Technetium Complexes for the Quantitation of Brain Amyloid

Technetium Complexes for the Quantitation of Brain Amyloi

Technetium Complexes for the Quantitation of Brain Amyloid

Technetium Complexes for the Quantitation of Brain Amyloi

β-Azidoalanine as an IR Probe: Application to Amyloid Aβ(16-22) Aggregation

β-Azidoalanine dipeptide 1 was synthesized, and its azido stretching vibration in H2O and dimethyl sulfoxide (DMSO) was studied by using Fourier transform (FT) IR spectroscopy. The dipole strength of the azido stretch mode is found to be about 19 and 5 times larger than those of the CN and SCN stretch modes, respectively, which have been used as local environmental IR sensors. The azido stretch band in H2O is blue-shifted by about 14 cm−1 in comparison to that in DMSO, indicative of its sensitivity to the electrostatic environment. To test the utility of β-azidoalanine as an IR probe of the local electrostatic environment in proteins, azidopeptide 4 was prepared by its incorporation into Aβ(16-22) peptide of the Alzheimer’s disease amyloid β-protein at position Ala21. The amide I IR spectrum of 4 in D2O suggests that the azidopeptide thus modified forms in-register β-sheets in aggregates as observed for normal Aβ(16-22). The azido peak frequency of 4 in aggregates is almost identical to that in DMSO, indicating that the azido group is not exposed to water but to the hydrophobic environment. We believe that β-azidoalanine will be used as an effective IR probe for providing site-specific information about the local electrostatic environments of proteins

TfNN¹⁵N: A γ-¹⁵N‑Labeled Diazo-Transfer Reagent for the Synthesis of β-¹⁵N‑Labeled Azides

Azides are infrared (IR) probes that are important for structure and dynamics studies of proteins. However, they often display complex IR spectra owing to Fermi resonances and multiple conformers. Isotopic substitution of azides weakens the Fermi resonance, allowing more accurate IR spectral analysis. Site-specifically 15N-labeled aromatic azides, but not aliphatic azides, are synthesized through nitrosation. Both 15N-labeled aromatic and aliphatic azides are synthesized through nucleophilic substitution or diazo-transfer reaction but as an isotopomeric mixture. We present the synthesis of TfNN15N, a γ-15N-labeled diazo-transfer reagent, and its use to prepare β-15N-labeled aliphatic as well as aromatic azides

Osmium Tetroxide Anchored to Porous Resins Bearing Residual Vinyl Groups: A Highly Active and Recyclable Solid for Asymmetric Dihydroxylation of Olefins

OsO4 was simply immobilized onto resins such as Amberlite XAD-4 or XAD-7 bearing residual vinyl groups. The resulting osmylated resins are air-stable, nonvolatile, and much easier to handle than their homogeneous counterpart (OsO4). Moreover, the resin-bound OsO4 exhibited excellent catalytic activity in the asymmetric dihydroxylation of olefins and was easily recovered and reused in five consecutive reactions without any significant decrease in product yield. Turnover time, however, was significantly increased for the fourth and fifth reactions

Site-Specific Hydrogen-Bonding Interaction between <i>N</i>-Acetylproline Amide and Protic Solvent Molecules: Comparisons of IR and VCD Measurements with MD Simulations

The effects of solute−solvent interactions on solution structures of small peptides have been paid a great deal of attention. To study the effect of hydrogen-bonding interactions on peptide solution structures, we measured the amide I IR and VCD spectra of N-acetylproline amide (AP) in various protic solvents, i.e., D2O, MeOD, EtOD, and PrOD, and directly compared them with theoretically simulated ones. The numbers of protic solvent molecules hydrogen-bonded to the two peptide bonds in the AP were quantitatively determined by carrying out the molecular dynamics (MD) simulations and then compared with the spectral analyses of the experimentally measured amide I bands. The two peptides in the AP have different propensities of forming H-bonds with protic solvent molecules, and the H-bond population distribution is found to be strongly site-specific and solvent-dependent. However, it is found that adoption of the polyproline II (PII) conformation by AP in protic solvents does not strongly depend on the hydrogen bond network-forming ability of protic solvents nor on the solvent polarity. We present a brief discussion on the validity as well as limitation of the currently available force field parameters used for the present MD simulation study

Efficient and Inexpensive Synthesis of ¹⁵N‑Labeled 2‑Azido-1,3-dimethylimidazolinium Salts Using Na¹⁵NO₂ Instead of Na¹⁵NNN

