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Developing green and convenient strategies for constructing C−S bonds is attractive, as it is indispensable for numerous essential biological and pharmaceutical compound syntheses. Herein, an efficient, cost‐effective method for synthesizing 2,4‐dinitroaryl thioether derivatives is achieved by ipso nucleophilic substitution of an aromatic sulfonic acid group by thiol to construct a new C−S bond. This methodology neither requires the assistance of any transition metal catalyst nor harsh reaction conditions. Such thioether formation from aryl sulfonic acids is new. [ABSTRACT FROM AUTHOR]

Although amyloids are a well-known pathological structure, functional amyloids are beneficial. Functional amyloids can be engineered to cultivate desired functionality that can destroy malicious amyloids. However, not much is known about such amyloid destructors. On the other hand, nearly all approaches to developing a drug against pathogenic amyloidoses have failed. Therefore, novel approaches are needed. Herein, a rationally designed catalytic triad based "proteolytic functional amyloid (PFA)" formed by linking a target protein recognizing unit with a Gly-integrated non-native Glu-His-Cys segment is reported. The proteolytic mechanism of the designed PFA is boosted by thiol/disulfide exchange cleavage. Rigorous MALDI-TOF and FRET-based analyses indicated that the PFAs cleaved Aβ12-21 (model Aβ) and the pathogenic Aβ1-40 site selectively in vitro. PFA significantly inhibited the aggregation of Aβ1-40 and broke-down the preformed fibrillar amyloids into non-toxic metabolites. Such a platform may be helpful in not only the on-demand chemical degradation of pathogenic amyloids but also the targeted degradation of other malicious proteins. PFAs are the first "amyloid-destroying" amyloids. [ABSTRACT FROM AUTHOR]

Beauty in the self-assembly patterns of isomeric dipeptides of Boc-Ant- L -Phg-OMe (1) bearing two rigid, unnatural amino acids (Ant: anthranilic acid, Phg: phenylglycine) is demonstrated. Additionally, self-assembly and morphological variation by the incorporation of a D -amino acid, Boc-Ant- D -Phg-OMe (2), and corresponding reversed sequences of both peptides, Boc- L -Phg-Ant-OMe (3) and Boc- D -Phg-Ant-OMe (4), respectively, are explored. FT-IR study indicated the presence of conformational heterogeneity in the reverse peptides. SC-XRD suggested that 1 and 2 contain helical and β sheet-like layer architectures, respectively, whereas 3 and 4 exhibited different kinds of helical structures, sheet-like layer architectures, and molecular channels. Optical microscopy, FESEM, FETEM, and AFM images suggested that both C-terminal L - and D -Phg containing peptides (1 and 2) self-assembled to form a vesicular morphology and their reversed sequences, i.e., N-terminal L - and D -Phg containing peptides (3 and 4), displayed a well-organized rod-like fiber structure. TGA analysis revealed that the obtained supramolecular structures have significant thermal stability. [ABSTRACT FROM AUTHOR]

The self-assembly of peptides forming various micro to nanostructures has several applications in nanobiotechnology. β-Sheet based peptides are well known as they are abundant in nature, e.g., silk and amyloid fibrils. Therefore, the self-assembly of small β-sheet peptides and their potent applications are well explored to date. On the other hand, various helical secondary structures are also abundant in nature. Like β-sheet peptides, small peptide-based helical assemblies are not explored enough, but they also attract attention for fabricating various artificial nanomaterials in recent times. This highlight focuses on single-crystal X-ray diffraction (SC-XRD) based analysis of the supramolecular arrangement, conformation, and higher-order assembly of small helical peptides. We outline the role of building blocks and their structural beauty to adopt helical assembly, including single-, double- and triple-stranded helices. We also describe their micro or nano-level structures obtained from the solution and their potent applications as drug delivery vehicles, as porous materials for N2 adsorption, and for nanomaterial fabrication. [ABSTRACT FROM AUTHOR]

