Practical asymmetric synthesis of a novel γ-secretase inhibitor

An efficient route to γ-secretase inhibitor hydroxyl thiophene sulfonamide 1 is described. The approach contains nine steps with an overall yield of 8%. The synthesis highlights a diastereoselective methylation using Evans' oxazolidinone method and a chiral Strecker reaction via Davis' sulfonimine protocol.     

Supramolecular peptide helix from a novel double turn forming peptide containing a β-amino acid

A single-crystal X-ray diffraction study of the terminally protected tetrapeptide Boc-β-Ala-Aib-Leu-Aib-OMe 1 (Aib: α-aminoisobutyric acid; β-Ala: β-Alanine) reveals that it adopts a new type of double turn structure which self-associates to form a unique supramolecular helix through intermolecular hydrogen bonds. Scanning electron microscopic studies show that peptide 1 exhibits amyloid-like fibrillar morphology in the solid state.     

Nakinadine A, a novel bis-pyridine alkaloid with a β-amino acid moiety from sponge Amphimedon sp.

A novel cytotoxic bis-3-alkylpyridine alkaloid with a β-amino acid moiety, nakinadine A (1), has been isolated from an Okinawan marine sponge Amphimedon sp., and the structure and stereochemistry were elucidated by spectroscopic data.     

Protonation states of the catalytic dyad of β-secretase (BACE1) in the presence of chemically diverse inhibitors: a molecular docking study

In this molecular docking study, the protonation states of the catalytic Asp dyad of the beta-secretase (BACE1) enzyme in the presence of eight chemically diverse inhibitors have been predicted. BACE1 catalyzes the rate-determining step in the generation of Alzheimer amyloid beta peptides and is widely considered as a promising therapeutic target. All the inhibitors were redocked into their corresponding X-ray structures using a combination of eight different protonation states of the Asp dyad for each inhibitor. Five inhibitors were primarily found to favor two different monoprotonated states, and the remaining three favor a dideprotonated state. In addition, five of them exhibited secondary preference for a diprotonated state. These results show that the knowledge of a single protonation state of the Asp dyad is not sufficient to search for the novel inhibitors of BACE1 and the most plausible state for each inhibitor must be determined prior to conducting in-silico screening.     

Synthesis of novel β2,2-amino acid from D-mannose and attempted synthesis of peptides from the amino acid

The study describes the synthesis of new α,α-disubstituted β-amino acid (β^2,2-Caa) and attempts the synthesis of peptides from it. The β^2,2-Caa was prepared from D-(+)-mannose, using crossed aldol and Cannizzaro reactions.     

The first chemical synthesis of F-4-GlcAβ(1→3)GlcNAc-UDP with the potential of novel substrate and enzyme inhibitor for hyaluronic acid synthases (HASs)

The first chemical synthesis of F-4-GlcAβ(1→3)GlcNAc-UDP is described here. This compound can serve as a novel substrate to study the catalytic mechanism of hyaluronic acid synthases (HASs) and has potential to be donor for these enzymes that extend HA chain at the reducing end. Moreover, it may also behave as inhibitor for the enzymes that act on non-reducing end in the assembly of HA chain.     

Synthesis of bicyclic β-lactamase inhibitor relabactam derivatives from a relabactam intermediate

We have developed highly efficient chemistry to prepare two key intermediates from a Relabactam intermediate available from the process chemistry. The new intermediates enabled us to quickly synthesize other Ralebactam derivatives such as compound 1.     

A novel alkenoic acid ester and a new benzophenone from Ranunculus ternatus

A novel alkenoic acid ester,(E)-4-hydroxy-dodec-2-enedioic acid-12-O-methyl ester and a new benzophenone,ethyl (S)-3-[2- (3,4-dihydroxybenzoyl)-4,5-dihydroxyphenyl]-2-hydroxypropanoate,together with a known compound,(E)-4-hydroxy-dodec-2- enedioic acids were isolated from the roots of Ranunculus ternatus.Their structures were elucidated by spectroscopic methods.     

A practical entry to β-aryl-β-alkyl amino alcohols: application to the synthesis of a potent BACE1 inhibitor

The 1,2-addition of alkyl Grignard reagents to readily available N-tert-butanesulfinyl ketimines, bearing an α-silyloxy substituent, proceeds in high yields and excellent diastereocontrol. The utility of the present method was demonstrated by the synthesis, in enantiomerically pure form, of one recently disclosed β-secretase (BACE1) inhibitor.     

