Amide Moiety Research Articles

Stereo‐ and Chemoselective Enrichment of sp3 Character in Post‐Ugi Morpholines

AbstractWe conducted a systematic study on synthesis and modification of morpholine core using Ugi adducts derived from propiolic acid and glycolaldehyde dimer. The assembly step involved triphenylphosphine‐promoted 6‐exo‐dig umpolung oxa‐Michael cyclization of Ugi‐derived hydroxypropargylamides yielding 2‐methylenemorpholin‐3‐one derivatives. Subsequent heterogeneous catalytic hydrogenation of the exocyclic double bond proceeded in a highly diastereoselective fashion establishing a relative cis configuration in the resulting sp3‐enriched morpholinone scaffold. Finally, chemoselective amide reduction with lithium aluminum hydride (LAH) allowed to obtain fully saturated morpholines while leaving the more sterically hindered exocyclic amide moiety intact. Taken together these findings outline the strategy for controlled reduction of the inherent rigidity of post‐Ugi scaffolds.

Structure-Activity Relationship Study of Splicing Modulators on Hsh155/SF3B1 through Chemical Synthesis and Yeast Genetics.

Meayamycins are synthetic analogs of the natural product FR901464 and exhibit potent anticancer activity against human cancers. They bind SF3B1 and PHF5A, components of the human spliceosome, and they alter pre-mRNA splicing. Detailed analysis of the active site led us to investigate a narrow pocket within the binding site that surrounds the α,β-unsaturated amide portion of meayamycin. We describe the synthesis and biological activity of two new analogs bearing a methyl substituent on the α or β position of the amide. With these analogs, we investigated the discrete interactions within the narrow region of SF3B1 using a human/yeast chimeric SF3B1 protein and found that the V1078 residue of SF3B1 affects compound binding at the amide moiety.

Biomimetic Dehydrogenative Intermolecular Formal Allylic Amidation of Branched α‐Olefins

AbstractAllylic amide moieties are commonly encountered in natural products and are privileged structures in pharmaceuticals and agrochemicals. Moreover, because allylic amide can be to converted into an array of high‐value motifs, they have been widely employed in organic synthesis. However, the development of catalytic systems for intermolecular allylic amidation of olefins, particularly branched α‐olefins, has proven to be challenging. Here, a biomimetic, synergistic catalytic method is reported that combines photoredox, cobalt, and Brønsted base catalysis for the synthesis of substituted allylic amides from branched α‐olefins and simple imides without using oxidants. This low‐cost, operationally simple method features a broad substrate scope and excellent functional group compatibility. Moreover, it is successfully used for the functionalization of several structurally complex molecules demonstrating the method's potential utility for medicinal chemistry applications. Mechanistic studies revealed that C(sp3)─N bond formation is mediated by a nitrogen‐centered radical intermediate, which is generated via a sequence involving deprotonation and single‐electron oxidation.

Complexes of Iron(II), Cobalt(II), and Nickel(II) with DOTA-Tetraglycinate for pH and Temperature Imaging Using Hyperfine Shifts of an Amide Moiety.

Paramagnetic complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA4-) derivatives have shown potential for molecular imaging with magnetic resonance. DOTA-tetraglycinate (DOTA-4AmC4-) coordinated with lanthanide metal ions (Ln3+) demonstrates pH/temperature sensing with Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) and Chemical Exchange Saturation Transfer (CEST), respectively, detecting nonexchangeable (e.g., -CHy, where 3 ≥ y ≥ 1) and exchangeable (e.g., -OH or -NHx, where 2 ≥ x ≥ 1) protons. Herein, we report paramagnetic complexes of divalent transition-metal ions (M2+ = Fe2+, Co2+, Ni2+) with DOTA-4AmC4- that endow a unique amide proton (-NH) moiety for pH/temperature sensing. Crystallographic data reveal that DOTA-4AmC4- coordinates with M2+ through oxygen and nitrogen donor atoms, ranging in coordination numbers from 8-coordinate in Fe(II)DOTA-4AmC2-, 7-coordinate in Co(II)DOTA-4AmC2-, and 6-coordinate in Ni(II)DOTA-4AmC2-. The -CHy protons in M(II)DOTA-4AmC2- displayed modest pH/temperature sensitivities, but -NH protons exhibited higher intensity, suggesting prominent BIRDS properties. The pH sensitivity was the highest for Ni(II)DOTA-4AmC2- (1.42 ppm/pH), followed by Co(II)DOTA-4AmC2- (0.21 ppm/pH) and Fe(II)DOTA-4AmC2- (0.16 ppm/pH), whereas temperature sensitivities were comparable (i.e., 0.22, 0.13, and 0.17 ppm/°C, respectively). The CEST image contrast for -NH in M(II)DOTA-4AmC2- was much weaker compared to that of Ln(III)DOTA-4AmC-. Given its high pH sensitivity and low cytotoxicity, Ni(II)DOTA-4AmC2- shows promise for use in preclinical BIRDS-based pH imaging.

