Charge‐Induced Secondary Structure Transformation of Amyloid‐Derived Dipeptide Assemblies from β‐Sheet to α‐Helix

Secondary structures such as α‐helix and β‐sheet are the major structural motifs within the three‐dimensional geometry of proteins. Therefore, structure transitions from β‐sheet to α‐helix not only can serve as an effective strategy for the therapy of neurological diseases through the inhibition of β‐sheet aggregation but also extend the application of α‐helix fibrils in biomedicine. Herein, we present a charge‐induced secondary structure transition of amyloid‐derived dipeptide assemblies from β‐sheet to α‐helix. We unravel that the electrostatic (charge) repulsion between the C‐terminal charges of the dipeptide molecules are responsible for the conversion of the secondary structure. This finding provides a new perspective to understanding the secondary structure formation and transformation in the supramolecular organization and life activity.     

Synthesis of a Structure‐Definite α‐Cyclodextrin‐Based Macromolecular [3]Rotaxane Using a Size‐Complementary Method

The challenging synthesis of an α‐cyclodextrin (CD)‐based macromolecular rotaxane with definite structure was fulfilled using a size‐complementary method. A new peracetylated (PAc) α‐CD‐based size‐complementary [3]rotaxane was prepared and its thermal dissociation kinetics studied. The de‐slippage mechanism was found to be different from that of the native α‐CD‐based system. PAcα‐CD‐based size‐complementary [3]rotaxanes were employed as initiators for a ring‐opening polymerization of ?‐caprolactone to obtain the macromolecular [3]rotaxanes. Detailed investigation of component dissociation showed the highly movable character of the wheel on the polymer main chain. A general method for controlling the movement of wheels in rotaxane frameworks, even in polymer systems, was established. This will enable the development of new supramolecular architectures and molecular machines.     

Self‐Assembled Cyclic d,l‐α‐Peptides as Generic Conformational Inhibitors of the α‐Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies

Many peptides and proteins with large sequences and structural differences self‐assemble into disease‐causing amyloids that share very similar biochemical and biophysical characteristics, which may contribute to their cross‐interaction. Here, we demonstrate how the self‐assembled, cyclic d,l ‐α‐peptide CP‐2 , which has similar structural and functional properties to those of amyloids, acts as a generic inhibitor of the Parkinson′s disease associated α‐synuclein (α‐syn) aggregation to toxic oligomers by an ?off‐pathway“ mechanism. We show that CP‐2 interacts with the N‐terminal and the non‐amyloid‐β component region of α‐syn, which are responsible for α‐syn′s membrane intercalation and self‐assembly, thus changing the overall conformation of α‐syn. CP‐2 also remodels α‐syn fibrils to nontoxic amorphous species and permeates cells through endosomes/lysosomes to reduce the accumulation and toxicity of intracellular α‐syn in neuronal cells overexpressing α‐syn. Our studies suggest that targeting the common structural conformation of amyloids may be a promising approach for developing new therapeutics for amyloidogenic diseases.     

Direct Catalytic Asymmetric Mannich‐type Reaction of α,β‐Unsaturated γ‐Butyrolactam with Ketimines

We report a direct catalytic asymmetric Mannich‐type addition of α,β‐unsaturated γ‐butyrolactam to α‐ethoxycarbonyl ketimines promoted by a soft Lewis acid/Brønsted base cooperative catalyst. A thiophosphinoyl group on the nitrogen of ketimines was crucial for both electrophilic activation and α‐addition of γ‐butyrolactams. The obtained aza‐Morita–Baylis–Hillman‐type products bear an α‐amino acid architecture with a tetra‐substituted stereogenic center.     

Two‐Step Synthesis of Multifunctional γ‐Lactams from γ‐Lactone

We present herein an efficient and rapid method for the synthesis of N,1‐dialkyl‐4‐(2‐hydroxyethyl)‐5‐oxopyrrolidine‐3‐carboxamides based on the conversion of γ‐lactone to γ‐lactam via the conjugate addition of primary amines to an ethyl α‐functionalized acrylate followed by intramolecular cyclization.     

A Synthetic Study of Chiral α‐Hydroxy‐H‐Phosphinates Based on Proline Catalysis

A highly enantioselective synthesis of α‐hydroxyphosphinates was achieved based on the L ‐proline‐catalyzed aldol reaction of α‐acylphosphinates and acetone. Due to the preexisting chirality at the phosphorus center, mixtures of two diastereomers of the α‐hydroxyphosphinates were obtained in moderate to good yields, with simultaneously high enantioselectivity for both diastereomers. The products could be converted into α‐hydroxy‐H‐phosphinates with satisfactory yields. Furthermore, an unprecedented oxidation–reduction reaction of the α‐hydroxyphosphinates or α‐hydroxy‐H‐phosphinates to form phosphonates was observed, and the mechanism involved in such a chemical transformation is discussed.     