Semi-synthesis of an artificial scandium(iii) enzyme with a β-helical bio-nanotube

We have succeeded in preparing semi-synthesized proteins bound to Sc(3+) ion which can promote an epoxide ring-opening reaction. The Sc(3+) binding site was created on the surface of [(gp5βf)(3)](2) (N. Yokoi et al., Small, 2010, 6, 1873) by introducing a cysteine residue for conjugation of a bpy moiety using a thiol-maleimide coupling reaction. Three cysteine mutants [(gp5βf_X)(3)](2) (X = G18C, L47C, N51C) were prepared to introduce a bpy in different positions because it had been reported that Sc(3+) ion can serve as a Lewis-acid catalyst for an epoxide ring-opening reaction upon binding of epoxide to bpy and two -ROH groups. G18C_bpy with Sc(3+) can accelerate the rate of catalysis of the epoxide ring-opening reaction and has the highest rate of conversion among the three mutants. The value is more than 20 times higher than that of the mixtures of [(gp5βf)(3)](2)/2,2'-bipyridine and l-threonine/2,2'-bipyridine. The elevated activity was obtained by the cooperative effect of stabilizing the Sc(3+) coordination and accumulation of substrates on the protein surface. Thus, we expect that the semi-synthetic approach can provide insights into new rational design of artificial metalloenzymes.     

(4→4)-Di(2,3-anhydropentopyranosides), a novel class of potential enzyme inhibitors

An easy access in high yields to 4,4′-diepoxydisaccharides, is described reacting epoxy hydroxy enolate pyranosides with the corresponding triflates. This new class of synthons are of interest for further chemical transformations as well as potential enzyme inhibitors.     

Pycnalin, a new α-glucosidase inhibitor from Acer pycnanthum

A new compound, pycnalin (1), together with four known compounds, ginnalins A (2), B (3), C (4), and 3,6-di-O-galloyl-1,5-anhydro-D-glucitol (3,6-di-GAG) (5), were isolated from Acer pycnanthum. The structure of 1 was determined on the basis of 2D-NMR spectral data and synthesis of 1. Pycnalin (1) is the first 1,5-anhydro-D-mannitol linked to a gallic acid, while compounds 2-5 were 1,5-anhydro-D-glucitol linked to gallic acids. All compounds were tested in vitro for α-glucosidase inhibitory and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities. Pycnalin (1) exhibited moderate α-glucosidase inhibitory activity as well as free radical scavenging activity. Ginnalin A (2) and 3,6-di-GAG (5), which have two galloyl groups, exhibited potent α-glucosidase inhibition, compared to those of other compounds 1, 3, and 4 containing a galloyl group. These results suggest that α-glucosidase inhibition is influenced by the number of galloyl groups.     

Enantioselective syntheses of (−)-pinellic acid, α- and β-dimorphecolic acid

An efficient enantioselective convergent approach for the synthesis of (−)-pinellic acid 1, α- and β-dimorphecolic acid (2 and 3) from 1,9-nonane diol is described. The synthetic strategy features Sharpless asymmetric hydroxylation, Sonogashira coupling and Birch reduction.     

Biodegradation of β-1,4-linked polyglucuronic acid (cellouronic acid)

Biodegradability of -1,4-linked polyglucuronic acid (cellouronicacid), which was prepared from regenerated cellulose by2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO)-mediated oxidation underaqueous conditions, was examined by enzymatic treatments and incubationtreatments with microorganisms collected from some soil samples. Degradation ofcellouronic acid was traced by size exclusion chromatography (HPSEC) or totalorganic carbon (TOC) of the treated products or solutions, respectively.Cellouronic acid was depolymerized by a commercial crude cellulase anddecreasedin its weight average degree of polymerization from about 1600 to 40 by thecellulase treatment at 20 °C for 40 days. ¹³C-NMRanalysis and liquid chromatography of the treated products showed thathydrolysis-type enzymes present in the crude cellulase as contaminantsprimarilydepolymerized cellouronic acid to give glucuronic acid. When aqueous solutionscontaining cellouronic acid were incubated with soil microorganisms for morethan 3 days, the TOC values decreased to less than 20% of the initial value,depending on molecular weight of the cellouronic acid used. The decreasing rateof TOC for cellouronic acid was clearly higher than that ofcarboxymethylcellulose, which is one of the cellulose derivatives havingcarboxymethyl substituents. These results imply that cellouronic acid has bothbiodegradability and metabolizability in the natural environment.     

