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Chemistry (Weinheim An Der Bergstrasse,... Aug 2023Amide derivatization is useful to access valuable organic compounds considering the ready availability of molecules containing amide functionality. Current methods to...
Amide derivatization is useful to access valuable organic compounds considering the ready availability of molecules containing amide functionality. Current methods to derivatize amide mainly focus on the synthesis of carbonyl-containing compounds and amines. Incorporating both parts of the initial amide into the new derivatives is rare. Herein, we describe a simple and practical amide derivatization through amino acid insertion to prepare more complex amides. This insertion is applicable to a wide range of amino acids and more importantly, the chiral information is completely conserved during the insertion. Comparison of this insertion strategy with conventional amide synthesis demonstrates the synthetic advantages of this new protocol.
Topics: Amides; Amino Acids
PubMed: 37259820
DOI: 10.1002/chem.202301729 -
Nature Communications Jun 2023General anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating...
General anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating inhibitory ion channels and inhibiting excitatory ion channels, with the net effect of dampening nervous system excitability. Neuromuscular blockers act by antagonizing nicotinic acetylcholine receptors at the motor endplate; these excitatory ligand-gated ion channels are also inhibited by general anesthetics. The mechanisms by which anesthetics and neuromuscular blockers inhibit nicotinic receptors are poorly understood but underlie safe and effective surgeries. Here we took a direct structural approach to define how a commonly used anesthetic and two neuromuscular blockers act on a muscle-type nicotinic receptor. We discover that the intravenous anesthetic etomidate binds at an intrasubunit site in the transmembrane domain and stabilizes a non-conducting, desensitized-like state of the channel. The depolarizing neuromuscular blocker succinylcholine also stabilizes a desensitized channel but does so through binding to the classical neurotransmitter site. Rocuronium binds in this same neurotransmitter site but locks the receptor in a resting, non-conducting state. Together, this study reveals a structural mechanism for how general anesthetics work on excitatory nicotinic receptors and further rationalizes clinical observations in how general anesthetics and neuromuscular blockers interact.
Topics: Humans; Receptors, Nicotinic; Anesthetics; Anesthetics, Intravenous; Anesthetics, General; Etomidate; Muscles
PubMed: 37264005
DOI: 10.1038/s41467-023-38827-5 -
The Journal of Clinical Endocrinology... Jan 2021Endogenous Cushing syndrome (CS) is characterized by excess cortisol secretion, which is driven by tumorous secretion of corticotropin in the majority of patients.... (Review)
Review
CONTEXT
Endogenous Cushing syndrome (CS) is characterized by excess cortisol secretion, which is driven by tumorous secretion of corticotropin in the majority of patients. Untreated, CS results in substantial morbidity and mortality. Tumor-directed surgery is generally the first-line therapy for CS. However, hypercortisolism may persist or recur postoperatively; in other cases, the underlying tumor may not be resectable or its location may not be known. Yet other patients may be acutely ill and require stabilization before definitive surgery. In all these cases, additional interventions are needed, including adrenally directed medical therapies.
EVIDENCE ACQUISITION
Electronic literature searches were performed to identify studies pertaining to adrenally acting agents used for CS. Data were abstracted and used to compile this review article.
EVIDENCE SYNTHESIS
Adrenally directed medical therapies inhibit one or several enzymes involved in adrenal steroidogenesis. Several adrenally acting medical therapies for CS are currently available, including ketoconazole, metyrapone, osilodrostat, mitotane, and etomidate. Additional agents are under investigation. Drugs differ with regards to details of their mechanism of action, time course of pharmacologic effect, safety and tolerability, potential for drug-drug interactions, and route of administration. All agents require careful dose titration and patient monitoring to ensure safety and effectiveness, while avoiding hypoadrenalism.
CONCLUSIONS
These medications have an important role in the management of CS, particularly among patients with persistent or recurrent hypercortisolism postoperatively or those who cannot undergo tumor-directed surgery. Use of these drugs mandates adequate patient instruction and close monitoring to ensure treatment goals are being met while untoward adverse effects are minimized.