2‐Phenylquinoline–Sugar Hybrids as Photoswitchable α‐Glucosidase Inhibitors

Purpose‐designed 2‐phenylquinoline (PQ)‐sugar hybrids 1 and 2 were synthesized and evaluated for their photodegradation activities against an α‐glucosidase target. The results indicated that PQ‐mannose hybrid 2 selectively and effectively photodegraded α‐glucosidase and significantly inhibited its enzymatic activity upon irradiation with long‐wavelength UV light in the absence of any additives under neutral and aqueous conditions. Furthermore, 2 selectively and effectively inhibited α‐glucosidase activity only with photo‐irradiation even in complex cell lysate.     

Ligand‐Controlled α‐ and β‐Arylation of Acyclic N‐Boc Amines

The palladium‐catalyzed ligand‐controlled arylation of α‐zincated acyclic amines, obtained by directed α‐lithiation and transmetalation, is described. Whereas PtBu₃ gave rise to α‐arylated Boc‐protected amines, more flexible N‐phenylazole‐based phosphine ligands induced major β‐arylation through migrative cross‐coupling.     

Cold Denaturation of α‐Synuclein Amyloid Fibrils

Although amyloid fibrils are associated with numerous pathologies, their conformational stability remains largely unclear. Herein, we probe the thermal stability of various amyloid fibrils. α‐Synuclein fibrils cold‐denatured to monomers at 0–20 °C and heat‐denatured at 60–110 °C. Meanwhile, the fibrils of β2‐microglobulin, Alzheimer’s Aβ1‐40/Aβ1‐42 peptides, and insulin exhibited only heat denaturation, although they showed a decrease in stability at low temperature. A comparison of structural parameters with positive enthalpy and heat capacity changes which showed opposite signs to protein folding suggested that the burial of charged residues in fibril cores contributed to the cold denaturation of α‐synuclein fibrils. We propose that although cold‐denaturation is common to both native proteins and misfolded fibrillar states, the main‐chain dominated amyloid structures may explain amyloid‐specific cold denaturation arising from the unfavorable burial of charged side‐chains in fibril cores.     

Synthesis of new 2,2′‐disubstituted 5,5′‐dimethyl‐4,4′‐bitriazoles and 2‐(4‐Triazolyl)quinoxalines

Thermal rearrangement of 3‐acylisoxazole arylhydrazones allowed facile preparation of 2H‐1,2,3‐triazoles which were firstly reacted with isoamyl nitrite and then with an opportune arylhydrazine to produce the corresponding α‐hydroxyiminohydrazones 8a‐h . The reaction of compounds 8a‐h with phosphorus pentachloride afforded the desired 4,4′‐bitriazoles 1a‐h . The α‐hydroxyiminoketone derivative 7 or the α‐diketone 14 reacted easily with 1,2‐phenylenediamine to afford 1,2,3‐triazoles 2a‐c bearing the quinoxaline moiety at position 4. Improved yields of the quinoxalines 2a‐c were obtained when 1,2‐phenylenediamine was reacted with the dioxime 15.     

α‐d‐Glucofuranose and α‐d‐allofuranose diacetonides and silyl ether of α‐d‐glucofuranose diacetonide in dithiophosphorylation reactions

α‐d ‐Glucofuranose and α‐d ‐allofuranose diacetonides react with 2,4‐diorganyl 1,3,2,4‐dithiadiphosphetane‐2,4‐disulfides to form optically active dithiophosphonates in 78–81% yields, which are transformed into the corresponding ammonium salts in 90–97% yields by the treatment of n‐hexadecylamine. The S‐silyldithiophosphonate was prepared in 93% yield by the reaction of 2,4‐bis(butoxyphenyl) 1,3,2,4‐dithiadiphosphetane‐2,4‐disulfide with silyl ether of α‐d ‐glucofuranose diacetonide. One of the salts obtained possesses antibacterial activity against Staphylococcus aureus ATCC 6538‐P.     

