Cleavage Of Amide Bond Research Articles

Degradation of iodinated X-ray contrast media by advanced oxidation processes: A literature review with a focus on degradation pathways

Available online Iodinated X-ray contrast media (ICMs) are clinical drugs used to enhance the imaging effect. Triiodobenzene ring structures of ICMs lead to its extremely high chemical stability, biological inertness, which makes it difficult to be completely removed by traditional water treatment processes. Hence, considerable concentration of ICMs can be frequently detected in aquatic environment. Relying on the strong oxidation capacity of HO• or SO4•‒, various advanced oxidation processes (AOPs) have demonstrated substantial removal efficiency for ICMs. It is evident that ICMs can be decomposed mainly through (1) deiodination, (2) dehydration, (3) decarboxylation, (4) H-abstraction, (5) hydroxyl addition, (6) hydroxyl substitution, (7) oxidation of alcohol groups, (8) cleavage of amide bond, and (9) amino oxidation. However, during the ICMs removal process, the C-I bonds of ICMs molecules are broken, giving rise to the formation of cytotoxic iodination disinfection by-products (I-DBPs) that are potentially more harmful to the ecosystem and human health than their parent compounds. To better understand the technology gaps, this review elaborates the major AOPs which are effective for ICMs removal and emphasizes on the main degradation routes of ICMs in different oxidation system. Some prevailing concerns and challenges are discussed for optimizing the ICMs treatment process.

Sunlight-driven photocatalytic mineralization of antibiotic chemical and selected enteric bacteria in water via zinc tungstate-imprinted kaolinite

ABSTRACT This study reports the synthesis of sunlight-active zinc oxide-tungstate-kaolinite photocatalytic composite prepared via a green process (solvent-free mechano-thermal process) at an optimum temperature of 500°C for 1 h in a furnace. Electron Paramagnetic Resonance (EPR) study suggests the presence of W5+ defect states in the prepared photocatalytic composite (ZnWK-5), which is responsible for its photoactivity in visible light. Results from further analysis show that hole (h+) and superoxide radical ( . O2 −) are the major contributors to the photocatalytic efficiency of ZnWK-5 photocatalytic composite. This photocatalytic composite was used to treat water containing an antibiotic chemical-ampicillin (AMP) under sunlight. Mass spectrometry analysis of the treated water suggests that the mechanism of photodegradation of AMP is via several bond and ring cleavages, including amide bond, phenyl ring, and β-lactam ring cleavages. These cleavage reactions were followed by subsequent mineralization of ca. 98% after 5 h without the formation of toxic products. The introduction of phosphate and carbonate anions had a serious negative impact on the photocatalytic activity of the composite. However, the photocatalytic composite completely disinfected water contaminated with gram-(−ve) and gram-(+ve) bacteria. Even after five re-use cycles, the photocatalytic composite maintained a 90% photodegradation efficiency of ampicillin in water.

Serendipitous discovery of (L)‐valine mediated in situ formation of two‐dimensional coordination polymer by tripodal ligand with transition metals

AbstractA new methodology for 2D coordination polymer formation has been reported by in situ amide bond cleavage of the ligand L at room temperature under a mild condition in the presence of aqueous pyridine. The ligand is formed by the coupling of (L)‐valine with benzene‐1,3,5‐tricarboxylic acid (btcH3). The three amide bonds present on the tripodal ligand, easily break and forms 2D coordination polymer with btc−3 as {[(btc)(py)3(H2O)(Co)1.5].(py)(H2O)2}n (1), {(btc)0.66(py)3(H2O)Ni}n (2), and {[(btc)(py)3Zn1.5](H2O)2}n (3). The tripodal ligand L has been characterized by 1H NMR, 13C NMR, IR, and mass spectra and their corresponding coordination polymers 1, 2, and 3, respectively, have been characterized by single‐crystal X‐ray diffraction and thermogravimetric analysis.