Topics: Adrenal Glands; Cushing Syndrome; Etomidate; Humans; Imidazoles; Ketoconazole; Metyrapone; Mitotane; Molecular Targeted Therapy; Pyridines
PubMed: 33118025
DOI: 10.1210/clinem/dgaa778 -
Organic & Biomolecular Chemistry Sep 2022As a major class of foldamers, aromatic oligoamide foldamers have attracted intense interest. The rigidity of aromatic residues and amide linkages allows the development... (Review)
Review
As a major class of foldamers, aromatic oligoamide foldamers have attracted intense interest. The rigidity of aromatic residues and amide linkages allows the development of foldamers with readily predictable, stable conformations. Aromatic oligoamide foldamers having backbones fully constrained by intramolecular hydrogen bonds have attracted wide attention. Depending on their lengths, such foldamers adopt crescent or helical conformations with highly negative inner cavities. Cyclizing the backbone of the aromatic oligoamides affords the corresponding macrocycles which are characterised by persistent shapes and non-deformable inner cavities. With their defined, inner cavities, such aromatic oligoamide foldamers and macrocycles have served as hosts for cationic and polar guests, and as transmembrane channels for transporting ions and molecules. Recent synthetic progress resulted in the construction of multi-turn hollow helices that offer three-dimensional inner pores with adjustable depth. Reducing the number of backbone-constraining hydrogen bonds leads to oligoamides which, with their partially constrained backbones, undergo either solvent- or guest-dependent folding. One class of such aromatic olgioamide foldamders, which offer multiple backbone amide NH groups as hydrogen-bond donors, are designed to bind anions with adjustable affinities.
Topics: Amides; Anions; Hydrogen Bonding; Molecular Conformation; Molecular Structure
PubMed: 36040143
DOI: 10.1039/d2ob01467j -
Bioorganic & Medicinal Chemistry Letters Sep 2019Isosteric replacement of amide groups is a classic practice in medicinal chemistry. This digest highlights the applications of most commonly employed amide isosteres in... (Review)
Review
Isosteric replacement of amide groups is a classic practice in medicinal chemistry. This digest highlights the applications of most commonly employed amide isosteres in drug design aiming at improving potency and selectivity, optimizing physicochemical and pharmacokinetic properties, eliminating or modifying toxicophores, as well as providing novel intellectual property of lead compounds.
Topics: Amides; Chemistry, Pharmaceutical; Drug Design; Molecular Structure
PubMed: 31377035
DOI: 10.1016/j.bmcl.2019.07.033 -
Journal of the American Chemical Society Jul 2023The amidated peptides are an important class of biologically active compounds due to their unique biological properties and wide applications as potential peptide drugs...
The amidated peptides are an important class of biologically active compounds due to their unique biological properties and wide applications as potential peptide drugs and biomarkers. Despite the abundance of free amide motifs (Asn, Gln, and C-terminal amide) in native peptides, late-stage modification of the amide unit in naturally occurring peptides remains very rare because of the intrinsically weak nucleophilicity of amides and the interference of multiple competing nucleophilic residues, which generally lead to undesired side reactions. Herein, chemoselective arylation of amides in unprotected polypeptides has been developed under an air atmosphere to afford the -aryl amide peptides bearing various functional motifs. Its success relies on the combination of gold catalysis and silver salt to differentiate the relative inert amide among a collection of reactive nucleophilic amino acid residues (e.g., -NH, -OH, and -COOH), favoring the C-N bond coupling toward amides over other more nucleophilic groups. Experimental and DFT studies reveal a crucial role of the silver cation, which serves as a transient coordination mask of the more reactive reaction sites, overcoming the inherently low reactivity of amides. The excellent biocompatibility of this strategy has been applied to functionalize a wide range of peptide drugs and complex peptides. The application could be further extended to peptide labeling and peptide stapling.
Topics: Silver; Peptides; Amides; Amino Acids; Catalysis
PubMed: 37377433
DOI: 10.1021/jacs.3c03840 -
ChemSusChem Mar 2022Formation of amide bonds is of immanent importance in organic and synthetic medicinal chemistry. Its presence in "traditional" small-molecule active pharmaceutical... (Review)
Review
Formation of amide bonds is of immanent importance in organic and synthetic medicinal chemistry. Its presence in "traditional" small-molecule active pharmaceutical ingredients, in linear or cyclic oligo- and polypeptidic actives, including pseudopeptides, has led to the development of dedicated synthetic approaches for the formation of amide bonds starting from, if necessary, suitably protected amino acids. While the use of solid supported reagents is common in traditional peptide synthesis, similar approaches targeting amide bond formation in continuous-flow mode took off more significantly, after a first publication in 2006, only a couple of years ago. Most efforts rely upon the transition of traditional approaches in flow mode, or the combination of solid-phase peptide synthesis principles with flow chemistry, and advantages are mainly seen in improving space-time yields. This Review summarizes and compares the various approaches in terms of basic amide formation, peptide synthesis, and pseudopeptide generation, describing the technological approaches and the advantages that were generated by the specific flow approaches. A final discussion highlights potential future needs and perspectives in terms of greener and more sustainable syntheses.