Fabrication of amorphous lamellar freestanding poly(N‐dodecyl acrylamide) films and their mechanical properties

AbstractAn amorphous lamellar freestanding film composed of poly(N‐dodecyl acrylamide) (pDDA) was prepared by annealing a micrometer‐thick film under humid conditions (humid‐annealing). pDDA was blade‐coated onto a glass substrate, and its lamellar formation was studied by XRD and polarized optical microscopy (POM). The XRD pattern indicates that pDDA formed a highly oriented lamellar structure by humid‐annealing at 80 °C for 6 h. Moreover, the POM image of the cross‐section of the film indicates that lamellar formation started at the polymer–substrate interface, and the amorphous lamella covered the entire film area without randomly oriented regions. In contrast, the open Nicol microscopic image exhibited large cracks in the highly oriented film owing to shrinkage of the film. A crack‐free film was prepared using water‐saturated chloroform as the solvent for blade coating. Water is thought to adsorb to an amide moiety to induce a ‘pre‐lamellar’ structure in the solution. The formation of pre‐lamellae and the decrease in the humid‐annealing temperature reduced the shrinkage of the film by lamellar formation to form a crack‐free film. The mechanical properties of the crack‐free, freestanding pDDA films were studied using a simple tensile test. The film became increasingly stronger with the formation of an amorphous lamellar structure. These results indicate that the mechanical properties of polymer films can be improved without crystallization. © 2024 The Author(s). Polymer International published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

The structure and properties of monoprotonated propiolamide and diprotonated cellocidin

Abstract Propiolamide and cellocidin were investigated in superacidic media. In both acetylenic amides, the amide moiety is immediately monoprotonated in anhydrous HF, HF/SbF5 and HF/BF3. An increase of SbF5 does not lead to a more highly protonated species. The salts were characterized by low-temperature Raman, NMR and room temperature IR spectroscopy, as well as by single-crystal X-ray diffraction. The experimental data are discussed together with results of quantum-chemical calculations on the M06-2X/aug-cc-pVTZ level of theory, which are consistent with the observation of pure monoprotonation. The second protonation of the amide moiety or the triple bond is not observed due to the high positive charge caused by the monoprotonation.

TEMPO‐Catalyzed Continuous‐Flow Aerobic Oxidations of Alcohols on Silica

Abstract2,2,6,6′‐Tetramethylpiperidine‐N‐oxyl (TEMPO) is a highly efficient oxidation catalyst, valued for its environmentally benign nature, particularly in comparison to transition‐metal catalysts. Despite their merits, TEMPO‐based catalysts are not notably cost‐effective. Immobilization of TEMPO onto supports offers a promising strategy to overcome this limitation. In this work, we present the synthesis and application of immobilized TEMPO catalysts 2–5, prepared via a straightforward condensation reaction, for the aerobic oxidation of alcohols. These catalysts demonstrate remarkable activity for alcohol oxidations under continuous‐flow conditions, employing nitric acid as the co‐catalyst. Notably, catalyst 2 immobilized by COOH silica gel exhibits outstanding performance for the oxidation of benzyl alcohol by oxygen gas, achieving a turnover frequency (TOF) of 15 h−1 and a turnover number (TON) exceeding 300. Catalyst 2 further demonstrates broad substrate scope, effectively oxidizing primary, secondary, and benzylic alcohols. Post‐reaction analysis of spent catalyst 2 reveals that deactivation primarily stems from nitrosation of the N−O bond. Interestingly, the amide moiety remains intact despite the harsh acidic reaction conditions.

The Investigation of Hsp90C-Terminal Inhibitors Containing Amide Bioisosteres.