An improved, one‐pot two‐step process is described to convert carboxylic acid to amides, dipeptides, esters, and hydroxamates using Oxyma and thionyl chloride. The addition of Oxyma to thionyl chloride in the presence of Hunig's base results in a mixture of probably Oxyma‐sulfinyl chloride and sulfinyl diOxyma, two new intermediates, which successfully converts the carboxylic acid into its Oxyma ester. Adding a nucleophile to the generated Oxyma ester leads to corresponding amide, ester, or hydroxamic acid formation at room temperature. The procedure is mild and well tolerant to various carboxylic acids, including N‐protected amino acids and different nucleophiles such as methyl esters of amino acids and alcohols. 32 examples with moderate to good yield (67–86 %) are reported. A rigorous mechanism investigation is performed using 1H and 13C‐NMR. By‐product Oxyma can be recovered and recycled. Thionyl chloride has been used for such coupling reactions in industries and academia for a few hundred years to date. Nevertheless, minimum racemization, side reaction, and waste generation make the addition of Oxyma (this methodology) a valuable improvement. [ABSTRACT FROM AUTHOR]

An improved, one‐pot two‐step process is described to convert carboxylic acid to amides, dipeptides, esters, and hydroxamates using Oxyma and thionyl chloride. The addition of Oxyma to thionyl chloride in the presence of Hunig's base results in a mixture of probably Oxyma‐sulfinyl chloride and sulfinyl diOxyma, two new intermediates, which successfully converts the carboxylic acid into its Oxyma ester. Adding a nucleophile to the generated Oxyma ester leads to corresponding amide, ester, or hydroxamic acid formation at room temperature. The procedure is mild and well tolerant to various carboxylic acids, including N‐protected amino acids and different nucleophiles such as methyl esters of amino acids and alcohols. 32 examples with moderate to good yield (67–86 %) are reported. A rigorous mechanism investigation is performed using 1H and 13C‐NMR. By‐product Oxyma can be recovered and recycled. Thionyl chloride has been used for such coupling reactions in industries and academia for a few hundred years to date. Nevertheless, minimum racemization, side reaction, and waste generation make the addition of Oxyma (this methodology) a valuable improvement. [ABSTRACT FROM AUTHOR]

Herein, we investigated the supramolecular assembly of a modified Yamaguchi reagent TCB-OBt. Interestingly, each molecule is interconnected through novel chalcogen–chalcogen (O⋯O) interaction, π–π stacking, and aromatic C–H⋯O interaction. Hirshfeld surface analysis confirmed the existence of uncommon O⋯O interactions. A well-organized supramolecular layer structure and helical arrangement were observed in the crystal structure. TCB-OBt crystallized in the O-substituted desmotropic form. DFT calculations suggest that the O-substituted form is more stable than the N-substituted form (TCB-(N)-OBt). Morphology analysis indicates the formation of a fantastically well organized, continuous block-shaped system. Furthermore, the designed reagent works as an efficient activating reagent for amide bond formation with good yields under mild reaction conditions. Use of this reagent avoided intractable acid chlorides, and this new mixed-anhydride-based reagent may further be applicable for many other organic transformations. [ABSTRACT FROM AUTHOR]

Direct conversion of carboxylic acids to ureas, carbamates, and thiocarbamates in a single pot via Curtius rearrangement is accomplished. One recently established coupling reagent, Ethyl‐2‐cyano‐2‐(2‐nitrophenylsulfonyloximino)acetate (ortho‐NosylOXY, I), is successfully used for the racemization free synthesis of ureas, di‐peptidyl ureas, and carbamates with moderate to good yield (82–69%). This single‐pot hassle‐free procedure works with a diverse range of N‐protecting groups Fmoc, Boc, and Cbz. Various amine, including aromatic, methyl esters of amino acids, t‐butylamine, alcohols, and thiols, are used as nucleophiles. A detailed NMR‐based mechanism study is incorporated here. Racemization suppression, easy removal of by‐products, and less waste generation make this methodology useful. [ABSTRACT FROM AUTHOR]