The Human Ntn-Hydrolase Superfamily: Structure, Functions and Perspectives.

N-terminal nucleophile (Ntn)-hydrolases catalyze the cleavage of amide bonds in a variety of macromolecules, including the peptide bond in proteins, the amide bond in N-linked protein glycosylation, and the amide bond linking a fatty acid to sphingosine in complex sphingolipids. Ntn-hydrolases are all sharing two common hallmarks: Firstly, the enzymes are synthesized as inactive precursors that undergo auto-proteolytic self-activation, which, as a consequence, reveals the active site nucleophile at the newly formed N-terminus. Secondly, all Ntn-hydrolases share a structural consistent αββα-fold, notwithstanding the total lack of amino acid sequence homology. In humans, five subclasses of the Ntn-superfamily have been identified so far, comprising relevant members such as the catalytic active subunits of the proteasome or a number of lysosomal hydrolases, which are often associated with lysosomal storage diseases. This review gives an updated overview on the structural, functional, and (patho-)physiological characteristics of human Ntn-hydrolases, in particular.

Cyclodextrin-Oligocaprolactone Derivatives-Synthesis and Advanced Structural Characterization by MALDI Mass Spectrometry.

Cyclodextrins have previously been proven to be active in the catalysis of cyclic ester ring-opening reactions, hypothetically in a similar way to lipase-catalyzed reactions. However, the way they act remains unclear. Here, we focus on β-cyclodextrin’s involvement in the synthesis and characterization of β-cyclodextrin-oligocaprolactone (CDCL) products obtained via the organo-catalyzed ring-opening of ε-caprolactone. Previously, bulk or supercritical carbon dioxide polymerizations has led to inhomogeneous products. Our approach consists of solution polymerization (dimethyl sulfoxide and dimethylformamide) to obtain homogeneous CDCL derivatives with four monomer units on average. Oligomerization kinetics, performed by a matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) optimized method in tandem with 1H NMR, revealed that monomer conversion occurs in two stages: first, the monomer is rapidly attached to the secondary OH groups of β-cyclodextrin and, secondly, the monomer conversion is slower with attachment to the primary OH groups. MALDI MS was further employed for the measurement of the ring-opening kinetics to establish the influence of the solvents as well as the effect of organocatalysts (4-dimethylaminopyridine and (–)-sparteine). Additionally, the mass spectrometry structural evaluation was further enhanced by fragmentation studies which confirmed the attachment of oligoesters to the cyclodextrin and the cleavage of dimethylformamide amide bonds during the ring-opening process.

An Integrated Strategy for Assessing the Metabolic Stability and Biotransformation of Macrocyclic Peptides in Drug Discovery toward Oral Delivery.

Macrocyclic peptides (MCPs) are an emerging class of promising drug modalities that can be used to interrogate hard-to-drug ("undruggable") targets. However, their poor intestinal stability is one of the major liabilities or obstacles for oral drug delivery. We therefore investigated the metabolic stability and biotransformation of MCPs via a systematic approach and established an integrated in vitro assay strategy to facilitate MCP drug discovery, with a focus on oral delivery liabilities. A group of diverse MCPs were incubated with representative matrices, including simulated intestinal fluid with pancreatin (SIFP), human enterocytes, liver S9 fractions, liver lysosomes, plasma, and recombinant enzymes. The results revealed that the stability and biotransformation of MCPs varied, with the major metabolic pathways identified in different matrices. Under the given conditions, the selected MCPs generally showed better stability in plasma compared to that in SIFP. Our data suggest that pancreatic enzymes act as the primary metabolic barrier for the oral delivery of MCPs, mainly through hydrolysis of their backbone amide bonds. Whereas in enterocytes, multiple metabolic pathways appeared to be involved and resulted in metabolic reactions such as oxidation and reduction in addition to hydrolysis. Further studies suggested that lysosomal peptidase cathepsin B could be a major enzyme responsible for the cleavage of side-chain amide bonds in lysosomes. Collectively, we developed and implemented an integrated assay for assessing the metabolic stability and biotransformation of MCPs for compound screening in the discovery stage toward oral delivery. The proposed question-driven assay cascade can provide biotransformation insights that help to guide and facilitate lead candidate selection and optimization.

