s can invade preformed native G4s, whereas no invasion was observed between N+and native G4s, possibly due to the increased thermal stability of [N+TG4T]4. The N+ modification makes d(TG4T) fully resistant to enzymatic digestion, which could be useful for intracellular application of N+-modified DNA or RNA.
- Su, Yongdong,Edwards, Patrick J. B.,Stetsenko, Dmitry A.,Filichev, Vyacheslav V.
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Read Online
- Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures
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Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t1/2 > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 ? resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-Aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel.
- Schwertz, Geoffrey,Witschel, Matthias C.,Rottmann, Matthias,Bonnert, Roger,Leartsakulpanich, Ubolsree,Chitnumsub, Penchit,Jaruwat, Aritsara,Ittarat, Wanwipa,Sch?fer, Anja,Aponte, Raphael A.,Charman, Susan A.,White, Karen L.,Kundu, Abhijit,Sadhukhan, Surajit,Lloyd, Mel,Freiberg, Gail M.,Srikumaran, Myron,Siggel, Marc,Zwyssig, Adrian,Chaiyen, Pimchai,Diederich, Fran?ois
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supporting information
p. 4840 - 4860
(2017/06/28)
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- Copper-catalyzed C-N coupling in the synthesis of integrase inhibitors of immunodeficiency viruses
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This contribution describes the total synthesis of a complex macrocyclic integrase inhibitor, a key enzyme involved in the infection process of various immunodeficiency viruses. The key transformation of the synthetic strategy was the selective C-N coupling of a sulfonamide to a heteroaryl bromide in the presence of potentially competing amide and carbamate functionalities. The transformation was accomplished with CuI catalysis using bypiridine as the ligand in the presence of base and enabled a convergent approach to the target molecule.
- Lin, Jinguan,Houpis, Ioannis N.,Liu, Renmao,Wang, Youchu,Zhang, Jianqian
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p. 205 - 214
(2014/05/20)
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- Second generation of hydroxyethylamine BACE-1 inhibitors: Optimizing potency and oral bioavailability
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BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimer's disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.
- Charrier, Nicolas,Clarke, Brian,Cutler, Leanne,Demont, Emmanuel,Dingwall, Colin,Dunsdon, Rachel,East, Philip,Hawkins, Julie,Howes, Colin,Hussain, Ishrut,Jeffrey, Phil,Maile, Graham,Matico, Rosalie,Mosley, Julie,Naylor, Alan,O'Brien, Alistair,Redshaw, Sally,Rowland, Paul,Soleil, Virginie,Smith, Kathrine J.,Sweitzer, Sharon,Theobald, Pam,Vesey, David,Walter, Daryl S.,Wayne, Gareth
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supporting information; experimental part
p. 3313 - 3317
(2009/04/06)
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- Substituted 1,2-ethylenediamines, Methods for Preparing Them and Uses Thereof
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The present invention relates to substituted 1,2-ethylenediamines of general formula (I) wherein the groups R1 to R15, A, B, L, i as well as X1-X4 are defined as in the specification and claims and the use thereof for the treatment of Alzheimer's disease (AD) and similar diseases.
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Page/Page column 222
(2010/11/24)
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- HYDROXYETHYLAMINE DERIVATIVES FOR THE TREATMENT OF ALZHEIMER'S DISEASE
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The present invention relates to novel hydroxyethylamine compounds of formula (I): (I) having Asp2 (-secretase, BACE1 or Memapsin) inhibitory activity, processes for their preparation, to compositions containing them and to their use in the treatment of diseases characterised by elevated-amyloid levels or-amyloid deposits, particularly Alzheimer's disease.