Heat Shock Protein 90 (Hsp90) is responsible for the proper folding and maturation of ~400 client protein substrates, many of which are directly associated with the ten hallmarks of cancer. Hsp90 is a great target for cancer therapy including melanoma, since Hsp90 inhibition can disrupt multiple oncogenic pathways simultaneously. In this study, we report the synthesis and anti-proliferative activity manifested by a series of Hsp90 C-terminal inhibitors against mutant BRAF and wild-type BRAF melanoma cells. Furthermore, we explored structure-activity relationships (SAR) for the amide moiety of 6 (B1), a novel Hsp90C-terminal inhibitor via introduction of amide bioisosteres. Compound 6 displayed an IC50 of 1.01 μM, 0.782 μM, 0.607 μM and 1.413 μM against SKMel173, SKMel103, SKMel19 and A375 cells, respectively.

Soloxolone N-3-(Dimethylamino)propylamide Restores Drug Sensitivity of Tumor Cells with Multidrug-Resistant Phenotype via Inhibition of P-Glycoprotein Efflux Function.

Multidrug resistance (MDR) remains a significant challenge in cancer therapy, primarily due to the overexpression of transmembrane drug transporters, with P-glycoprotein (P-gp) being a central focus. Consequently, the development of P-gp inhibitors has emerged as a promising strategy to combat MDR. Given the P-gp targeting potential of soloxolone amides previously predicted by us by an absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis, the aim of the current study was to experimentally verify their P-gp inhibitory and MDR reversing activities in vitro. Screening of soloxolone amides as modulators of P-gp using molecular docking and cellular P-gp substrate efflux assays revealed the ability of compound 4 bearing a N-3-(dimethylamino)propylamide group to interact with the active site of P-gp and inhibit its transport function. Blind and site-specific molecular docking accompanied by a kinetic assay showed that 4 directly binds to the P-gp transmembrane domain with a binding energy similar to that of zosuquidar, a third-generation P-gp inhibitor (ΔG = -10.3 kcal/mol). In vitro assays confirmed that compound 4 enhanced the uptake of Rhodamine 123 (Rho123) and doxorubicin (DOX) by the P-gp-overexpressing human cervical carcinoma KB-8-5 (by 10.2- and 1.5-fold, respectively (p < 0.05, unpaired t-test)) and murine lymphosarcoma RLS40 (by 15.6- and 1.75-fold, respectively (p < 0.05, unpaired t-test)) cells at non-toxic concentrations. In these cell models, 4 showed comparable or slightly higher activity than the reference inhibitor verapamil (VPM), with the most pronounced effect of the hit compound in Rho123-loaded RLS40 cells, where 4 was 2-fold more effective than VPM. Moreover, 4 synergistically restored the sensitivity of KB-8-5 cells to the cytotoxic effect of DOX, demonstrating MDR reversal activity. Based on the data obtained, 4 can be considered as a drug candidate to combat the P-gp-mediated MDR of tumor cells and semisynthetic triterpenoids, with amide moieties in general representing a promising scaffold for the development of novel therapeutics for tumors with low susceptibility to antineoplastic agents.

Design, Synthesis, and Bioactivity Evaluation of Novel 1,3,4-Thiadiazole Sulfone-Derived Compounds Incorporating an Amide Moiety as Active Antibacterial Agents

Design, Synthesis, and Bioactivity Evaluation of Novel 1,3,4-Thiadiazole Sulfone-Derived Compounds Incorporating an Amide Moiety as Active Antibacterial Agents

First Demonstration of In Vivo PDE11A4 Target Engagement for Potential Treatment of Age-Related Memory Disorders.

PDE11A4 is a target of interest for the treatment of age-related memory disorders. A previous report from our laboratories described an amide series of potent, selective PDE11A4 inhibitors that was metabolically unstable. Investigation of heterocyclic amide isosteres for the labile amide moiety revealed distinct structure-activity relationships and identified several compounds with potency comparable to the amide series. This manuscript describes the characterization of structure-activity and structure-property relationships in this set, leading to the identification of an orally bioavailable, brain-penetrant, selective and potent PDE11A4 inhibitor. Target engagement experiments demonstrated PDE11A4 inhibition in the hypothalamus of mice that was absent in PDE11A4 knock out animals.

Modular Synthesis of α-Aryl Acrylamido Carboxylic Acids by Triple C-F Bond Cleavage of (Trifluoromethyl)alkenes with Unprotected Amino Acids.

A straightforward and efficient strategy for the construction of tertiary and secondary α-aryl acrylamido carboxylic acids is reported. This N-acrylation protocol of unprotected amino acids is achieved by triple C-F bond cleavage of (trifluoromethyl)alkenes. This method features mild conditions, is operationally simple, is free of transition metals and racemization, can be used on a gram scale, and is compatible with various functional moieties. Mechanistic studies indicate that oxygen atom exchange happens among H2O, NaOH, and amino acids, and the oxygen atom of the amide moiety of the product is incorporated by the ipso-defluorooxylation of (trifluoromethyl)alkene.