Chemical recycling of waste poly-p-phenylene terephthamide via selective cleavage of amide bonds catalyzed by strong Brönsted base in alcohols.

Poly-p-phenylene terephthamide (PPTA) is widely applied in bulletproof products and composite materials because of its high strength, high modulus, high temperature resistance and creep resistance. The PPTA molecule with highly symmetrical and regular structure is linear structure formed by the alternating connection of benzene ring and amide bond, and the amide bonds between the molecular chains form strong hydrogen bonds. Therefore, the dissolution and depolymerization of PPTA is very challenging. In this work, an efficient catalytic system was developed for the controllable degradation of waste PPTA, and the high-value added monomers terephthalic acid (TPA) and p-phenylenediamine (PPD) were recovered. The results show that the amide bonds of PPTA can be selectively cleaved by the strong Brönsted base catalysts in alcohols, especially in the NaOH/n-butanol system. Under the optimal degradation conditions (5wt% NaOH in n-butanol, 180°C, 6h), the percentage degradation of PPTA is 100%, and the yields of TPA and PPD are 92.0% and 91.5%, respectively. In addition, it is found that the wettability of n-alcohols on PPTA monofilament and the addition of a small amount of water have important influences on the degradation of PPTA. The work elucidates the degradation mechanism of PPTA, and reveals the important factors affecting the depolymerization of PPTA.

From amides to urea derivatives or carbamates with chemospecific C–C bond cleavage at room temperature

A general method for copper-catalyzed chemospecific C–C bond cleavage of amides to synthesize urea derivatives and carbamates at room temperature was reported.

Precise gene delivery systems with detachable albumin shell remodeling dysfunctional microglia by TREM2 for treatment of Alzheimer's disease

Intervention of the over-activated microglia-aggravated neuroinflammation represents a promising therapeutic strategy for Alzheimer's disease (AD). Upregulation of triggering receptor expressed on myeloid cells-2 (TREM2) attenuates the neuroinflammatory processes and normalizes the dysfunctional microglia. However, Trem2-gene therapy for AD by the effective non-invasive delivery systems is unexploited. Herein, we report the microglia-targeted gene delivery systems (PHSA@PF/pTREM2) composed of a core of fluorinated polyethylenimine condensing the TREM2-encoding plasmid (PF/pTREM2) and a shell of human serum albumin conjugated with both cis-aconitic anhydride and neural cell adhesion molecule-mimetic peptide P2 (PHSA). Thanks to the shedding effect of the albumin coated, PHSA@PF/pTREM2 exhibit prolonged blood circulation and low cytotoxicity. PHSA@PF/pTREM2 achieve brain accumulation as high as 2.17% injected dose per gram of brain and the microglial-targeting effect (targeting specificity of 41.9%) via the systemic administration. The nanocomplexes can be detached PHSA-shell in the acidic endo-lysosomes via the cleavage of cis-aconitic amide bond, resulting in PF/pTREM2 exposure for efficient endo-lysosomal escape and gene transfection. PHSA@PF/pTREM2 upregulate the TREM2 level and regulate microglial polarization toward M2-phenotype for remodeling the inflammatory microenvironment and enhanced Aβ clearance, leading to an improvement of cognitive performance in APP/PS1 mice. This work provides a promising gene delivery platform to reverse dysfunctional microglia for AD therapy.

Simultaneous Evaluations of pH and Enzyme Activity with a CEST MRI Contrast Agent.