A method for Beckmann rearrangement using ethyl 2‐cyano‐2‐(2‐nitrobenzenesulfonyloxyimino) acetate (o‐NosylOXY) under microwave irradiation is reported. Ketoximes (19 examples) are converted to the corresponding amides/lactams with 69–97% yields in ∼10 minutes without any Lewis acid or co‐catalyst. This is an example of halogen‐free organocatalytic Beckmann rearrangement. Nuclear magnetic resonance (NMR)‐ and high‐resolution mass spectrometry (HRMS)‐based detailed mechanistic investigation suggest that o‐NosylOXY acts as an initiator. Such initiators are reported before based on density functional theory (DFT) calculations. However, we report here the HRMS signatures of two transient intermediates, the nitrilium ion and the nitrilium ion's dimeric species. Rigorous NMR‐based investigation of the reaction mechanism is performed. Our results indicate that the reported Beckmann rearrangement proceeds via two consecutive rearrangements. [ABSTRACT FROM AUTHOR]

The self‐assembly of N‐ and C‐protected alternating L/L and D/L amino acids containing dipeptides, Boc‐L‐Val‐L‐Ile‐OMe (1), Boc‐D‐Val‐L‐Ile‐OMe (2), Boc‐L‐Ile‐L‐Val‐OMe (3), and Boc‐L‐Ile‐D‐Val‐OMe (4) has been investigated. Field emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM) images indicated that 1 and 3 self‐associated to form highly organized straight net microrods, whereas 2 and 4 self‐assembled to form hexagonal hollow microtube‐like architecture in the acetonitrile‐water medium. To understand the physical basis of such differential behavior, we performed X‐ray diffraction pattern analyses. The single‐crystal X‐ray diffraction (SC‐XRD) study revealed that 1 and 2 self‐assembled to form slightly different helix‐like architectures. The higher‐order association of 2 exhibited a hollow hexagonal tube‐like superstructure. The thermal stability of the nanostructures also varied based on the chiroptical composition of the dipeptides. Experimental findings were corroborated well with computational studies. The obtained results may be helpful in nano‐biotechnology as well as in material science. [ABSTRACT FROM AUTHOR]

We demonstrate a simple and effective methodology for acetalization and thioacetalization of aldehydes by catalytic amount of ethyl‐2‐cyano‐2‐(2‐nitrophenylsulfonyloximino)acetate (ortho‐NosylOXY), a novel peptide coupling reagent. This safe reagent successfully transforms the aldehydes into cyclic acetals, 1,3‐dithiolanes, and 1,3‐dithianes. The reaction is compatible with electron‐withdrawing and donating substituents containing aldehydes and different kinds of diols and dithiols. Also, the reaction worked well with an α,β‐unsaturated aldehyde, and an aliphatic aldehyde. Yields are impressive (71 to 95 %) at a moderate temperature and short time. Hence, broad substrate scope, high yield, easy isolation of the products, and catalytic nature of the reagent make this methodology an environment‐friendly alternative to the existing ones. [ABSTRACT FROM AUTHOR]

A miniaturized mimic of the active site of a protease, chymotrypsin, was linked to a target recognition unit to generate "Miniature Artificial Proteases" (mAPs). Time-resolved MALDI-TOF data analyses indicated that mAPs cleaved every amide bond between Lys16–Phe20 of the amyloid β fragment (Aβ12–21) and Aβ1–40, resulting in inhibition of fibrillization and disruption of the preformed amyloid. Such a platform may offer not only new therapeutic options against various amyloidoses but also novel routes for the selective knockdown of specific proteins. [ABSTRACT FROM AUTHOR]