Discovery of Two Novel Phthalide Phytotoxins from the Wheat Tan Spot Fungal Pathogen Pyrenophora tritici-repentis.

The Dothideomycete fungal pathogen Pyrenophora tritici-repentis (Ptr) is the causal agent of the tan spot disease of wheat. The proteinaceous necrotrophic effectors ToxA and ToxB are well characterized. A nonproteinaceous effector called ToxC has also been partially characterized. Ptr produces a number of other small molecular weight compounds, but these remain poorly characterized. In this study, two novel compounds, designated ToxE1 and ToxE2, capable of inducing chlorotic symptoms on wheat leaves in a cultivar-specific manner, were purified from Ptr liquid cultures. There is no evidence that these compounds correspond to ToxC. Most isolates produced ToxE1, ToxE2, or both, and both compounds were detected in infected wheat leaves. The structures of both analogues were elucidated by NMR spectroscopy and comprise a phthalide core structure with an amide moiety. We postulate that these compounds have a general phytotoxic effect and may have an ancillary role in disease development.

Enhanced Efficiency of Amide‐Substituted Quinuclidine‐Boranes as Hydridic Hydrogen Atom Transfer Catalysts for Photoinduced Hydroalkylation of Unactivated Olefins†

Comprehensive SummaryAn amide‐substituted quinuclidine‐borane has been identified as a more efficient hydridic hydrogen atom transfer (HAT) catalyst for the hydroalkylation of unactivated olefins under visible‐light irradiation. 1H NMR titration experiments reveal that the amide moiety of the quinuclidine‐borane catalyst forms stronger hydrogen bonds with the carbonyl substrates, thereby improving the reaction yields. Furthermore, it was found that the reaction yields correlate well with the association constant between the quinuclidine‐borane catalyst and the carbonyl substrate. A scale‐up reaction using a continuous‐flow photoreactor has also been demonstrated.

Synthesis of Lactams via a Chiral Phosphoric Acid-Catalyzed Aniline Cyclization.

The enantioenriched lactams disclosed in this work are synthesized concisely in four steps. In the penultimate reaction, a benzylamine species complexes with a chiral phosphoric acid to produce benzo-fused δ-lactams equipped with an all-carbon quaternary stereocenter. Partial and full reductions were carried out on the ester and amide moieties, and a Suzuki-Miyaura cross-coupling expanded the molecule from the aromatic ring. Finally, our method was successful at a >1 g scale, indicating that the method has important practical use.

Selective Cleavage and Structural Stability of Double Crosslinked Aromatic Polyamide Porous Materials

AbstractA porous, crosslinked aromatic polyamide having COCl and COOH groups (referred to as PA herein) prepared had a mesoporous structure and comprised agglomerates of particles with average diameters of approximately 30 nm. The PA was found to swell with significant deformation in response to water vapor, but was almost unchanged after exposure to toluene vapor. The polymeric structure returned to its original porous morphology after removal of the solvents, demonstrating that the PA possessed affinity for specific solvents and shape memory. The chemical composition and porous structure of the PA were also not affected by heating to 330 °C. The COCl groups in the PA could be modified by reaction with 2,4,6‐triaminopyrimidine (TAP), resulting in a doubly crosslinked structure based on the reaction with the TAP as well as the existing amide moieties in the polymer. The degree of modification was highly dependent on the reaction solvent used. The porous structure of the PA was essentially unchanged after this modification. The TAP‐based crosslinks in the modified PA could be selectively cleaved along with vaporization of the TAP by heating at 330 °C, which no change to the porous structure. Thus, the PA showed excellent heat resistance and structural stability.

Design, sonic solvothermal synthesis, synergistically improved bioactivity and photo-self-degradability of sulfonyl phenylpyrazole two-site alkaloids fused amides and amine units as GABA receptor inhibitors

