Amide Cleavage Research Articles

Acid- and Base-Mediated Hydrolysis of Dichloroacetamide Herbicide Safeners.

Safeners are used extensively in commercial herbicide formulations. Although safeners are regulated as inert ingredients, some of their transformation products have enhanced biological activity. Here, to fill gaps in our understanding of safener environmental fate, we determined rate constants and transformation products associated with the acid- and base-mediated hydrolysis of dichloroacetamide safeners AD-67, benoxacor, dichlormid, and furilazole. Second-order rate constants for acid- (HCl) and base-mediated (NaOH) dichloroacetamide hydrolysis (2.8 × 10–3 to 0.46 and 0.3–500 M–1 h–1, respectively) were, in many cases (5 of 8), greater than those reported for their chloroacetamide herbicide co-formulants. In particular, the rate constant for base-mediated hydrolysis of benoxacor was 2 orders of magnitude greater than that of its active ingredient co-formulant, S-metolachlor. At circumneutral pH, only benoxacor underwent appreciable hydrolysis (5.3 × 10–4 h–1), and under high-pH conditions representative of lime-soda softening, benoxacor’s half-life was 13 h—a timescale consistent with partial transformation during water treatment. Based on Orbitrap LC–MS/MS analysis of dichloroacetamide hydrolysis product mixtures, we propose structures for major products and three distinct mechanistic pathways that depend on the system pH and compound structure. These include base-mediated amide cleavage, acid-mediated amide cleavage, and acid-mediated oxazolidine ring opening. Collectively, this work will help to identify systems in which hydrolysis contributes to the transformation of dichloroacetamides, while also highlighting important differences in the reactivity of dichloroacetamides and their active chloroacetamide co-formulants.

Synthesis of Indole‐ and Pyrrole‐Fused Seven‐Membered Nitrogen Heterocycles via Acid‐Base Switchable Cyclization Involving Cleavage of Amide C−N Bonds

AbstractWe report the method for synthesis of indole‐ and pyrrole‐fused seven‐membered nitrogen heterocycles by means of acid‐base switchable cyclization reactions. The reactions involved cleavage of amide C−N bonds, chemoselective N‐1 or C‐3 acylation, and 1,4‐Michael addition. This method could be used to construct two different kinds of seven‐membered rings in one step from the same starting material without the need for a transition‐metal catalyst.magnified image

Degradation of polybenzimidazole in alkaline solution with first-principles Modeling

Membrane-based polybenzimidazole (mPBI) emerges as an exciting electrolyte membrane for alkaline fuel cells and water electrolyzers due to its useful ion conductivity range after being doped with aqueous KOH. However, the polymer degradation at highly alkaline concentrations limits its practical use. Herein, the density functional theory (DFT) calculations are used to study the degradation mechanism of mPBI molecule in an alkaline solution. The pristine mPBI molecule deprotonates to form an ionized molecule in an alkaline solution, with the ionized form being predominant at high pH. The nucleophilic hydroxide at the C2 position initiates the degradation, whereas the formation of the fully deprotonated ionic form suppresses the hydroxide ion attack. The degradation reaction then proceeds by ring-opening and chain scission reactions. The ring-opening reaction is preferred with an ancillary hydroxide ion or water molecule during the proton transfer process. The rate-determining state is the transition state involving the amide cleavage during the chain scission. Combining implicit-explicit solvation models is found to stabilize intermediate and transition states, lowering the energy barrier. With one or two explicit water molecules, the free energy barrier agrees well with experimental polymer lifetimes. An increase in KOH concentration increases the degradation rate, agreeing with experiments.

Inherently nitric oxide containing polymersomes remotely regulated by NIR for improving multi-modal therapy on drug resistant cancer

The therapeutic potential of nitric oxide (NO) has been highly attractive to tumor treatment, especially for surmounting the multidrug resistance (MDR) of cancer. However, the NO-involved therapy remains extremely challenging because of the difficulty to simultaneously control the NO release rate and real-time concentration. Herein, we construct NO-containing polymersomes with high amount of NO donors inherently grown on the polymer chains to keep the stability. These polymersomes can be simultaneously loaded with photosensitizer of IR780 iodide on the membrane layer and chemotherapeutic of DOX·HCl in the lumen. NO release can be triggered by the reduction conditions, and further accelerated by remote NIR irradiation due to the increased local temperature. The instantaneous NO release with high concentration significantly inhibits the P-gp expression and sensitize the chemotherapy, thus overcoming the tumor MDR and improving the anti-tumor activity. Meanwhile, DOX·HCl release is highly promoted at the intracellular conditions because of the cleavage of acid-labile cis-aconitic amide at endo/lysosomal pH, and the improved hydrophilicity of the membrane layer after NO release. The in vivo results show that the single intravenous injection of polymersome formulation companying with NIR irradiation exerts multi-modal therapies of chemotherapy, PTT/PDT, and NO-therapy on the MCF-7/R tumor models, showing superior and combinational treatment efficacy with the complete eradication of tumors and few side effects.