Topics: Amides; Amino Acids; Chemistry Techniques, Synthetic; Peptides; Solid-Phase Synthesis Techniques
PubMed: 35015338
DOI: 10.1002/cssc.202102708 -
Angewandte Chemie (International Ed. in... Dec 2022In contrast to ketones and carboxylic esters, amides are classically seen as comparatively unreactive members of the carbonyl family, owing to their unique structural... (Review)
Review
In contrast to ketones and carboxylic esters, amides are classically seen as comparatively unreactive members of the carbonyl family, owing to their unique structural and electronic features. However, recent decades have seen the emergence of research programmes focused on the selective activation of amides under mild conditions. In the past four years, this area has continued to rapidly develop, with new advances coming in at a fast pace. Several novel activation strategies have been demonstrated as effective tools for selective amide activation, enabling transformations that are at once synthetically useful and mechanistically intriguing. This Minireview comprises recent advances in the field, highlighting new trends and breakthroughs in what could be called a new age of amide activation.
Topics: Amides; Catalysis; Esters; Ketones
PubMed: 36124856
DOI: 10.1002/anie.202212213 -
Chemical Communications (Cambridge,... Sep 2022Incorporating a chiral non-coordinating substitution at the N-terminal end within peptoids facilitates regio-selective amide bond hydrolysis mediated by a transition...
Incorporating a chiral non-coordinating substitution at the N-terminal end within peptoids facilitates regio-selective amide bond hydrolysis mediated by a transition metal ion and/or an acidic buffer as evident by X-ray crystallographic analysis, supported by ESI-MS. This opens up a new direction for peptidomimetic compounds towards future application in chemistry, biology and medicine.
Topics: Amides; Crystallography, X-Ray; Hydrolysis; Peptoids
PubMed: 35979818
DOI: 10.1039/d2cc02717h -
Drug Design, Development and Therapy 2023Remimazolam tosilate (RT) is a novel ultrashort-acting γ-aminobutyric acid subtype A (GABA) agonist, with several advantages including rapid induction and recovery,... (Randomized Controlled Trial)
Randomized Controlled Trial Clinical Trial
BACKGROUND
Remimazolam tosilate (RT) is a novel ultrashort-acting γ-aminobutyric acid subtype A (GABA) agonist, with several advantages including rapid induction and recovery, stable haemodynamics, and mild respiratory inhibition. However, studies have not been conducted to explore the haemodynamic effects of RT in elderly hypertensive subjects undergoing non-cardiac surgery. Therefore, we sought to compare the effects of anaesthesia induction using different doses of RT and etomidate on the haemodynamics of this group of patients.
METHODS
Patients were recruited into this single-center, prospective, randomized, double-blind trial from October 2022 to June 2023. A total of 150 hypertensive elderly undergoing non-cardiac surgery were randomly assigned into 0.2 mg/kg RT group (Group RL), 0.3 mg/kg RT group (Group RH) and 0.3 mg/kg etomidate group (Group E). The primary outcome of the study was haemodynamic changes (mean arterial pressure fluctuation value -∆MAP and heart rate fluctuation value -∆HR) observed during anaesthesia induction. Secondary outcomes included incidence of adverse cardiovascular events and adverse drug reactions (injection pain and myoclonus), cumulative doses of vasoactive drugs and vital signs at different time points.
RESULTS
Patients in Group E and Group RL had significantly lower haemodynamic fluctuations (∆MAP), lower incidence of hypotension and cumulative dose of ephedrine than subjects in Group RH. Patients in groups RL and RH had significantly lower incidence of injection pain and myoclonus compared with patients in group E. The results showed no statistically significant differences in ∆HR, hypertension, bradycardia, tachycardia, and time to loss of eye-opening reflex and start of intubation, and vital signs at different time points among the three groups.
CONCLUSION
Use of low-dose RT (0.2 mg/kg) for induction of non-cardiac surgical anaesthesia in elderly hypertensive patients is more effective in maintaining haemodynamic stability and has fewer adverse effects compared with etomidate.
Topics: Humans; Aged; Etomidate; Myoclonus; Prospective Studies; Hemodynamics; Hypertension; Anesthesia, General; Pain; Propofol
PubMed: 37789968
DOI: 10.2147/DDDT.S425590