Amide alkaloids and amine alkaloids play an important role in insecticidal and antibacterial activity, respectively. What activity is produced when they fuse with phenylpyrazole parent structure to form a two-site alkaloid? A series of sulfonyl phenylpyrazole alkaloids (PAs) incorporating amides and amine two-site moiety were diversified designed and one-pot sonic solvothermal synthesized for the first time, which were fully characterized and crystal analysis. Preliminary bioassays indicated that PA5b had excellent insecticidal bioactivity against 3rd instar larvae of P. xylostella and M. separata and 4.1 times more bacteriostatic activity against A. tumefaciens than parent compound. The results of molecular docking revealed that amides and amine units in PAs had strong synergistic interactions with GABA receptors, such as hydrogen, halogen and hydrophobic bonds, resulting in high insecticidal activity and strong bacteriostatic effects through two-site combination. Furthermore, PA5b formed π-cation interactions with the GABA receptor, verified by crystal structure and Hirshfeld surface analysis. Photophysical tests exhibited that amide and amine moiety of PAs expanded the conjugation system to improve their light absorption and fluorescence, and PAs possessed photo-self-degradability under simulated natural light irradiation, which could be reconverted to phenylpyrazole parental fragments, thus improving their bioactivity and reducing residues. The structure-properties relationship of sulfonyl phenylpyrazole two-site alkaloids was analyzed by CoMFA modeling and Hirshfeld surface for the presence of bioactive sites at the sulfone and amine sites. These findings lay the foundation for the development of two-site alkaloid insecticides and provide new ideas for their natural degradation and fluorescent detection.

Aminophenylboronic acid-modified nitrogen-doped graphene quantum dots and their applications in lysine sensing based on interplaying fluorescent mechanisms.

Using nitrogen-doped graphene quantum dots (N-GQDs) and 3-aminophenylboronic acid (APBA), a novel fluorescence nanosensorwas developed. This nanosensor exhibits high selectivity and sensitivity for lysine detection. Its sensing mechanism involves the suppression of electron transfer from APBA to the N-GQDs unit, thereby inhibiting photoinduced electron transfer and initiating internal charge transfer. At an optimal pH of 7, the protonated α-amine and ε-amine groups of lysine interact with the amide and boronic acid moieties, respectively. This interaction results in a redshift of fluorescence, substantially enhancing the response signal. A linear response was observed within a concentration range 0.40-3.01μM, with the detection limit being 0.005μM. A similar linear range was also achieved for the determination of lysine in human serum. Density functional theory calculations correlating molecular orbits and geometries support UV-vis and fluorescence findings. Additionally, the nanosensor wassuccessfully applied to detect lysine in living cells and real samples, including milk and honey. For practical application, we construct a lysine-specific sensing platform using a commercial chip (TCS34725) that collects red, blue, and green signals, thereby facilitating the convenient use of the nanosensor. Overall, this study offers new perspectives on the development and application of fluorescent nanosensors for detecting individual amino acids.

Self-Assembly of Thienopyrrole-Fused Thiadiazoles Containing an Amide Linker: Control of Supramolecular Polymerization Mechanism and Chiroptical Properties by Trialkoxy Side Chains.

Three thienopyrrole-fused thiadiazole (TPT) fluorescent dyes featuring a common amide linker and different alkoxy substituents on peripheral trialkoxybenzene moieties were synthesized, and their self-assembly behavior in solution was investigated. The obtained results revealed a substantial steric effect of the alkoxy substituents on the supramolecular polymerization mechanism, which results from a combination of π-stacking and hydrogen (H)-bonding interactions. Detailed spectroscopic measurements revealed that with increasing steric demand of the substituents, the supramolecular polymerization processes in pure methylcyclohexane (MCH) or a mixture of MCH and toluene become temperature-sensitive and enthalpically favorable, resulting in a change from the isodesmic assembly mechanism to the cooperative mechanism. Theoretical calculations suggested that in TPTs with bulky substituents, steric hindrance causes the H-bonding array of the amide moieties to be aligned along the stacking axis of the π-systems; thus, the H-bonding interactions are strengthened compared to those in TPTs with less bulky substituents, compensating for the weakened π-stacking interactions. A chiral TPT derivative with (S) stereogenic centers was found to form homochiral helical supramolecular assemblies that generate discernible circularly polarized luminescence. Achiral TPTs also generate helical assemblies to which preferential helicity can be imparted through the external chiral bias of the solvents (R)- and (S)-limonene.

Chirality Interplay between the Interior and Exterior of Metal–Organic Cages

AbstractA series of metal–organic cages featuring two stereogenic elements, in terms of the twisting of amide moieties within the ligand backbones and the rotation of diazaanthracene segments along the ligand ridges, were exploited. These two chiral components are correlative and serve as relays for transmitting chirality information between the internal and external cages. The chirality information induced by a chiral guest inside the cage cavity can pass through the cage framework and influence the orientation of the diazaanthracene segments on the periphery of the cage. In turn, the chirality of a stereogenic center within the diazaanthracene segments can transfer back into the cavity, enabling discrimination of enantiomeric guests.