15N-Labeled azides are important probes for infrared and magnetic resonance spectroscopy and imaging. They can be synthesized by reaction of primary amines with a 15N-labeled diazo-transfer reagent. We present the synthesis of 15N-labeled 2-azido-1,3-dimethylimidazolinium salts 1 as a 15N-labeled diazo-transfer reagent. Nitrosation of 1,3-dimethylimidazolinium-2-yl hydrazine (2) with Na15NO2 under acidic conditions gave 1 as a 1:1 mixture of α- and γ-15N-labeled azides, α- and γ-1, rather than γ-1 alone. The isotopomeric mixture thus obtained was then subjected to the diazo-transfer reaction with primary amines 3 to afford azides 4 as a 1:1 mixture of β-15N-labeled azides β-4 and unlabeled ones 4′. The efficient and inexpensive synthesis of 1 as a 1:1 mixture of α- and γ-1 using Na15NO2 instead of Na15NNN facilitates their wide use as a 15N-labeled diazo-transfer reagent for preparing 15N-labeled azides as molecular probes

Isonitrile as an Ultrasensitive Infrared Reporter of Hydrogen-Bonding Structure and Dynamics

Infrared (IR) probes based on terminally blocked β-isocyanoalanine (AlaNC) and <i>p</i>-isocyanophenylalanine (PheNC) amino acids were synthesized. These isonitrile (NC)-derivatized compounds were extensively characterized by FTIR and femtosecond IR pump–probe spectroscopies, and a direct comparison was made with popularly used nitrile (CN)- and azide (N₃)-derivatized analogs. It is shown that the isonitrile stretch frequency exhibits extremely high sensitivity to hydrogen-bonding interactions. In addition, the IR intensity of the isonitrile group is much higher than that of the nitrile group and almost as intense as that of the azido group. Furthermore, its vibrational lifetime is much longer than that of the nitrile and azido groups. To elucidate the origin of such a high H-bond sensitivity and IR intensity observed for isonitrile, extensive quantum chemical calculations were performed. It is shown that the Coulombic contributions to the vibrational frequency shifts of the isonitrile and nitrile stretch modes have opposite signs but similar magnitudes, whereas the contributions of exchange repulsion and charge delocalization to their frequency shifts are comparable. Therefore, the isonitrile stretch frequency is much more sensitive to H-bonding interactions because the blue-shifting exchange-repulsion effects are additionally enforced by such electrostatic effects. It is also shown that the much higher IR intensity of the isonitrile group compared to that of the nitrile group is due to the configuration reversal of the atomic electronegativity between the NC and CN groups. Owing to these features, we believe that isonitrile is a much better IR reporter of H-bonding structure and dynamics than the widely used nitrile and azide

Site-selective Intramolecular Hydrogen-Bonding Interactions in Phosphorylated Serine and Threonine Dipeptides

To study the phosphorylation effect on the peptide conformation, we carried out nuclear magnetic resonance (NMR), circular dichroism (CD), Fourier transform (FT)-IR, and vibrational circular dichroism (VCD) experiments with serine and threonine dipeptides (SD and TD) and their phosphorylated ones (pSD and pTD). It is found that both unphosphorylated and phosphorylated serine and threonine dipeptides adopt two conformations, polyproline II (PII) and β-strand. The pH-dependent NMR study shows that the side-chain dianionic phosphoryl group can form direct intramolecular hydrogen bonds with the backbone amide protons at both the acetyl and amide ends of pTD, but only at the acetyl end of pSD. Temperature- and pH-dependent CD studies reveal that, unlike pSD, pTD undergoes conformational transition from PII to β-strand upon double ionization of the phosphoryl group. The subtle but distinct differences between pTD and pSD in site-selective intramolecular hydrogen-bonding interaction and charge-dependent conformational transition may sometimes become significant when choosing between serine and threonine for the conformational control of peptides and proteins by phosphorylation

Switching Regioselectivity in Crossed Acyloin Condensations between Aromatic Aldehydes and Acetaldehyde by Altering <i>N</i>-Heterocyclic Carbene Catalysts

An unprecedented high level of regioselectivities (up to 96%) in the intermolecular crossed acyloin condensations of various aromatic aldehydes with acetaldehyde was realized by an appropriate choice of N-heterocyclic carbene catalysts