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Breast cancer stands as the cancer with the highest incidence and mortality rates among women globally, in which triple-negative breast cancer has been ranked as the most difficult one. Bazedoxifene (BZA), a third-generation selective estrogen receptor modulator (SERM), has been exhibited notable inhibitory effect on both hormone-dependent breast cancer cells and triple-negative breast cancer cells, but showing very low in vivo effeacy. In order to obtain more effective antitumor derivatives than BZA, we have employed a structurally diverse design and synthesis of 57 novel 2-phenylindole amides for detecting their cytotoxities against triple-negative mammary cancer cell line, CMT-7364. Among them, 21 compounds demonstrated significant inhibitory activity against CMT-7364 cells (IC50 < 20 µM). Notably, compound 49 stood out, displaying both similar tumor cell inhibition (20 % reduce in IC50 value) and higher selectivity (4.6 times higher in SI value), compared to Bazedoxifene. Additionally, compound 49 exhibited desirable antitumor effects in a CMT-7364 cell-derived mouse in vivo model, achieving the best inhibition rate of 43.1 % and establishing strong molecular bonding with GP130. Our findings are also supported by comprehensive SAR and 3D-QSAR analyses. Furthermore, the best potent compound 49 was determined to block the cell cycle of canine breast cancer cells in the G0G1 phase in a time-dependent manner, by inducing apoptosis and autophagy. In conclusion, this work presents a valuable lead compound as a potential GP130 inhibitor against triple-negative breast cancer cell lines, laying the foundation for further antitumor drug development.
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α-Silylalkylamines and α-borylalkylamines are versatile synthetic intermediates and attractive scaffolds found in pharmaceutical drugs and agrochemicals. Despite great progress on synthetic methods for preparation of α-silylalkylamines or α-borylalkylamines, there are no general strategies for preparation of α-boryl-α-silylalkylamines and the reactivity has not been explored. Here we report deoxygenative geminal silylboration of amides using silylboronates in the presence of alkoxide base catalyst, producing α-boryl-α-silylalkylamines. The silicon and boron groups in α-boryl-α-silylalkylamines are found to be utilized to chemoselective transformations, such as protonation and alkylation. This protocol serves various α-silylalkylamines and α-borylalkylamines from readily available amides.
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Twelve polyphenol derivatives were obtained in a protective activity-guided isolation from the Portulaca oleracea L. extract on a cell model of human umbilical vein endothelial cells (HUVECs) under diethylhexyl phthalate (DEHP) exposure. Among them, methyl (3,4,5-trimethoxybenzoyl) valylprolinate (PP-10) performed the most protective activity and inhibited DEHP exposure-induced HUVECs' apoptosis. PP-10 also inhibited the DEHP-induced inflammatory cytokines (TNF-α, IL-6, IL-1ß, and IL-8) and adhesion molecule (ICAM-1 andVCAM-1) overexpression. Furthermore, DEHP-induced NLRP3 inflammasomes' and NF-κB signaling pathway activation was significantly inhibited after the PP-10 treatments. Of note, the current results suggest the potential application of Portulaca oleracea L. and PP-10 in the prevention of DEHP-induced inflammatory damages in HUVECs.
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In this work, we developed a visible-light-driven method for the selective synthesis of amides and N-acylureas from carboxylic acids and thioureas. This protocol was featured as avoidance of additional oxidants and transition metal catalysts, simple manipulations, low cost, broad substrate scope, and good functional group tolerance. As only oxygen serves as the oxidation reagent, this method provides a promising synthesis candidate for the formation of N-aryl amides and N-acylureas, including late-stage functionalization of complex pharmaceutical molecules and biologically active molecules.
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Recent advancements in the application of lipid biomarkers as paleoenvironmental indicators have provided invaluable insights into the dynamics of climatic variations, vegetative histories, and anthropogenic impacts. However, our current understanding of nitrogen-containing lipid biomarkers (NCLBs) in sedimentary deposits remains limited, notwithstanding their potential significance in global nitrogen cycling. To bridge this research gap, a comprehensive study was conducted to characterize the distribution patterns of n-alkyl amides (NAAs) and n-alkyl nitriles (NANs) in representative paleo-lake and loess sedimentary profiles from the arid region of northwestern China (NWC). The widespread occurrence of these NCLBs across late Quaternary strata, with distinct distribution patterns observed in various settings, suggests their formation under diverse environmental conditions. The prevalence of NAAs in arid sedimentary deposits can primarily be attributed to the diverse array of local biota, including vascular plants, algae, and fungi, rather than being solely associated with biomass burning, as commonly assumed. Furthermore, the distribution patterns of NANs closely align with those of NAAs, indicating their formation through thermally induced dehydration of precursor NAAs. Both groups of NCLBs exhibit significant preservation potential in sediments within NWC, which is believed to be intimately linked to the region's arid and cold climate as well as its neutral or weakly alkaline depositional setting. These findings underscore the prospective use of NAAs as indicators of environmental changes and NANs as potential markers of past fire-related activities, making them valuable tools for paleoenvironmental reconstructions of late Quaternary strata, especially in arid, cold, and weakly alkaline regions.