A mild, practical, and straight forward method for Boc deprotection and its use in peptide synthesis both in solution and on solid support is presented. Boc protecting group is removed from the N‐terminal amino acid of the amino acid and the peptide using environment‐friendly cost‐effective Lewis acid, FeCl3. The deprotected amino group undergoes C−N bond formation with the next Boc‐protected amino acid in the presence of a suitable coupling reagent and base. A library of di‐ to tetrapeptides is synthesized with moderate to good yield from standard and nonstandard Boc‐protected amino acids in solution. Most importantly, this protocol can be used for the solid‐phase peptide synthesis (SPPS) using Boc‐protected amino acids on the acid‐sensitive Rink amide resin, which is usually used for Fmoc chemistry. This protocol thus allows practicing Boc chemistry in a greener manner, and on‐demand switching from Fmoc to Boc chemistry and vice‐versa while synthesizing one oligopeptide on the same resin. The inherent orthogonality of Fmoc and Boc chemistry allows facile synthesis of branched and cyclized peptides on the resin as well. [ABSTRACT FROM AUTHOR]

The conformation and self-assembly of N- and C-protected tripeptides, Boc-Gly- L -Phg- D -Phe-OMe (1, Phg: phenylglycine) and Boc-Gly- L -Phg- D -Phg-OMe (2), have been investigated. The effect of the insertion of two non-coded amino acid residues, L -Phg/ D -Phe and L -Phg/ D -Phg, consecutively on the structure of two tripeptides has been investigated. The single crystal X-ray diffraction analysis of 1 and 2 suggested that both peptides adopted an anti-parallel β-sheet structure but they further self-assembled to form supramolecular single helix and double helix-like architectures, respectively, by various non-covalent interactions in the crystalline state. To the best of our knowledge, this is the first crystallographic report where alternating D / L unnatural amino acid containing small tripeptides exhibited double helix-like architectures. The conformation of these peptides was examined by 2D NMR, solvent dependent NMR titration, and CD spectroscopic studies in solution. Peptides 1 and 2 self-aggregated to form a bunch of flower-petal-like and flower-like architectures, respectively, in an acetonitrile–water medium under a field emission scanning electron microscope (FESEM). [ABSTRACT FROM AUTHOR]

Inspired by the unique mechanism of proteolytic maturation of host cell factor-1, we designed small peptide-based constructs that selectively recognized amyloid β (Aβ) and cleaved it in a non-catalytic manner initially around the α-secretase cleavage-site, thus termed as “artificial α-secretases”. “Artificial α-secretases” also cleaved Aβ on the cleavage-sites of other Aβ processing enzymes by prolonged treatment, as evidenced by time-resolved MALDI-TOF-mass analyses. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, involves the formation of the extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles. The current therapies against AD are symptomatic with limited benefits but associated with major side effects. Inhibition of self-aggregation of Aβ peptides into higher order cross-β structure is one of the potential therapeutic approach which may counter oligomerization of Aβ peptide.Objective: The present study aimed to evaluate the neuroprotective and anti-inflammatory potential of a synthetic Pro-Drug type peptide (PDp) against Aβ-induced toxicity in rat model of AD.Methods: Intra-hippocampal microinjection of toxic Aβ40 (IHAβ40) by stereotaxic surgery was performed in the male Sprague-Dawley rats to generate an Aβ-induced AD model. Sub-chronic toxicity of synthetic PDp using hematological, biochemical, and histopathological parameters was investigated. Evaluation of PDp on Aβ-induced neurodegeneration and neuroinflammation was performed.Results: PDp inhibits plaque formation with increase in Nissl granule staining in the rat hippocampus. Aβ-induced toxicity associated imbalance in reactive oxygen species and antioxidant enzymes activity such as superoxide dismutase and catalase in the rat brain was overcome by PDp treatment. Tau protein hyperphosphorylation was normalized with PDp treatment. Also, the neuroinflammatory response was suppressed with PDp treatment.Conclusion: The present study depicts the potential neuroprotective role of PDp against Aβ-induced toxicity in rat. PDp inhibits plaque formation thereby normalizing oxidative stress, inhibiting tau protein hyperphosphorylation, and suppressing neuroinflammatory responses. Future studies done in this direction will pave way for new therapeutic strategies. [ABSTRACT FROM AUTHOR]