Recent Advances in the Use of Sodium Dispersion for Organic Synthesis

AbstractThis short review describes the recent emergence of organosodium chemistry, motivated by the requirements of modern synthetic chemistry for sustainability, and powered by the use of sodium dispersion, a form of sodium that is commercially available, easy to handle, and has a large active surface area. We present recent methods for the preparation of organosodium compounds using sodium dispersion, and their applications to synthesis. Sodium amides and phosphides are also briefly discussed.1 Introduction2 Sodium Dispersion3 Preparation of Organosodium Compounds3.1 Two-Electron Reduction of Aryl Halides3.2 Halogen–Sodium Exchange3.3 Directed Metalation3.4 Cleavage of C–C and C–Heteroatom Bonds4 Synthetic Applications4.1 Reduction in Combination with a Proton Source4.1.1 Bouveault–Blanc Reduction4.1.2 Birch Reduction4.1.3 Reductive Deuteration4.1.4 Chemoselective Cleavage of Amides and Nitriles4.2 Difunctionalization of Alkenes and Alkynes5 Sodium Amides and Phosphides6 Conclusions and Outlook

Concurrent detection of cabozantinib as an anticancer agent and its major metabolites in human serum using fluorescence-coupled micellar liquid chromatography

A novel, highly sensitive, simple, and rapid strategy was designed and developed for simultaneous determination of cabozantinib (CBZ) as an anticancer agent and its main metabolites including monohydroxy sulfate (EXEL-1646), N -oxide (EXEL-5162(, amide cleavage product (EXEL-5366), and 6-desmethyl amide cleavage product sulfate) EXEL-1644). Measurements were done through a micellar liquid chromatography (MLC) method coupled with fluorescence detection. The high-performance liquid chromatography (HPLC) was performed using a Kinetex C18 100 Å column as well as acetonitrile, cetyltrimethylammonium bromide (CTAB; 0.2 mol.L −1 ), and tris buffer (pH 8.5) solutions as the mobile phase at a 40:50:10 (v/v) ratio. The method’s linearity (20 to 700 ng.mL −1 ), limit of detection (LOD; 2.11 to 3.69 ng.mL −1 ), limit of quantification (LOQ; 20 to 30 ng.mL −1 ), intra- and inter-day precisions (RSD < 4.00%), selectivity, recovery, and robustness were fully evaluated. According to the obtained results, the developed method can be used for simple and rapid (~35 min) quantification of CBZ as an anticancer drug and its major metabolites in human serum samples with high sensitivity and low cost.

Antitumor Effect of Hyperoside Loaded in Charge Reversed and Mitochondria-Targeted Liposomes.

IntroductionHyperoside (HYP), a flavonol glycoside compound, has been shown to significantly inhibit the proliferation of malignant tumors. Mitochondria serve as both “energy factories” and “suicide weapon stores” of cells. Targeted delivery of cytotoxic drugs to the mitochondria of tumor cells and tumor vascular cells is a promising strategy to improve the efficacy of chemotherapy.ObjectiveWe report a novel dual-functional liposome system possessing both extracellular charge reversal and mitochondrial targeting properties to enhance drug accumulation in mitochondria and trigger apoptosis of cancer cells.MethodsL-lysine was used as a linker to connect 2,3-dimethylmaleic anhydride (DMA) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to yield a new compound, DSPE-Lys-DMA (DLD). Then, DLD was mixed with other commercially available lipids to form charge reversed and mitochondria-targeted liposomes (DLD-Lip). The size, morphology, zeta potential, serum stability, and protein adsorption of the HYP loaded DLD-Lip (HYP/DLD-Lip) were measured. The release profile, cellular uptake, in vitro and in vivo toxicity, and anticancer activity of HYP/DLD-Lip were investigated.ResultsThe results showed that the mean diameter of the liposomes was less than 200 nm. The zeta potential of the liposomes was negative at pH 7.4. However, the zeta potential was positive at weak acidic pH values with the cleavage of the DMA amide. The charge reversion of HYP/DLD-Lip facilitated the cellular internalization and mitochondrial accumulation for enhanced antitumor effect. The strongest tumor growth inhibition (TGI 88.79%) without systemic toxicity was observed in DLD/HYP-Lips-treated CBRH-7919 tumor xenograft BALB/C mice.ConclusionThe charge reversed and mitochondria-targeted liposomes represented a promising anticancer drug delivery system for enhanced anticancer therapeutic efficacy.