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Humans suffer from various diseases that require more specific drugs to target them. Among the different potent agents, ß-lactamases serve as good antibacterial agents; however, ß-lactamases are resistant to such antibiotics. The present study was designed to prepare efficient ß-lactamase inhibitor amides (12-15) from inexpensive, easily accessible, and bioactive precursors; Morita Baylis Hillman (MBH) adducts (5-8). The adducts (5-8) were primarily prepared by treating their respective aldehydes with the corresponding acrylate in the presence of an organic Lewis base at ambient temperature. The compounds were characterized using mass spectrometry, FTIR and NMR spectroscopy. Furthermore, in silico studies (using AutoDock Tools and AutoDock Vina programs) on the adduct and corresponding amide product revealed that all MBH adducts (5-8) and their product amides (12-15) are significant inhibitors of ß-lactamase. Additionally, among the MBH adducts, adduct 7 showed the highest binding affinity with ß-lactamase, whereas amide 15 was identified as a highly potent antibacterial based on its docking score (-8.6). In addition, the absorption, distribution, metabolism, and excretion (ADME) test of the synthesized compounds demonstrated that all compounds showed drug-likeness properties.
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Cinnamomum tamala leaf (CTL), also known as Indian bay leaf, is used all over the world for seasoning, flavoring, and medicinal purposes. These characteristics could be explained by the presence of several essential bioactive substances and lipid derivatives. In this work, rapid screening and identification of the chemical compounds in supercritical (SC)-CO2 extracts of CTL by use of UPLC-Q-TOF-MSE with a multivariate statistical analysis approach was established in both negative and positive mode. A total of 166 metabolites, including 66 monocarboxylic fatty acids, 52 dicarboxylic fatty acids, 27 fatty acid amides, and 21 cinnamic acid derivatives, were tentatively identified based on accurate mass and the mass spectrometric fragmentation pattern, out of which 142 compounds were common in all SC-CO2 extracts of CTL. Further, PCA and cluster hierarchical analysis clearly discriminated the chemical profile of analyzed extracts and allowed the selection of SC-CO2 extract rich in fatty acids, fatty acid amides, and other bioactive constituents. The result showed that the higher number of compounds was detected in CTL4 (300 bar/55 °C) extract than the other CTL extracts. The mono- and di-carboxylic fatty acids, fatty acid amides, and cinnamic acid derivatives were identified in CTL for the first time. UPLC-Q-TOF-MSE combined with chemometric analysis is a powerful method to rapidly screen the metabolite profiling to justify the quality of CTL as a flavoring agent and in functional foods.
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Amidas , Cinamatos , Cinnamomum , Ácidos Grasos , Extractos Vegetales , Hojas de la Planta , Cinamatos/química , Cinamatos/análisis , Extractos Vegetales/química , Ácidos Grasos/química , Ácidos Grasos/análisis , Hojas de la Planta/química , Cromatografía Líquida de Alta Presión/métodos , Amidas/química , Cinnamomum/química , Dióxido de Carbono/química , Quimiometría , Cromatografía con Fluido Supercrítico/métodos , Espectrometría de Masas/métodosRESUMEN
This study delves into the therapeutic efficacy of A. pyrethrum in addressing vitiligo, a chronic inflammatory disorder known for inducing psychological distress and elevating susceptibility to autoimmune diseases. Notably, JAK inhibitors have emerged as promising candidates for treating immune dermatoses, including vitiligo. Our investigation primarily focuses on the anti-vitiligo potential of A. pyrethrum root extract, specifically targeting N-alkyl-amides, utilizing computational methodologies. Density Functional Theory (DFT) is deployed to meticulously scrutinize molecular properties, while comprehensive evaluations of ADME-Tox properties for each molecule contribute to a nuanced understanding of their therapeutic viability, showcasing remarkable drug-like characteristics. Molecular docking analysis probes ligand interactions with pivotal site JAK1, with all compounds demonstrating significant interactions; notably, molecule 6 exhibits the most interactions with crucial inhibition residues. Molecular dynamics simulations over 500ns further validate the importance and sustainability of these interactions observed in molecular docking, favoring energetically both molecules 6 and 1; however, in terms of stability, the complex with molecule 6 outperforms others. DFT analyses elucidate the distribution of electron-rich oxygen atoms and electron-poor regions within heteroatoms-linked hydrogens. Remarkably, N-alkyl-amides extracted from A. pyrethrum roots exhibit similar compositions, yielding comparable DFT and Electrostatic Potential (ESP) results with subtle distinctions. These findings underscore the considerable potential of A. pyrethrum root extracts as a natural remedy for vitiligo.
