Synthesis of enantiopure, axially chiral, C-tetrasubstituted α-amino acids with binaphthyl-based crowned side chains and 3D-structural analysis of their peptides

The syntheses of the terminally protected, crowned, C^α-tetrasubstituted α-amino acids with only axial chirality, the two diastereomers Boc-(S)-Bip[(R)-Binol-22-C-6]-OMe and Boc-(R)-Bip[(R)-Binol-22-C-6]-OMe, and their respective enantiomers Boc-(R)-Bip[(S)-Binol-22-C-6]-OMe and Boc-(S)-Bip[(S)-Binol-22-C-6]-OMe, all derived from 2′,1′:1,2; 1″,2″:3,4-dibenzcyclohepta-1,3-diene-6-amino-6-carboxylic acid (Bip), were performed by bis-alkylation with cyclization of racemic (R+S)-Boc-[HO]₂-Bip-OMe, possessing two phenolic OH groups at the 6,6′-positions of the biphenyl frame of Bip, using (+)-(R)- and (−)-(S)-Binol[(OCH₂CH₂)₂OTs]₂ (2,2′-bis[5-tosyloxy-3-oxa-1-pentyloxy]-1,1′-binaphthyl), respectively, as the alkylating agent followed by chromatographic separation. Two series of terminally protected model peptides to the hexamer level, containing the (R)-Bip[(S)-Binol-22-C-6] residue at i and i+3 positions of the sequence, combined with either l-Ala or l-Ala/Aib, were synthesized by solution methods. Their 3D-structural analyses by FTIR absorption and NMR suggest that these peptides preferentially adopt folded secondary structures.     

Discrimination between an Antiparallel and a Parallel β5.6-Helix Using 1Hα-NMR Spin-Lattice Relaxation

The ¹H-NMR spectrum of Boc-(L -Val-D -Val)₄-OH in CDCl₃ can be attributed either to an antiparallel or to a parallel double-stranded β^5.6-helical structure. To resolve this ambiguity, T₁-measurements have been carried out for the α-protons of Boc-(L -Val-D -Val)₄-OH and its monodeuterated analogue Boc-(L -Val-D -Val)₂ -α-²H-L -Val-D -Val-L -Val-D -Val-L -Val-D -Val-OH. The results show that the H^α of the fifth residue in one strand is close to the H^α of the seventh residue in the other strand, as expected for an antiparallel arrangement, a conclusive demonstration that the correct structure of Boc-(L -Val-D -Val)₄-OH is antiparallel.     

Two dinuclear copper (II) and nickel (II) complexes based on 4‐(diethylamino)salicylaldehyde: X‐ray structures,spectroscopic, electrochemical,antibacterial, Hirshfeld surfaces analyses,and time‐dependent density functional theory calculations

The quinazoline‐type ligand 2‐(4‐diethylamino‐2‐hydroxyphenyl)‐4‐methyl‐1,2‐dihydroquinazoline 3‐oxide ( HL ¹ ; H is the deprotonatable hydrogen) was prepared. Two 2‐D supramolecular complexes [Cu₂( L ² )₂(NO₃)₂] ( 1 ) and [Ni₂( L ² )₂(CH₃COO)₂] ( 2 ) ( L ² = 1‐(2‐{[(E)‐(4‐diethylamino‐2‐hydroxybenzylidene]amino} phenyl)ethanone oxime) were synthesized using HL ¹ and characterized by elemental analysis, spectroscopic methods, and single‐crystal X‐ray diffraction studies. It revealed that 1 had coordinated two nitrate ions whereas 2 had acetate ions. In the crystal structures, six‐coordinated Cu (II) complex 1 formed an infinite 2‐D and X‐shaped 3‐D supramolecular frameworks. Simultaneously, Ni (II) complex 2 assembled into wavy 2‐D networks. Furthermore, electrochemical properties and antimicrobial activities of all compounds were as well investigated. Afterwards, the electrophilic and nucleophilic attack sites identified by electrostatic potential (ESP) calculations confirmed that hydrogen bonds were observed in the optimized structure of the crystal, and the closest contact between the active atoms of both complexes was confirmed through Hirshfeld surface analysis and time‐dependent density functional theory (TD‐DFT) calculations.     