Structure-Acid Lability Relationship of N-Alkylated α,α-Dialkylglycine Obtained via a Ugi Multicomponent Reaction.

Using the classical Ugi four-component reaction to fuse an amine, ketone, carboxylic acid, and isocyanide, here we prepared a short library of N-alkylated α,α-dialkylglycine derivatives. Due to the polyfunctionality of the dipeptidic scaffold, this highly steric hindered system shows an interesting acidolytic cleavage of the C-terminal amide. In this regard, we studied the structure-acid lability relationship of the C-terminal amide bond (cyclohexylamide) of N-alkylated α,α-dialkylglycine amides 1a–n in acidic media and, afterward, it was established that the most important structural features related to its cleavage. Then, it was demonstrated that electron-donating effects in the aromatic amines, flexible acyl chains (Gly) at the N-terminal and the introduction of cyclic compounds into dipeptide scaffolds, increased the rate of acidolysis. All these effects are related to the ease with which the oxazolonium ion intermediate forms and they promote the proximity of the central carbonyl group to the C-terminal amide, resulting in C-terminal amide cleavage. Consequently, these findings could be applied for the design of new protecting groups, handles for solid-phase synthesis, and linkers for conjugation, due to its easily modulable and the fact that it allows to fine tune its acid-lability.

Hydrogen-bond-assisted transition-metal-free catalytic transformation of amides to esters

The amide C-N cleavage has drawn a broad interest in synthetic chemistry, biological process and pharmaceutical industry. Transition-metal, luxury ligand or excess base were always vital to the transformation. Here, we developed a transition-metal-free hydrogen-bond-assisted esterification of amides with only catalytic amount of base. The proposed crucial role of hydrogen bonding for assisting esterification was supported by control experiments, density functional theory (DFT) calculations and kinetic studies. Besides broad substrate scopes and excellent functional groups tolerance, this base-catalyzed protocol complements the conventional transition-metal-catalyzed esterification of amides and provides a new pathway to catalytic cleavage of amide C-N bonds for organic synthesis and pharmaceutical industry.

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.

Formation, isomerization, and dissociation of tyrosine-containing tripeptide radical cations

Two series of tripeptide radical cations ([AYG] · +, [AYG · ]+; [GYG] · +, [G · YG]+ and [GYG · ]+) were successfully prepared via multistage collision-induced dissociation (CID) of a ternary complex of copper-ligand-tripeptide [Cu(L)Peptide]2+ (L=4′-chloro-2,2′:6′,2′′terpyridine (4Cl-tpy); Peptide=alanyl-tyrosyl-glycine (AYG) or glycyl-tyrosyl-glycine (GYG) tripeptide). The gas-phase isomerization and dissociation mechanism of isomeric AYG radical ions, and the different dissociation behaviors between AYG and GYG radical ions, have been obtained by observing their gas-phase dissociation reactions combined with density functional theory (DFT) calculation. Studies have revealed that: (1) [AYG · ]+ and [AYG] · + produced almost identical CID spectra (their main product ions are [x2+H] · + ions), suggesting that interconversion occurs prior to dissociation. (2) The dissociation paths of [A · YG]+ and [G · YG]+ are the same (both of which produces [b2−H] · + fragment ions by cleavage of amide C−N bond, indicating that [A · YG]+ cannot isomerize to [AYG · ]+ and [AYG] · +. DFT calculation gives the gas-phase stability order of these three peptide radical ions ([A · YG]+ > [AYG · ]+ > [AYG] · +) and their isomerization/dissociation energy barriers. Isomerization energy barrier (47.4 kcal/mol) of [AYG · ]+ ® [AYG] · + is lower than dissociation energy barrier (72.7 kcal/mol) of [AYG · ]+, but higher than that (44.3 kcal/mol) of [AYG] · +, thereby the gas-phase dissociation mechanism of [AYG · ]+ undergoes a two-step reaction: the first step is the isomerization process of [AYG · ]+ ® [AYG] · +, and the second step is the dissociation reaction of [AYG] · + ® [x2+H] · +, which produces [x2+H] · + fragment ions by cleavage of N-terminal Cα−C bond in [AYG] · +. (4) The gas-phase dissociation characteristics of [GYG] · + and [AYG] · + are dramatically different. [GYG] · + mainly produces [z2−H] · + by cleavage of the second N−Cα bond (counting from the N-terminal amino acid residue).