The self-assembly of N- and C-protected tripeptides, Boc-Gly-Phe-Phe-OMe (1) and its analog Boc-Gly-Phg-Phe-OMe (2, Phg = phenylglycine), has been investigated. The presence of just an extra methylene (–CH2–) group in the side chain of one of the amino acids resulted in significant changes in their molecular arrangement and supramolecular structure. The single crystal X-ray diffraction analysis suggested that 1 adopted a type II β-turn-like conformation, known as open turn identified by the absence of any intramolecular hydrogen bond, which further self-assembled to form a herringbone helix-like architecture through non-covalent interactions. To the best of our knowledge, this is the first report on a designed open turn tripeptide without a kink-forming element. However, in spite of the presence of a non-standard amino acid 2 adopted a β-sheet conformation which further self-organized to form a helical architecture through non-covalent interactions in the crystalline form. The conformations of these peptides in solution were also investigated by solvent dependent NMR titration, 2D NOESY, and CD spectroscopic experiments. These peptides exhibited two different flower-like architectures in acetonitrile–water medium under an optical microscope and a field emission scanning electron microscope (FESEM). [ABSTRACT FROM AUTHOR]

Both N- and C-protected dipeptides, Boc-Val-Val-OMe (1) and Boc-Ile-Ala-OMe (2), bearing sequence homogeneity with the C-terminus of Alzheimer's Aβ39–40 and Aβ41–42, respectively, exhibit intermolecular hydrogen-bonded supramolecular parallel β-sheet structures in crystalline form. But the higher order aggregation of 2 showed a clear supramolecular cross-β-sheet structure unlike that of 1. FESEM images indicated that, while 1 self-assembled into a highly organized two ended spear-like architecture, 2 formed a hollow hexagonal tube-like structure, in a methanol–water solvent mixture. These molecules self-assembled into the ordered structures which found to bind with the amyloid binding dyes thioflavin T (ThT) and Congo red. FT-IR and PXRD also support the formation of the β-sheet structure both in solution and in the solid state. These results may help in understanding amyloidogenesis and design principle of nanostructures. [ABSTRACT FROM AUTHOR]

A novel concept for the controlled, sequential onset of peptide assembly in vitro is presented. Exploring the immense potential of peptide and protein synthesis, switch-peptides might become a general tool for the study of early steps in polypeptide self-assembly and inhibition as a key process in degenerative diseases.

Alzheimer's disease is most common neurodegenerative disorder and is characterized by increased production of soluble amyloid-β oligomers, the main toxic species predominantly formed from aggregation of monomeric amyloid-β (Aβ). Increased production of Aβ invokes a cascade of oxidative damages to neurons and eventually leads to neuronal death. This study was aimed to investigate the neuroprotective effects of a β-sheet breaker α/β-hybrid peptide ( BSBHp) and the underlying mechanisms against Aβ40-induced neurotoxicity in human neuroblastoma SH- SY5Y cells. Cells were pretreated with the peptide Aβ40 to induce neurotoxicity. Assays for cell viability, cell membrane damage, cellular apoptosis, generation of reactive oxygen species ( ROS), intracellular free Ca2+, and key apoptotic protein levels were performed in vitro. Our results showed that pretreatment with BSBHp significantly attenuates Aβ40-induced toxicity by retaining cell viability, suppressing generation of ROS, Ca2+ levels, and effectively protects neuronal apoptosis by suppressing pro-apoptotic protein Bax and up-regulating antiapoptotic protein Bcl-2. These results suggest that α/β-hybrid peptide has neuroprotective effects against Aβ40-induced oxidative stress, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Boc-Oxyma (Ethyl 2-( tert-butoxycarbonyloxyimino)-2-cyanoacetate) has been reported previously as an efficient coupling reagent for the synthesis of amides, peptides, esters, thioesters and hydroxamic acids. It is known for its excellent racemization suppression capability, and also as an environment friendly reagent as it generates only Oxyma as solid byproduct that can be recovered easily and recycled for the synthesis of the same reagent. In this update, we report a simple, efficient, environment friendly, chemoselective and racemization free method for the synthesis of ureas, carbamates and thiocarbamates from hydroxamic acids via Lossen rearrangement by using Boc-Oxyma. We have achieved racemization free di- and tri-peptidyl ureas with very good yield by using this protocol. A rigorous mechanistic investigation is also incorporated. [ABSTRACT FROM AUTHOR]