Synthesis of linear and cyclic homo-β-peptides based on a binaphthylic β-amino acid with only axial chirality

The terminally protected, linear, homo-β-peptides Boc-[(R)-β^2,2-HBin]_n-OMe (n = 2–6) as well as the cyclic homo-β-peptides c[(R)-β^2,2-HBin]₃ and c[(S)-β^2,2-HBin]₄, all derived from the 2′,1′:1,2;1″,2″:3,4-dinaphthcyclohepta-1,3-diene-6-aminomethyl-6-carboxylic acid residue β^2,2-HBin possessing only axial chirality, have been synthesized in solution by the EDC/AtOH coupling method for chain elongation, and by cyclization of pentafluorophenyl esters. A conformational analysis suggested the concomitant occurrence of different intramolecularly H-bonded forms for the linear oligomers in solution.     

Comparison of [18F]F-CNBI and [18F]F-CNPIFE as Positron Emission Tomography Probes for Noninvasive Imaging of Glycogen Synthase Kinase-3 in Normal Mice

Glycogen synthase kinase-3 α/β is involved in dysregulation of neuronal tau protein in Alzheimer's disease (AD). There is an unmet clinical need for a blood-brain barrier (BBB) permeable positron emission tomography (PET) probe for imaging of GSK-3α/β in the brain to understand the pathogenesis of AD. Herein, we synthesized two PET probes, [¹⁸F]F-CNBI and [¹⁸F]F-CNPIFE, and evaluated their BBB permeability and affinity towards GSK-3α/β. [¹⁹F]F-CNPIFE showed higher in-vitro binding towards GSK-3α/β (IC₅₀=19.4±2.5 nM; n=3, for GSK-3α, IC₅₀=19.4±3.8 nM; n=3, for GSK-3β) compared to [¹⁹F]F-CNBI (IC₅₀=107.6±26.0 nM; n=4, for GSK-3α, IC₅₀=105.3±18.2 nM; n=3, for GSK-3β). [¹⁸F]F-CNPIFE showed 9.5-fold higher brain uptake than [¹⁸F]F-CNBI, in normal FVB/NJ mice, which was increased by additional 1.5-fold on co-administration of [¹⁹F]F-CNPIFE with respect to [¹⁸F]F-CNBI. Overall, [¹⁸F]F-CNPIFE is a promising PET probe for GSK-3α/β imaging and warrants further evaluation in an AD mouse model.     

Synthesis and Biological Evaluation of RGD Peptidomimetic–Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers

Two small‐molecule–drug conjugates (SMDCs, 6 and 7 ) featuring lysosomally cleavable linkers (namely the Val–Ala and Phe–Lys peptide sequences) were synthesized by conjugation of the α_vβ₃‐integrin ligand cyclo[DKP–RGD]‐CH₂NH₂ ( 2 ) to the anticancer drug paclitaxel (PTX). A third cyclo[DKP–RGD]–PTX conjugate with a nonpeptide “uncleavable” linker ( 8 ) was also synthesized to be tested as a negative control. These three SMDCs were able to inhibit biotinylated vitronectin binding to the purified α_Vβ₃‐integrin receptor at nanomolar concentrations and showed good stability at pH 7.4 and pH 5.5. Cleavage of the two peptide linkers was observed in the presence of lysosomal enzymes, whereas conjugate 8 , which possesses a nonpeptide “uncleavable” linker, remained intact under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing the integrin receptor at different levels: the acute lymphoblastic leukemia cell line CCRF‐CEM (α_Vβ₃?) and its subclone CCRF‐CEM α_Vβ₃ (α_Vβ₃+). Fairly effective integrin targeting was displayed by the cyclo[DKP–RGD]–Val–Ala–PTX conjugate ( 6 ), which was found to differentially inhibit proliferation in antigen‐positive CCRF‐CEM α_Vβ₃ versus antigen‐negative isogenic CCRF‐CEM cells. The total lack of activity displayed by the “uncleavable” cyclo[DKP–RGD]–PTX conjugate ( 8 ) clearly demonstrates the importance of the peptide linker for achieving the selective release of the cytotoxic payload.     