An innovative impurity profiling of Avanafil using LC and LC-MS/MS with in-silico toxicity prediction

Degradation of the drug can lead to the formation of toxic substance hence drug quality and stability is a major concern by pharma regulators. A Selected phosphodiesterase type 5 inhibitor drug Avanafil (AV) structure has amide, arylchloro and hydroxide as functional groups which can easily eliminated during hydrolysis. Henceforth, thoroughly chemical stability of AV was carried out according to ICH guideline Q1A (R2). The drug and marketed tablet formulation undergoes degradation in hydrolytic (acid, base, neutral), thermal, photolytic, oxidative conditions and forms a total new sixteen degradation products (D.P.s) which were identified by LC, characterized by LC-MS/MS and probable degradation mechanism for each stress conditions are proposed. All sixteen D.P.s were identified by optimized LC conditions; C18 column using 10 mM ammonium acetate: ACN (60:40, v/v), pH 4.5 as mobile phase at 0.9 mL min−1 of flow rate, 239 nm wavelength at 20 °C column temperature and the method being LC-MS compatible characterized by LC-MS/MS confirmed by relative retention time (RRT). The structure of D.P.s was confirmed from the fragmentation pattern obtained by LC-MS/MS and further probable degradation mechanism for each stress condition is proposed. The drug and its marketed tablet formulation showed similar degradation peaks which were confirmed using RRT, photodiode array (PDA) and LC-MS. Drug degradation happens due to nucleophilic substitution reaction, amide hydrolysis, electron withdrawing properties of amide, dechlorination and bond cleavage due to energy. The amide group in AV structure can undergo hydrolysis, while due to aryl chloride and hydroxide group in structure it undergoes photodecomposition. A comprehensive stress study reveals that AV is more prone to degrade in light, temperature and moisture; hence AV requires proper storage condition temperature below 25 °C with protection to light and moisture. In silico toxicity prediction of physicochemical properties revealed that all the physicochemical parameters of impurities were within the acceptable limit which indicates that no impurity is at any risk of toxicity. In detail, the LC-MS/MS compatible AV degradation study is fully validated as per ICH Q2 (R1) guideline.

Abiotic and biotic transformation of torasemide - Occurrence of degradation products in the aquatic environment

The pharmaceutical torasemide is an important loop diuretic and was 2017 one of the ten most prescribed drugs in Germany. Despite its detection in different compartments of the urban water cycle including drinking water, no studies were so far performed to elucidate its fate in the environment and the occurrence of transformation products (TPs). Therefore, we investigated the phototransformation, microbial degradation, transformation with human liver microsomes and anodic oxidation of torasemide to obtain good coverage of environmentally relevant degradation products. Overall sixteen products were identified, covering the following reaction mechanisms: aromatic and aliphatic hydroxylation, including further oxidation to carboxylic acids and quinone imines, amide cleavage, N-dealkylation, N-dearylation, and sulfonamide hydrolysis to sulfonic acids. Especially the formation of quinone imines could be of concern as they are highly reactive electrophiles. Torasemide itself was observed in all investigated wastewater treatment plant (WWTP) samples and wastewater-impacted surface waters. The maximum detected concentration was about 350 ng L−1. Only three of the sixteen transformation products were generally observed in at least one of the samples and the most frequently detected TPs were the human metabolites hydroxytorasemide (TP 364a) and carboxytorasemide (TP 378a). The complete removal of TP 364a during wastewater treatment was in agreement with the results of microbial degradation experiments. TP 364a was most likely transformed into TP 378a, which was microbially less degraded in lab experiments. Based on estimated concentrations, TP 378a could reach about 1 μg L−1 in the investigated wastewater matrices.

Coordination among Bond Formation/Cleavage in a Bifunctional-Catalyzed Fast Amide Hydrolysis: Evidence for an Optimized Intramolecular N-Protonation Event.