A Modular Synthesis of Teraryl‐Based α‐Helix Mimetics,Part 2: Synthesis of 5‐Pyridine Boronic Acid Pinacol Ester Building Blocks with Amino Acid Side Chains in 3‐Position

One of the most common protein–protein interactions (PPI) is the interaction of the α‐helix of one protein with the surface of the second one. Terphenylic scaffolds are bioinspired motifs in the inhibition of PPIs and have been identified as suitable α‐helix mimetics. One of the challenging aspects of this strategy is the poor solubility of terphenyls under physiological conditions. In the literature pyrrolopyrimidine‐, pyrimidine‐ or pyridazine‐based mimetics have been reported to show improved solubility. We present a new convergent strategy for the synthesis of linear pyridine‐type teraryls based on a phenylic core unit. A general approach for the synthesis of 3,5‐disubstituted pyridine‐based boronic acid pinacol esters with amino acid side chains in the 3‐position (representing Phe, Leu, Ile, Lys, Asp, Asn) is presented and exploits the functional group tolerance of the Knochel–Grignard reagents. The building blocks have been used in a convergent in situ two‐step synthesis of teraryl α‐helix mimetics.     

A convenient synthesis of N‐t‐butyl‐N′‐aminocarbonyl‐N‐(substituted)benzoyl‐hydrazine containing α‐aminoalkylphosphonate groups in a one‐pot procedure

A variety of novel N‐t‐butyl‐N′‐aminocarbonyl‐N‐(substituted)benzoylhydrazines containing α‐aminoalkylphosphonate groups were synthesized. Treatment of α‐aminoalkylphosphonates with triphosgene yielded α‐isocyanatoalkylphosphonates, and subsequent addition with N‐t‐butyl‐N‐substituted benzoylhydrazines provided the title compounds in a one‐pot procedure with good yields. The triphosgene‐mediated reaction for the synthesis of α‐isocyanatoalkylphosphonates enjoys a number of advantages: the reaction is carried out under mild condition in good yield, triphosgene is relatively safe to handle because of its low vapor pressure and high stability, and the experimental procedure is simple. This method can be applicable to the synthesis of other α‐isocyanatoalkyl‐phosphonates and urylenediphosphonates. The structures of all of the products and by‐products were confirmed by ¹H NMR, ³¹P NMR, IR and mass spectroscopy, and elemental analysis. We also found that some of the compounds possess potential antitobacco mosaic virus (TMV) activities and anticancer activities. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:68–72, 2001     

Structural and Kinetic Dissection of the endo‐α‐1,2‐Mannanase Activity of Bacterial GH99 Glycoside Hydrolases from Bacteroides spp.

Glycoside hydrolase family 99 (GH99) was created to categorize sequence‐related glycosidases possessing endo‐α‐mannosidase activity: the cleavage of mannosidic linkages within eukaryotic N‐glycan precursors (Glc_1–3Man₉GlcNAc₂), releasing mono‐, di‐ and triglucosylated‐mannose (Glc_1–3‐1,3‐Man). GH99 family members have recently been implicated in the ability of Bacteroides spp., present within the gut microbiota, to metabolize fungal cell wall α‐mannans, releasing α‐1,3‐mannobiose by hydrolysing αMan‐1,3‐αMan→1,2‐αMan‐1,2‐αMan sequences within branches off the main α‐1,6‐mannan backbone. We report the development of a series of substrates and inhibitors, which we use to kinetically and structurally characterise this novel endo‐α‐1,2‐mannanase activity of bacterial GH99 enzymes from Bacteroides thetaiotaomicron and xylanisolvens. These data reveal an approximate 5 kJ mol^?1 preference for mannose‐configured substrates in the ?2 subsite (relative to glucose), which inspired the development of a new inhibitor, α‐mannopyranosyl‐1,3‐isofagomine (ManIFG), the most potent (bacterial) GH99 inhibitor reported to date. X‐ray structures of ManIFG or a substrate in complex with wild‐type or inactive mutants, respectively, of B. xylanisolvens GH99 reveal the structural basis for binding to D ‐mannose‐ rather than D ‐glucose‐configured substrates.     

The Reaction Studies of α‐Chloroformylarylhydrazines with Thiols,Thioureas and α‐Cyclodiketones

The reactions of α‐chloroformylarylhydrazines 1 with various types of mercaptan, thiourea and α‐cyclodiketone have been studied intensively. 1‐Arylhydrazinecarbothioates 2 were obtained via thioesterization when α‐chloroformylarylhydrazines reacted with thiols. On the other hand, compounds 3 were obtained when α‐chloroformylarylhydrazines reacted with thio‐containing heterocyclic compounds, which suggested a totally different mechanism in these types of reactions. Further studies on the reaction of α‐chloroformylarylhydrazines 1 with thiourea compounds confirmed a novel cyclization and de‐cyclization mechanism, which led to give 2‐arylhydrazinecarboximidamides 5 and 1,3,4‐thiadiazolin‐5‐ones 6 . In addition, various 1,3,4‐oxadiazines 9 were obtained by reacting α‐chloroformylarylhydrazines with α‐cyclodiketones, showing ring cyclization was involved in this type of reaction.     