Darstellung,Kristallstruktur, Schwingungsspektren und Normalkoordinatenanalyse von (Ph4P)2[OsN(N3)5] und 15N‐NMR‐Verschiebungen von Nitridoosmaten(VI,VIII)

Synthesis, Crystal Structure, Vibrational Spectra, and Normal Coordinate Analysis of (Ph₄P)₂[OsN(N₃)₅] and ¹⁵N NMR Chemical Shifts of Nitridoosmates(VI, VIII) The treatment of (Ph₄P)[OsNCl₄] with NaN₃ yields (Ph₄P)₂[OsN(N₃)₅], which crystal structure has been determined by single crystal X‐ray diffraction analysis (monoclinic, space group P 2₁/a, a = 20.484(6), b = 11.168(1), c = 20.666(4) Å, β = 97.35(3)°, Z = 4). The IR and Raman vibrations were assigned by a normal coordinate analysis based on the molecular parameters of the X‐ray determination. The valence force constants are f_d(Os≡N) = 8.52, f_d(Os–N^α) = 1.99, f_d(N^α–N^β) = 12.42, f_d(N^β–N^γ) = 12.73 and for the azido ligand in trans‐position to the nitrido group f_d(Os–N^{α ·} ) = 1.84, f_d(N^{α ·} –N^{β ·} ) = 11.91, f_d(N^{β ·} –N^{γ ·} ) = 12.18 mdyn/Å. The ¹⁵N NMR spectra of various nitridoosmates reveal the chemical shifts δ(¹⁵N) for K[OsO₃¹⁵N] = 387.6, K₂[Os¹⁵NCl₅] = 446.7, (Ph₄P)[Os¹⁵NCl₄] = 352.9, [(n‐C₆H₁₃)₄N]₂[Os¹⁵N(N₃)₅] = 307.3 and for [(n‐Pr)₄N]₂[Os¹⁵N(¹⁵NCO)₅] = 483,7 (Os≡N), –417,7 (OsNCO_eq) und –392,8 ppm (OsNCO_ax).     

1,2-Carbon shifts in [C4H8O]+˙ and [C5H10O]+˙ ions

Present results demonstrate that α,β-shifts of the functional group carbon strongly dominate β,α-methyl shifts in [C₄H₈O]⁺˙ and [C₅H₁₀O]⁺˙ ions, paralleling observations of others on methyl isobutyrate ions.     

Synthesis, crystal structure and characterization of a 2-D network organic-inorganic hybrid polymer with [α-BW12O40]5− as building blocks

A two-dimensional network compound [Ce(DMF)₄(H₂O)][α-BW₁₂O₄₀]·H₂O·(HDMA)₂ (HDMA = protoned dimethylamine, DMF = N,N-dimethylformamide) was synthesized from α-H₅BW₁₂O₄₀·nH₂O, Ce(NO₃)₃·6H₂O and DMF and characterized by IR, UV spectra and TG-DTA. The result of the X-ray single crystal diffraction indicates that the crystal is monoclinic, space group P2₁/n, with unit cell dimensional: a = 1.1983(3), b = 2.4216(5), c = 1.9517(4) nm, β = 92.91(3)°, Z = 4, R ₁ = 0.07710, wR ₂ = 0.1416. Structural analysis indicates that every [Ce(DMF)₄(H₂O)]³⁺ building block is surrounded by three adjacent [α-BW₁₂O₄₀]^5? polyanions, meanwhile, every [α-BW₁₂O₄₀]^5? polyanion interconnects with three neighboring [Ce(DMF)₄(H₂O)]³⁺ subunits, by making use of which two-dimensional network structure can be constructed. The result of thermogravimetric analysis manifests that the title compound has two-stage weight loss and the decomposition temperature of the title polyanionic framework is 560°C. The electrochemical analysis shows the title polyanion has three-step redox processes in the pH = 4–7 media.     