A density functional theory (DFT) computational analysis, using the ωB97X-D functional, of a rapid amide cleavage in 2-carboxyphthalanilic acid (2CPA), where the amide group is flanked by two catalytic carboxyls, reveals key mechanistic information: (a) General base catalysis by a carboxylate coupled to general acid catalysis by a carboxyl is not operative. (b) Nucleophilic attack by a carboxylate on the amide carbonyl coupled to general acid catalysis at the amide oxygen can also be ruled out. (c) A mechanistic pathway that remains viable involves general acid proton delivery to the amide nitrogen by a carboxyl, while the other carboxylate engages in nucleophilic attack upon the amide carbonyl; a substantially unchanged amide carbonyl in the transition state; two concurrent bond-forming events; and a spatiotemporal-base rate acceleration. This mechanism is supported by molecular dynamic simulations which confirm a persistent key intramolecular hydrogen bonding. These theoretical conclusions, although not easily verified by experiment, are consistent with a bell-shaped pH/rate profile but are at odds with hydrolysis mechanisms in the classic literature.

Supramolecular Catalysts Featuring Crown Ethers as Recognition Units

In its minimal expression, a supramolecular catalyst that acts on a single bound substrate consists of (i) a binding unit that is complementary to a non‐reacting part of the substrate, (ii) a reactive unit capable of catalyzing the reaction of the bound substrate, and (iii) a spacer connecting the two units in a geometry suitable for productive binding. When binding of two or more species is wanted, the number of binding units increases accordingly. This minireview deals with supramolecular catalysts that use crown ether units for the recognition of one or two reactants involved in a variety of reactions, including cleavage of esters and amides, hydride transfer from dihydropyridine to pyridinium, pyruvate decarboxylation, enolate allylation, radical addition to sodium metacrylate, reduction of NO2– anion to NO, C–H oxidation of aliphatic chains, and Diels‐Alder reactions.

Coupling of amides with ketones via C–N/C–H bond cleavage: a mild synthesis of 1,3-diketones

Amides react with enolizable ketones to give 1,3-diketones via C–N cleavage of amides and deprotonation of ketones.

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.

Selective C-C bond cleavage of amides fused to 8-aminoquinoline controlled by a catalyst and an oxidant.

Herein, copper-catalyzed direct C-C bond cleavage of amides fused to 8-aminoquinoline as a directing group to form urea in the presence of amines and dioxygen is reported. Compared to the previous C-H aminations of amides via C-H activation, this reaction presents a catalyst and oxidant controlled C-C bond cleavage strategy that enables amidation through a radical process. CuBr/Ag2CO3/O2 shows the best catalytic result at 150 °C. A series of aryl and alkyl amides were compatible with this transformation. Notably, this method provided access to cyclohexanone, one of the most important industrial materials. The pathway of this reaction was investigated.

FAAH inhibition as a preventive treatment for migraine: A pre-clinical study

BackgroundFatty-acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of endogenous fatty-acid amides, including the endocannabinoid anandamide (AEA). We previously reported that the peripherally restricted FAAH inhibitor URB937, which selectively increases AEA levels outside the central nervous system, reduces hyperalgesia and c-Fos expression in the trigeminal nucleus caudalis (TNC) and the locus coeruleus in an animal model of migraine based on nitroglycerin (NTG) administration. AimTo further investigate the relevance of FAAH inhibition in the NTG animal model of migraine by testing the effects of the globally active FAAH inhibitor URB597. MethodsOur experimental approach involved mapping neuronal c-Fos protein expression, measurement of AEA levels in brain areas and in trigeminal ganglia, evaluation of pain-related behavior and quantification of molecular mediators in rats that received URB597 (2 mg/kg i.p.) either before or after NTG administration (10 mg/kg, i.p.). ResultsPre-treatment with URB597 significantly reduced c-Fos immunoreactivity in the TNC and inhibited NTG-induced hyperalgesia in the orofacial formalin test. This behavioral response was associated with a decrease in neuronal nitric oxide synthase, calcitonin gene-related peptide and cytokine gene expression levels in central and peripheral structures. Administration of URB597 after NTG had no such effect. ConclusionsThe findings suggest that global FAAH inhibition may offer a therapeutic approach to the prevention, but not the abortive treatment, of migraine attacks. Further studies are needed to elucidate the exact cellular and molecular mechanisms underlying the protective effects of FAAH inhibition.

Na2CO3-promoted thioesterification via N–C bond cleavage of amides to construct thioester derivatives

A mild, efficient, and transition-metal-free catalytic strategy is developed to construct thioesters via selective N–C bond cleavage of Boc2-activated primary amides. This strategy is successfully carried out with stoichiometric Na2CO3 as the base and provides the corresponding products in moderate to excellent yields.