Transition‐Metal‐Free Formal Sonogashira Coupling and α‐Carbonyl Arylation Reactions

Transition‐metal‐free formal Sonogashira coupling and α‐carbonyl arylation reactions have been developed. These transformations are based on the nucleophilic aromatic substitution (S_NAr) of β‐carbonyl sulfones to electron‐deficient aryl fluorides, producing a key intermediate that, depending on the reaction conditions, gives the aromatic alkynes or α‐aryl carbonyl compounds. The development of these reactions is presented and, based on investigations under basic and acidic conditions, mechanisms have been proposed. To develop the formal Sonogashira coupling further, a milder, two‐step protocol is also disclosed that expands the reaction concept. The scope of these reactions is demonstrated for the synthesis of Sonogashira and α‐carbonyl arylated products from a range of electron‐deficient aryl fluorides with a variety of functional groups and aryl‐, heteroaryl‐, alkyl‐, and alkoxy‐substituted sulfone nucleophiles. These transition‐metal‐free reactions complement the metal‐catalyzed versions in terms of substitution patterns, simplicity, and reaction conditions.     

Transition‐Metal‐Free Formal Decarboxylative Coupling of α‐Oxocarboxylates with α‐Bromoketones under Neutral Conditions: A Simple Access to 1,3‐Diketones

A transition‐metal‐free formal decarboxylative coupling reaction between α‐oxocarboxylates and α‐bromoketones to synthesize 1,3‐diketone derivatives is presented. In this reaction, a broad scope of substrates can be employed, and neither a metal‐based reagent nor an additional base is required. DFT calculations reveal that this reaction proceeds through a coupling followed by decarboxylation mechanism and the α‐bromoketone unprecedentedly serves as a nucleophile under neutral conditions. The rate‐determining step is an unusual hydrogen‐bond‐assisted enolate formation by thermolysis.     

Energy/Hole Transfer Phenomena in Hybrid α‐Sexithiophene (α‐STH) Nanoparticle–CdTe Quantum‐Dot Nanocomposites

Considerable attention has been paid to hybrid organic–inorganic nanocomposites for designing new optical materials. Herein, we demonstrate the energy and hole transfer of hybrid hole‐transporting α‐sexithiophene (α‐STH) nanoparticle–CdTe quantum dot (QD) nanocomposites using steady‐state and time‐resolved spectroscopy. Absorption and photoluminescence studies confirm the loss of planarity of the α‐sexithiophene molecule due to the formation of polymer nanoparticles. Upon photoexcitation at 370 nm, a nonradiative energy transfer (73 %) occurs from the hole‐transporting α‐STH nanoparticles to the CdTe nanoparticles with a rate of energy transfer of 6.13×10⁹ s^?1. However, photoluminescence quenching of the CdTe QDs in the presence of the hole‐transporting α‐STH nanoparticles is observed at 490 nm excitation, which is due to both static‐quenching and hole‐transfer‐based dynamic‐quenching phenomena. The calculated hole‐transporting rate is 7.13×10⁷ s^?1 in the presence of 42×10^?8 M α‐STH nanoparticles. Our findings suggest that the interest in α‐sexithiophene (α‐STH) nanoparticle–CdTe QD hybrid nanocomposites might grow in the coming years because of various potential applications, such as solar cells, optoelectronic devices, and so on.     

Metal‐Free Photochemical Aromatic Perfluoroalkylation of α‐Cyano Arylacetates

We report here an operationally simple protocol for the direct aromatic perfluoroalkylation and trifluoromethylation of α‐cyano arylacetates. This metal‐free approach, which occurs at ambient temperature and under visible‐light irradiation, is driven by the photochemical activity of electron donor–acceptor (EDA) complexes, formed in situ by the interaction of transiently generated enolates and perfluoroalkyl iodides. Preliminary mechanistic studies are reported.     

Decarbonylative Radical Coupling of α‐Aminoacyl Tellurides: Single‐Step Preparation of γ‐Amino and α,β‐Diamino Acids and Rapid Synthesis of Gabapentin and Manzacidin A

A new radical‐based coupling method has been developed for the single‐step generation of various γ‐amino acids and α,β‐diamino acids from α‐aminoacyl tellurides. Upon activation by Et₃B and O₂ at ambient temperature, α‐aminoacyl tellurides were readily converted into α‐amino carbon radicals through facile decarbonylation, which then reacted intermolecularly with acrylates or glyoxylic oxime ethers. This mild and powerful method was effectively incorporated into expeditious synthetic routes to the pharmaceutical agent gabapentin and the natural product (?)‐manzacidin A.