Towards cyclic,conformationally constrained,fluorine-containing β-amino acid derivatives from d-glucose

Novel, potentially bioactive, fluorinated branched-chain monosaccharides were obtained by reaction of diethylaminosulphur trifluoride (DAST) with a series of methyl 3-C-cyano-3-ethoxycarbonyl-β-d-glucopyranoside derivatives, including the 4,6-O-benzylidene derivative and their 3-C-(N-protected aminomethyl) reduction products, as well as the phenyl 3-C-cyano-3-ethoxycarbonyl-1-thio-α-d-(and β-d-)glucopyranosides. The absolute configuration at C(3) was unambiguously assigned for all compounds on the basis of X-ray crystallographic analysis of methyl 4,6-O-benzylidene-3-C-cyano-3-deoxy-3-ethoxycarbonyl-β-d-glucopyranoside, corroborating the previous tentative assignment by other authors for the 4,6-unprotected compound. The course of the fluorination depended on the reaction temperature and the substitution pattern of the substrate. Thus, for methyl 3-C-cyano-3-ethoxycarbonyl-β-d-glucopyranoside, fluorination occurred exclusively at C(6), but for the phenylthio analogue, a 2-deoxy-2-phenylthio-α-d-manno-configured glycosyl fluoride and its 6-fluoro derivative were obtained, resulting from the expected rearrangement reaction, whilst starting from the phenylthio α anomer, only the unrearranged 6-fluoro compound was formed. Rearrangement was also observed in the fluorination of methyl 4,6-O-benzylidene-3-C-(N-protected aminomethyl)-β-d-glucopyranoside, which led to the 2-O-methyl-α-d-mannopyranosyl fluoride derivative as the sole product. This methodology may constitute a simple route to enantiopure conformationally constrained cyclic fluorinated β-amino acids having the α carbon atom shared with a pyranose ring, although only moderate yields were achieved, particularly in the fluorination step.     

Polyvinylsulfonic acid as a novel Brønsted acid catalyst for the synthesis of bis(indolyl)methanes

Abstract

Polyvinylsulfonic acid as a novel, biodegradable, and efficient Brønsted acid catalyst for the reaction of indoles with aldehydes to obtain bis(indolyl)methanes has been reported. The catalyst exhibited remarkable activity, recyclability, and tolerated a wide variety of functional groups providing the desired bis(indolyl)methanes in excellent yield (64–96%) at room temperature using ethanol as a solvent. The effect of different reaction parameters like solvent, temperature, catalyst doses, and recyclability were investigated for the title reaction.     

Hot electron capture dissociation distinguishes leucine from isoleucine in a novel hemoglobin variant, Hb Askew, β54(D5)Val→Ile

Population migration has led to the global dispersion of human hemoglobinopathies and has precipitated a need for their identification. An effective mass spectrometry-based procedure involves analysis of the intact α- and β-globin chains to determine their mass, followed by location of the variant amino acid residue by direct analysis of the enzymatically digested chains and low-energy collision induced dissociation of the variant peptide. Using this procedure, a variant was identified as either β54Val→Leu or β54Val→Ile, since the amino acids leucine and isoleucine cannot be distinguished using low-energy collisions. Here, we describe how hot electron capture dissociation on a Fourier transform-ion cyclotron resonance mass spectrometer was used to distinguish isoleucine from leucine and identify the mutation as β54(D5)Val→Ile. This is a novel variant, and we have named it Hb Askew.     

Synthesis,luminescence, and cyclic voltammetric studies of novel binuclear ruthenium(II) complexes prepared from β-diketonate derivatives

Two bis-(β-diketonate) ligands [H₂L¹ = 3,6-bis-(4,4,4-trifluorobutane-1,3-dione)-9-butyl-carbazole and H₂L² = 3,6-bis-(4,4,4-trifluorobutane-1,3-dione)-9-hexyl-carbazole] were synthesized, and their corresponding dinuclear ruthenium(II) complexes [Ru₂(bpy)₄(L¹)](PF₆)₂ (1) and [Ru₂(bpy)₄(L²)](PF₆)₂ (2) (bpy = 2,2′-bipyridine)] were prepared by the reaction of Ru(bpy)₂Cl₂ · 2H₂O with H₂L¹ and H₂L² in ethanol, respectively. The structure of the ligand H₂L² was determined by single-crystal X-ray diffraction. The spectral properties of the ligands and their complexes have been studied. The absorption spectra of the complexes exhibit intense ligand-centered bands in the UV region and metal-to-ligand charge-transfer bands in the visible region. The two-photon absorption (TPA) coefficient β and TPA cross-section σ were determined by the Z-scan technique, which revealed that the two complexes exhibit strong TPA due to electronic extensive delocalization. The complexes undergo a reversible or quasi-reversible one-electron metal-centered redox process at E _1/2 = +0.93 V and E _1/2 = +0.92 V, respectively.     

(S)-ABOC: a rigid bicyclic β-amino acid as turn inducer

In order to investigate the ability of the (S)-aminobicyclo[2.2.2]octane-2-carboxylic acid 1 (H-(S)-ABOC-OH) to induce reverse turns into peptides, two model tripeptides, in which this bicyclic unit was incorporated into the second position, were synthesized and analyzed by FT-IR, CD, NMR, and X-ray studies.