Supramolecular systems composed of α-helical peptides

Hydrophobic helical peptides having alternating hydrophobic amino acid and Aib in the sequence were synthesized to construct supramolecular systems. Three types of supramolecular systems were constructed by the peptides and the derivatives in different environments. First, the dispersion of TFA · H-(Ala-Aib)₈-OBzl in water was studied by dynamic light scattering, which suggests the formation of a vesicular structure with an average diameter of 76 nm. We call the peptide assembly in water “peptosome”. Second, Boc-Ser(Ant)-(Ala-Aib)₈-OMe spanned the phospholipid bilayer membrane and formed a helix-bundle structure. The bundle structure was supported by ion-channel formation in the membrane. Third, Boc-(Ala-Aib)₈-OMe and Boc-(Leu-Aib)₈-OBzl formed a two-dimensional crystal at the air-water interface. Boc-(Ala-Aib)₁₂-OBzl also formed a monolayer in a solid state at the air-water interface, but the helix orientation was perpendicular to the interface, which presents a contrast to the parallel orientation of the former hexadecapeptides.     

Preparation and characterization of molybdenum and tungsten compounds with diazabutadiene ligands constructed from amino esters and glyoxal: Crystal structures of meso and C2-symmetric isomers of Mo(CO)4(dab-asp(OMe)-OMe)

The title compounds were prepared by heating solutions of ester protected amino acids (H-l-Ala-OEt, H-β-Ala-OEt, H-l-Val-OMe, GABA-OMe, H-l-Asp(OMe)-OMe) and glyoxal in the presence of M(CO)₄(pip)₂ (M=Mo, W). The resulting novel complexes, M(CO)₄(dab-xxx-OR) (dab=diazabutadiene), contain an N,N′-diimine ligand and were characterized by ¹H- and ¹³C-NMR, IR, and UV-vis measurements. The low energy band in the visible portion of the electronic spectrum is assigned to a MLCT transition and exhibits solvatochromism. The valine, alanine and aspartic ester derivatives have C₂ symmetry resulting from the C₂ symmetry of the ligand. The reaction of the alanine and aspartic amino esters in the presence of NEt₃ produces diastereomeric mixtures caused by racemization at the amino acid α-carbon. Racemization is not observed during the formation of the valine derivatives. The crystal structures of (R,S)-Mo(CO)₄(dab-asp(OMe)-OMe) (5-RS), and (S,S)-Mo(CO)₄(dab-asp(OMe)-OMe) (5-SS), were determined. The structure of 5-RS confirms that racemization at the α-carbon occurred. 5-SS has C₂ symmetry.     

13C-NMR und konformation eines membran-modifizierenden synthetischen nonadekapeptid-analogons von alamethicin und seiner zwischenstufen

The ¹³C-NMR spectra of the synthetic membrane modifying nonadecapeptide Boc-(Aib-l-Ala)₅-Gly-Ala-Aib-Pro-Ala- Aib-Aib-Glu(OBz)-Gln-OMe (Aib = α-aminoisobutyric acid), and of synthetic intermediates were used for conformational analysis in solution. The assignments of the ¹³C-NMR signals of Aib are based on the magnetic nonequivalence (MNE) of the geminal C_β-signals in asymmetric environment resulting in a shift difference of 0.2–0.5 ppm due to neighbouring chiral residues. More than 4 ppm MNE are observed due to α-helical conformation and about 2.5 ppm for Aib situated in the corners of a rigid β-turn. The Ala-C_α signal is also sensitive to different secondary structures. The C_α signal for C-terminal alanine is found at 49–50 ppm, and for alanine within unordered oligopeptides it absorbs at 50–51 ppm. α-Helical environment shifts the Ala-C_α signal to lower field down to 54 ppm. In methanolic solution the nonadecapeptide shows a α-helical N-terminal region. For the C-terminus beginning with proline-14 no periodically ordered conformation is observed, and we suggest a sequence of β-turns. Furthermore the typical E/Z isomerism of the prolyl-peptide bond can be observed on proline itself and on its neighbour alanine.     