The extracellular tumor microenvironment of many solid tumors has high acidosis and high protease activity. Simultaneously assessing both characteristics may improve diagnostic evaluations of aggressive tumors and the effects of anticancer treatments. Noninvasive imaging methods have previously been developed that measure extracellular pH or can detect enzyme activity using chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI). Herein, we developed a single-hybrid CEST agent that can simultaneously measure pH and evaluate protease activity using a combination of dual-power acidoCEST MRI and catalyCEST MRI. Our agent showed CEST signals at 9.2 ppm from a salicylic acid moiety and at 5.0 ppm from an aryl amide. The CEST signal at 9.2 ppm could be measured after selective saturation was applied at 1 and 4 μT, and these measurements could be used with a ratiometric analysis to determine pH. The CEST signal at 5.0 ppm from the aryl amide disappeared after the agent was treated with cathepsin B, while the CEST signal at 9.2 ppm remained, indicating that the agent could detect protease activity through the amide bond cleavage. Michaelis-Menten kinetics studies with catalyCEST MRI demonstrated that the binding affinity (as shown with the Michaelis constant KM), the catalytic turnover rate (kcat), and catalytic efficiency (kcat/KM) were each higher for cathepsin B at lower pH. The kcat rates measured with catalyCEST MRI were lower than the comparable rates measured with liquid chromatography-mass spectrometry (LC-MS), which reflected a limitation of inherently noisy and relatively insensitive CEST MRI analyses. Although this level of precision limited catalyCEST MRI to semiquantitative evaluations, these semiquantitative assessments of high and low protease activity still had value by demonstrating that high acidosis and high protease activity can be used as synergistic, multiparametric biomarkers.

Selective Modification of Peptides through Cleavage of a Secondary Amide Bond

Selective Modification of Peptides through Cleavage of a Secondary Amide Bond

Advances in the Synthesis of Marine‐sourced Natural Product via the Preparation of Pyrimidinyl Benzamides by Amide Bond Formation

Efficient, scalable total synthesis of 4-Amino-N-(2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl) benzamide, a marine-sourced compound with antibacterial properties is introduced, highlighting the importance of nature and its selection process to produce effective antibacterial compounds, thus serving as a template in the development of new drugs. We proposed a one-pot process where 6-aminouracil was acylated using 4-N-Boc-aminobenzoyl chloride over an expansive range of solvents and temperatures. We also proposed a one-pot carbodiimide mediated carboxylic acid coupling with 6-aminouracil. Both processes were unsuccessful and the difficulty encountered in these approaches is likely due to the reduced nucleophilicity of the amino group of 6-aminouracil. Literature studies helped refocus our approach to exploit the pyrimidine character of the uracil as a workaround, employing a dialkoxy aminopyrimidine, which is a precursor to our specific uracil starting material. The 4-amino-2,6-dimethoxypyrimidine was extensively screened for the same two reactions using a variety of solvents and temperatures, with the key amide bond successfully being formed using benzoyl chloride in excess pyridine. The amide bond formation was further optimized, obtaining a purer, higher-yielding coupling product. Current work involves dealkylation of the pyrimidine to furnish the uracil moiety as the final step in a three-step total synthesis. The attempted acidic demethylation of a methoxypyrimidine substrate resulted in undesired amide bond cleavage. Future work involves attempting the demethylation of the methoxypyrimidine substrate using a variety of Lewis acids and if successful, testing the natural product's antibiotic properties. The pyrimidinyl benzamides themselves may have useful biological activities which would be worth investigating as well.