A metal-free and catalytic method for the synthesis of 2-substituted benzoxazoles and benzothiazoles from N-protected amino acids and carboxylic acids is described. The synthesis of benzoxazole on a solid support is demonstrated by the synthesis of benzoxazole attached to a human islet amyloid polypeptide, hIAPP22-27, fragment and benzoxazole derivatives of the side chain of aspartic acid on a modified fragment of Aβ18−21 (amyloid β) peptide. The reactions proceeded through a two-step mechanism. The coupling step is realized with a relatively new reagent, ethyl 2-cyano-2-(2-nitrobenzenesulfonyloxyimino)acetate ( ortho-NosylOXY), and the cyclization step takes place thanks to an inexpensive organocatalyst, para-toluenesulfonic acid, under microwave irradiation. To the best of our knowledge, this is the first report of the complete synthesis of benzoxazole derivatives of a polypeptide on a resin solid support. [ABSTRACT FROM AUTHOR]

D-/ L-Peptides such as gramicidin A (gA) adopt unique dimeric β -helical structures of different topologies. To overcome their conformational promiscuity and enrich individual components, a dynamic combinatorial approach assisted by thiol tags was developed. This method led to identification of the preferential formation of antiparallel dimers under a broad range of conditions, which was independent of peptide side-chain polarity. Exclusive formation of an antiparallel cyclic dimer was achieved in the presence of cesium ions. [ABSTRACT FROM AUTHOR]

Insertion of an anthranilic acid in an amyloidogenic peptide sequence generates a novel conformationally restricted α/β-hybrid peptide that inhibits amyloid formation of Aβ(1–40) and disrupts preformed fibrillar aggregates in vitro. Such β-sheet breaker hybrid peptides (BSBHps) may be useful for designing novel physiologically important compounds relevant to diverse amyloidoses and for studying the process of aggregation. [ABSTRACT FROM AUTHOR]

A milder and more efficient procedure for the synthesis of sulfonamides by activating sulfonic acid groups as the corresponding sulfonate esters of ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma) is reported. This method is greener than all other existing protocols for the purpose. Other important advantages lie in (a) its applicability to less nucleophilic anilines under ambient and milder conditions and (b) its compatibility with solid phase peptide synthesis and acid-labile groups such as trityl (Trt) and tBu, which empowers the solid phase synthesis of sulfonamides of various peptides. To illustrate this, the syntheses of three sulfonamide derivatives of the peptide GAILG-NH2, which is relevant in the context of drug design against type 2 diabetes, are demonstrated by using Fmoc-based solid-phase peptide synthesis (SPPS). [ABSTRACT FROM AUTHOR]

Here we report the synthesis and utility of ethyl 2-( tert-butoxycarbonyloxyimino)-2-cyanoacetate (Boc-Oxyma) as an efficient coupling reagent for racemization-free esterification, thioesterification, amidation reactions and peptide synthesis that uses equimolar amounts of acids and alcohols, thiols, amines or amino acids, respectively. Its application to solid phase as well as solution phase peptide synthesis is also demonstrated and a mechanistic investigation is discussed. Boc-Oxyma is similar to the well known coupling agent COMU {1-[1-cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylaminomorpholino]uronium hexafluorophosphate} in terms of its high reactivity and mechanism of action. However, it is not only much easier to prepare, but also to recover and reuse, thereby generating far less chemical waste. [ABSTRACT FROM AUTHOR]