6-Nitro-[1,10]phenanthroline-1-ium nitrate: crystal structure, ab initio calculations and protonation character

The title compound, 6-nitro-[1,10]phenanthroline-1-ium nitrate, has been synthesized and characterized by elemental analysis, electron absorption spectroscopy, IR, ¹H and ¹³C NMR spectroscopy. The X-ray crystal structure study showed that the compound crystallizes in the monoclinic system, space group Cc, with M_r=288.22 (C₁₂H₈N₄O₅), a=13.861(3), b=10.142(2), c=8.7320(17) Å, β=103.70(3)°, V=1192.6(4) Å³, Z=4, D_c=1.605 g/cm³, F(000)=592, μ(Mo Kα)=0.129 mm⁻¹, R=0.0439, wR=0.1125, GOF=1.110. In the crystal lattice, the molecules create a network structure through hydrogen bonds. Ab initio calculations of the structures, charges distribution, natural bond orbitals, topological analysis and thermodynamic functions of 5-nitro-[1,10]phenanthroline and its protonated cation were performed at HF/6-311G** and B3LYP/6-311G** levels of theory. The calculation results are in a good agreement with the X-ray data and show that the protonated structure is stable. The calculation of second order optical nonlinearity was carried out and a higher molecular hyperpolarizability of 24.66×10⁻³⁰ esu was predicted.     

Mass spectra of aliphatic dicarboxylic acids and their dimethyl esters: Cyclic structures for the [M − H2O]+˙ ions from the diacids and [M − MeOH]+˙ ions from the dimethyl esters

Methyl 2-oxocycIoalkane carboxylate structures are proposed lor the [M ? MeOH]^+˙ ions from dimethyl adipate, pimelate, suberate and azelate. This proposal is based on a comparison of the metastable ion mass spectra and the kinetic energy releases for the major fragmentation reaction of these species with the same data for the molecular ions of authentic cyclic β-keto esters. The mass spectra of α,α,α′,α′-d₄-pimelic acid and its dimethyl ester indicate that the α-hydrogens are involved only to a minor extent in the formation of [M ? ROH]^+˙ and [M ? 2ROH]^+˙ ions, while these α-hydrogens are involved almost exclusively in the loss of ROH from the [M ? RO˙]⁺ ions (R = H or CH₃). The molecules XCO(CH₂)₇COOMe (X = OH, Cl) form abundant ions in their mass spectra with the same structure as the [M ? 2MeOH]^+˙ ions from dimethyl azelate.     

A synthetic tripeptide as a novel organo-gelator: a structural investigation

A self-associating synthetic tripeptide [Boc-Ala(1)-Aib(2)-β-Ala(3)-OMe (Aib: α-amino-isobutyric acid, β-Ala: β-alanine)] forms thermoreversible transparent gels in various organic solvents and this offers the first example of a peptide gelator whose molecular self-assembly afforded for gelation has been characterised by single-crystal X-ray diffraction and FT-IR and NMR spectroscopic studies. The crystal structure of an analogous synthetic non-gelator tripeptide [Boc-Ala(1)-Gly(2)-β-Ala(3)-OMe] is also discussed in light of the self-assembly of the gelator tripeptide.     

‘Bis-ornithine’ (2,2-bis(aminopropyl)glycine): a new tetravalent template for assembling different functional peptides

Synthesis of bis-ornithine, a new C^α,α-disubstituted α-amino acid bearing orthogonally protected α and δ amine groups is reported. Bis-ornithine (bisOrn) and dipeptides containing bis-ornithine have been synthesized in solution up to multigram scale. As a first example, one of these compounds Boc-βAla-bisOrn(Alloc)₂-OH has been attached to a solid support and used as template for the synthesis of a symmetrical assemblage of peptides.     

Glycosides of marine invertebrates. Structure of holothurin A2 from the holothurianHolothuria edulis

The structure of a new glycoside fromHolothuria edulis, holothurin A₂, has been established with the aid of periodate oxidation, methylation, Smith degradation, and¹³C NMR spectroscopy. The structure of the glycoside has been determined as holost-9(11)-ene-3β,12α,17α-triol 3-0-{2-0-[3-0-methyl-β-D-glucopyranosyl-(1→3)-0-β-D-glucopyranosyl-(1→4)-0-β-D-quinovopyranosyl]-4-0-sulfate-β-D-xylopyranoside}.     