Heat induced hydrolytic cleavage of the peptide bond in dietary peptides and proteins in food processing

We investigate the hypothesis that proteins and peptides are thermally degraded by hydrolytic bond cleavage of amide bonds, hence yielding shorter peptides as main degradation products. A series of fifteen pentapeptides with varying sequences was subjected to heating. Products were investigated by targeted UHPLC-ESI-tandem mass spectrometry and targeted analysis revealed formation of 2,5-diketopiperazines, di- and tri-peptides. Relative quantities of the thermal degradation were determined to show that hydrolytic cleavage is an important, however not dominant degradation pathway. A series of dietary intact proteins were subjected to heating and products formed analyzed by MALDI-TOF mass spectrometry. For the majority of proteins larger degradation products with m/z values between 900 and 2500 could be observed, which we tentatively assign as hydrolytic cleavage products. For coffee globulin a series of eleven short peptides formed through thermal hydrolytic cleavage could be unambiguously identified formed through thermal proteolysis. The identical products could as well be identified in samples of roasted coffee clearly illustrating the occurrence and relevance of thermally induced proteolysis of proteins.

Accelerated Degradation of Aqueous Recalcitrant Iodinated Contrasting Media Using a UV/SO32- Advanced Reduction Process

Based on the formation of free radical-hydrated electrons by the activation of sulfite (SO32-), the UV/SO32- process is an advanced reduction process that can reduce pollutants. This study investigated the degradation kinetics, mechanism, influencing factors, and degradation pathways of sodium diatrizoate (DTZ), an iodinated contrasting media, during the UV/SO32- process. The degradation kinetics of DTZ were well fitted by the pseudo-first-order model, the degradation rate of which was higher than that of UV only and UV/H2 O2. The degradation rate of DTZ during the UV/SO32- process was positively correlated with the initial SO32- concentration. Weakly alkaline and alkaline conditions promoted the degradation of DTZ, while organic matter inhibited degradation during the UV/SO32- process. The degradation mechanism included direct photolysis and free radical attack, whereby free radical attack played a more important role than direct photolysis. Sulfite radicals dominated DTZ degradation efficiency, and hydrated electrons controlled the deiodination efficiency. The degradation pathways of DTZ during the UV/SO32- process included substitution, decarboxylation-hydroxylation, and amide bond cleavage.

A computational study of the reaction mechanism involved in the fast cleavage of an unconstrained amide bond assisted by an amine intramolecular nucleophilic attack.

In the present work, the fast amide bond cleavage of [3-((1R,5S,7s)-3-azabicyclo[3.3.1]nonane-7-carbonyl)-3-azabicyclo[3.3.1]nonane-7-carboxylic acid (bi-ATDO)], through an intramolecular nucleophilic attack of an amine group is evaluated. First, six possible peptide bond cleavage mechanisms, two of them including a water molecule, are described at the ωB97XD/6-311 + G(d,p)//MP2/6-311 + G(d,p) level of theory. The reaction consisting of an intramolecular nitrogen nucleophilic attack followed by a proton transfer and the amide bond cleavage is determined as the most favorable mechanism. The activation free energy computed for the latter is 20.5 kcal mol-1 , which agrees with the reported experimental result of 24.8 kcal mol-1 . Inclusion of a water molecule to assist the first step of the reaction results in an activation free energy increase of about 17 kcal mol-1 . All the steps in the most favorable mechanism are studied more in detail employing intrinsic reaction coordinate as well as the reaction force and reaction electronic flux analysis.

Monitoring the Degradation of Collagen Hydrogels by Collagenase Clostridium histolyticum.

Collagen-based hydrogels are investigated extensively in tissue engineering for their tunable physiochemical properties, biocompatibility and biodegradability. However, the effect of the integrity of the collagen triple helical structure on biodegradability is yet to be studied. In this study, we monitored the degradation of intact collagen (C-coll) and hydrolyzed collagen (D-coll) hydrogels in collagenase Clostridium histolyticum to understand their degradation process. Our results show that when peptides are present on the surface of the fibrils of D-coll hydrogels, cleavage of amide bonds occur at a much higher rate. The fibrillar structure of D-coll hydrogel results in a more pronounced breakdown of the gel network and dissolution of collagen peptides. The results from this work will improve the understanding of enzymatic degradation and the resulting bioabsorption of collagen materials used in drug delivery systems and scaffolds.