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- 3-(1,1-DIOXOTETRAHYDRO-1,2-THIAZIN-2-YL) or 3-(1,1-DOXO-ISOTHIAZOLIDIN-2YL) SUBSTITUTED BENZAMIDE COMPOUNDS AS ASP2 INHIBITORS
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The present invention relates to hydroxyethylene compounds of formula (I); having A sp2 (β-secretase, BACE1 or Memapsin) inhibitory activity, processes for their preparation, to compositions containing them and to their use in the treatment of diseases characterized by elevated β-amyloid levels or β-amyloid deposits, particularly Alzheimer's disease wherein R1 represents a group of formula Zc.
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Page/Page column 14; 15
(2010/02/09)
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- N-Nitroso Sultams: On the Direction of Approach of Nucleophiles to the Sulfonyl Group
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The N-nitroso derivatives of propanesultam, butanesultam, and pentanesultam were synthesized along with N-nitropropanesultam and N-nitro-N-methylmethanesulfonamide.The decompositions of the N-nitroso sultams, wich increase in rate with increasing ring size, yield the corresponding sultones and also varying amounts of regenerated sultams.These reactions are discussed in terms of higher energy pathway involving approach of the nucleophile in a direction between of sulfonyl oxygens (on the O, O, N face) and a lower energy pathway involving the conformer which permits approach of the nucleophile trans to and colinear with one of the coordinate covalent oxygen atoms (on R, O, N face). The mechanisms of the decomposition of the N-nitro sulfonamides and the tosyloxy diimide N-oxides are also discussed.N-nitrosopropanesultam (and the butyl analoque) are potent inhibitors of proteinase α-chymotrypsin.
- White, Emil H.,Lim, Hyung M.
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p. 2162 - 2166
(2007/10/02)
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- ω-HYDROXY-1-ALKANESULFONYL CHLORIDES
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The general synthesis of hydroxyalkanesulfonyl chlorides is illustrated by the preparation of 6-hydroxy-1-butanesulfonyl cloride (2e) and 5-hydroxy-1-pentanesulfonyl chloride (2d) as fairly stable, only liquids (of ca. 95percent purity) charecterized by Hmr, Cmr and infrared spectra, and by conversion both to the corresponding sultones (3) and to crystalline acetoxy-piperidides (6); 2d and 2e form apparent polymers, very slowly on standing at room temperature and more rapidly on heating, but on reaction with triethylamine yield the sultones (3d and 3e).A sample consisting mostly (>70percent) of 4-hydroxy-1-butanesulfonyl chloride (2c), prepared and charecterized similarly, was found to form the sultone (3c) slowly in non-polar solvents, much more readily in polar media (t1/2 ca. 20 min in water), and very rapidly in the presence of triethylamine.Effective concentrations for the spontaneous cyclization of 4-hydroxy-1-butanesulfonyl chlorides (2c) and the tertiary-amine induced cyclizations of 2d and 2e are estimated at roughly 3x102, 0.1, and 0.05 M, respectively.The mechanism of the chlorination reaction and the origins of the different products with different substrates and reaction conditions are discussed.
- King, J. F.,Webster, Michael R.,Chiba, Naoki,Allen, Julie K.,Parker, Kenneth J. M.,et al.
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p. 161 - 176
(2007/10/02)
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- Studies on Sulphochlorination of Paraffins. VI. Studies on the Sulphochlorination of individual Alkyl Chlorides
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The products of sulphochlorination of individual C2-C7 alkyl chlorides were studied by means of 1H- and 13C-n.m.r. spectroscopy.Gaschromatographic determination of the isomers formed was possible after the reaction of the chloroalkane sulphochloride mixture with dimethyl amine in ether.In no case geminal chloroalkane sulphochlorides were formed.Vicinal chlorosulphochlorides are formed,but substitution in greater distance from thechlorine is preferred if possible.Thus higher alkyl chlorides yield only verylittle amounts of vicinal chloroalkane sulphochlorides.The relative rates of sulphochlorination of alkyl chlorides were determined by competitive rections.
- Helwig, D.,Pritzkow, W.,Radeglia, R.,Schmidt-Renner, W.,Ziegler, J.
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p. 281 - 290
(2007/10/02)
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