Construction of α-phosphonolactams via rhodium (II)-catalyzed intramolecular C?H insertion reactions

The Rh(II)-catalyzed intramolecular C H insertion reactions of N,N-dialkyl-α-diazo-α-(diethylphosphono)acetamides 2a , f–j in CHCl₃ or ClCH₂CH₂Cl were found to give monocyclic and bicyclic α-phosphono-β-lactams, 3a and 3f–j , in 43–67% yields via regiospecific α-C H insertion of the N-alkyl groups. Similar treatment of N-benzyl-N-isopropyl-α-diazo-α-(diethylphosphono)acetamide ( 2b ) and the corresponding N-isobutyl-N-methylacetamide 2d in ClCH₂CH₂Cl afforded mixtures of β-lactams 3b (35%) and and 3b ′ (16%), β-lactam 3d (47%), and γ-lactam 4d (10%), respectively, each of which is formed by the competitive C H insertion reaction between benzylic and isopropyl α-C H bonds and between methyl α-C H and methine β-C H bonds, respectively. For the formation of β-lactams, the selectivity in the rhodium-mediated C H insertion in ClCH₂CH₂Cl follows the order methyl > methine > benzylic α-C H bond on N-substituents. The N,N-dibutyl-α-diazo homologue 2c and Nα[α-diazo-α-(diethylphosphono)acetyl]-2-methylindoline ( 2k ) exclusively produced γ-lactams 4c (67%) and 4k (81%) via insertion into the methylene β-C H and methyl β-C H bonds. tert-Butyl N-[α-diazo-α-(dibenzylphosphono)acetyl]-piperidine-2-carboxylate ( 2m ) on similar treatment, followed by deprotection of the benzyl ester afforded the 7-phosphono carbacepham 6 in 32% overall yield. Similar Rh(II)-catalyzed cyclization of N-methyl-N[4-benzyloxy-α-(diethylphosphono)-phenyl(diethyl-phosphono)methyl]-α-diazo-acetamide ( 2n ) led to 1-[4′-benzylphenyl(diethylphosphono)methyl] -3-(diethyl-phosphono)azetidin-2-one ( 3n ) in 78% yicld. The phosphono group at C-7 of 3f was converted into the acetylamino group via a four-step reaction. Application of chiral rhodium(II) carboxylates 12a–c to the insertion reactions of 2b , c produced α-phosphono-β-and γ-lactams, 3b and 4c , in 6–24% ee and 25–29% ee, respectively.     

Cadmium(II) complexes with monoiodo- and dibromodipyrromethenes: synthesis,molecular structure,spectral-luminescent properties,and stability in solutions

Cadmium(II) chelates with 4-iodo-, 5,5´-, and 4,4´-dibromo-2,2´-dipyrromethenes (HL¹, HL², and HL³, respectively) with the composition of [CdL₂] were synthesized. The influence of structural features of their molecules and properties of the medium on the characteristics of absorption and fluorescence spectra, and also on the thermodynamic stability constants in solutions was evaluated. The results of quantum chemical calculations revealed that the additional coordination interactions between the bromine atoms at the α-positions of dipyrromethene ligands and the complexing atom are possible in the molecular structure of α,α´- dibromosubstituted dipyrromethenate [Cd(L²)₂] in contrast with β-halogenated analogues [Cd(L¹)₂] and [Cd(L³)₂].     

Ionic Liquid-Induced Structural and Activity Changes in Hen Egg White Lysozyme

Lysozyme crystals in the presence of 1-butyl-3-methylimidazolium tetrafluoroborate ([C₄mim]BF₄), 1-butyl-3-methylimidazolium chloride ([C₄mim]Cl), 1-butyl-3-methylimidazolium bromide([C₄mim]Br), and 1,3-dimethylimidazolium iodine([dmim]I) were prepared, and the influence of ionic liquids (ILs) on the structure and activity change of lysozyme was investigated. Fourier transform infrared spectroscopy revealed the major secondary structures of α-helix and β-sheet for lysozyme. It was interesting to note that increases of the band near 2,935 and 1,656 cm^?1 from Raman spectroscopy are attributed to the unfolding of lysozyme molecules. A shift in amide III from 1,230 to 1,270 cm^?1 in adding [dmim]I occurs, indicating a transformation from β-sheet to random coil. With regard to adding [C₄mim]BF₄, [C₄mim]Cl, and [C₄mim]Br, α-helix and β-sheet are the predominant structures for lysozyme. The activity study showed that the ILs used brought a positive effect. Especially, [dmim]I leads to a drastic increase in relative activity, and its value reaches 50 %.