Combined KOH/BEt3 Catalyst for Selective Deaminative Hydroboration of Aromatic Carboxamides for Construction of Luminophores.

The selective catalytic C-N bond cleavage of amides into value-added amine products is a desirable but challenging transformation. Molecules containing iminodibenzyl motifs are prevalent in pharmaceutical molecules and functional materials. Here we established a combined KOH/BEt3 catalyst for deaminative hydroboration of acyl-iminodibenzyl derivatives, including nonheterocyclic carboxamides, to the corresponding amines. This novel transition-metal-free methodology was also applied to the construction of Clomipramine and luminophores.

Self-Adaptive Antibacterial Coating for Universal Polymeric Substrates Based on a Micrometer-Scale Hierarchical Polymer Brush System.

Surface-tethered hierarchical polymer brushes find wide applications in the development of antibacterial surfaces due to the well-defined spatial distribution and the separate but complementary properties of different blocks. Existing methods to achieve such polymer brushes mainly focused on inorganic material substrates, precluding their practical applications on common medical devices. In this work, a hierarchical polymer brush system is proposed and facilely constructed on polymeric substrates via light living graft polymerization. The polymer brush system with micrometer-scale thickness exhibits a unique hierarchical architecture consisting of a poly(hydroxyethyl methacrylate) (PHEMA) outer layer and an anionic inner layer loading with cationic antimicrobial peptide (AMP) via electrostatic attraction. The surface of this system inhibits the initial adhesion of bacteria by the PHEMA hydration outer layer under neutral pH conditions; when bacteria adhere and proliferate on this surface, the bacterially induced acidification triggers the cleavage of labile amide bonds within the inner layer to expose the positively charged amines and vigorously release melittin (MLT), allowing the surface to timely kill the adhering bacteria. The hierarchical surface employs multiple antibacterial mechanisms to combat bacterial infection and shows high sensitiveness and responsiveness to pathogens. A new paradigm is supplied by this modular hierarchical polymer brushes system for the progress of intelligent surfaces on universal polymer substrates, showing great potential to a promising strategy for preventing infection related to medical devices.

Parallel Determination of Polypeptide and Oligosaccharide Connectivities by Energy-Resolved Collison-Induced Dissociation of Protonated O-Glycopeptides Derived from Nonspecific Proteolysis.

Collision-induced dissociation (CID) is by far the most broadly applied dissociation method used for tandem mass spectrometry (MS/MS). This includes MS/MS-based structural interrogation of glycopeptides for applications in glycoproteomics. The end goal of such measurements is to determine the monosaccharide connectivity of the glycan, the amino acid sequence of the peptide, and the site of glycosylation for each glycopeptide of interest. In turn, this allows inferences with respect to the glycoprofile of the intact glycoprotein. For glycopeptide analysis, CID is best known for the ability to determine glycosidic topology of the oligosaccharide group; however, CID has also been shown to produce amide bond cleavage of the polypeptide group. Whether structural information is obtained for the glycan or the peptide has been found to depend on the applied collision energy. While these energy-resolved fragmentation pathways have been the subject of several studies on N-linked glycopeptides, there remains a dearth of similar work on O-linked glycopeptides. In this study, MS/MS via CID was shown to provide substantial peptide backbone fragmentation, in addition to glycosidic fragmentation, in an energy-dependent manner. While qualitatively similar to previous findings for N-glycopeptides, the energy-resolved CID (ER-CID) of O-glycopeptides was found to be substantially more sensitive to the collision energy setting. Thus, deliberately obtaining either glycan or peptide dissociation is a more delicate undertaking for O-glycopeptides. Establishing a more complete understanding of O-glycopeptide ER-CID is likely to have a substantive impact on how O-glycoproteomic analysis is approached in the future.

Transamidation via C–N bond cleavage of amides and tertiary amines

Double C–N bond cleavage of amides and tertiary amines afforded the transamidated products in good yields.