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Janus Quinasa 1 , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Extractos Vegetales , Raíces de Plantas , Vitíligo , Vitíligo/tratamiento farmacológico , Vitíligo/metabolismo , Humanos , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Raíces de Plantas/química , Janus Quinasa 1/química , Janus Quinasa 1/metabolismo , Janus Quinasa 1/antagonistas & inhibidoresRESUMEN
Cinnamic acids are aromatic acids primarily found in plants and plant-derived food. Phenolic cinnamic acids, with one or more hydroxyl groups in the aromatic ring, often contribute to the biological activities attributed to these compounds. The presence of hydroxyl groups and a carboxyl group makes cinnamic acids very hydrophilic, preventing them from crossing biological membranes and exerting their biological activities. To alleviate this condition, a panel of synthetic modifications have been made leading to a diverse set of phenolic cinnamic structures. In this review, an overview of the natural phenolic cinnamic acid derivatives and their plant sources (more than 200) is described. The synthetic approaches to obtain the referred derivatives (more than 200) namely esters and amides are reviewed. Further, their anti-inflammatory activity (more than 70 compounds) is scrutinized. Finally, future directions will be indicated to translate the research on phenolic cinnamic derivatives into potentially effective anti-inflammatory drugs.
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Antiinflamatorios , Cinamatos , Fenoles , Cinamatos/química , Cinamatos/farmacología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Humanos , Animales , Fenoles/química , Fenoles/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Plantas/química , Estructura MolecularRESUMEN
The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are responsible for continued propagation of neglected tropical diseases such as African sleeping sickness, Chagas disease and leishmaniasis respectively. Following a report that captopril targets Leishmania donovani dipeptidyl carboxypeptidase, a series of simple proline amides and captopril analogues were synthesized and found to exhibit 1-2 µM in vitro inhibition and selectivity against Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. The results were corroborated with computational docking studies. Arguably, the synthetic proline amides represent the structurally simplest examples of in vitro pan antiprotozoal compounds.
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Captopril , Trypanosoma brucei brucei , Trypanosoma cruzi , Captopril/farmacología , Captopril/química , Captopril/síntesis química , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma brucei brucei/enzimología , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/enzimología , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , Estructura Molecular , Leishmania/efectos de los fármacos , Leishmania/enzimología , Antiprotozoarios/farmacología , Antiprotozoarios/química , Antiprotozoarios/síntesis química , HumanosRESUMEN
Two new sulphur-containing amides, glylucidamides C-D (1-2), along with twelve known analogues (3-14) were isolated and characterised from the leaves of Glycosmis lucida. The chemical structures of 1 and 2 were elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons their data with those reported in the literatures. All new compounds were evaluated for their anti-inflammatory activities via examining the inhibitory activity on nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro.
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Ergot alkaloids are fungal natural products with important roles in agriculture and medicine. We used heterologous expression and gene knockout approaches to investigate potential roles for the product of a major facilitator superfamily transporter gene (easT) recently found in an ergot alkaloid biosynthetic gene cluster in Aspergillus leporis. A strain of Aspergillus fumigatus previously engineered to accumulate lysergic acid, but which did not convert the precursor agroclavine to lysergic acid efficiently or secrete lysergic acid well, was chosen as an expression host for easT. Expression of easT in this strain resulted in accumulation of significantly more pathway intermediates but no detectable lysergic acid. Secretion of ergot alkaloids was reduced in the easT-expressing strain. EasT localized to discrete vesicle-like structures in the cytosol of A. fumigatus, with no localization detected in the plasma membrane. When easT was knocked out in A. leporis, accumulation of lysergic acid amides was reduced relative to the wild type. There was no negative effect on secretion of ergot alkaloids in the knockout mutant. The data indicate that easT encodes a product that contributes to accumulation of ergot alkaloids, perhaps by transporting intermediates between cellular compartments, but does not have a significant role in secreting ergot alkaloids.
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The current paper deals with new metabolites of different groups produced by Azotobacter chroococcum XU1. The strain's metabolic diversity is strongly altered by different factors, and some secondary metabolites are being reported for the first time for this species. As an abiotic/biotic stress response, the strain produced a broad spectrum of indole ring-containing compounds, n-alkanes (eicosane, heneicosane, docosane, tetracosane, and hexacosane), alkanes (7-hexyl eicosane and 2-methyloctacosane), saturated fatty acids (hexanoic and octanoic acids), esters (hexadecanoic acid methyl and pentadecanoic acid-14-methyl-methyl esters), and amides (9-Octadecenamide, (Z)- and 13-Docosenamide, (Z)-). Furthermore, to mitigate the abiotic stress the strain actively produced exopolysaccharide (EPS) to biosorb the Na+ ions. Apart from these metabolites, A. chroococcum XU1 synthesized lactones, namely 1,5-d-gluconolactone and d, l-mevalonic acid lactone in response to carbon source modification. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-024-01212-x.
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A glioma is a type of tumor that acts on the Central Nervous System (CNS) in a highly aggressive manner. Gliomas can occasionally be inaccurately diagnosed and treatments have low efficacy, meaning that patients exhibit a survival of less than one year after diagnosis. Due to factors such as intratumoral cell variability, inefficient chemotherapy drugs, adaptive resistance development to drugs and tumor recurrence after resection, the search continues for new drugs that can inhibit glioma cell growth. As such, analogues of endocannabinoids, such as fatty acid amides (FAAs), represent interesting alternatives for inhibiting tumor growth, since FAAs can modulate several metabolic pathways linked to cancer and, thus, may hold potential for managing glioblastoma. The aim of this study was to investigate the in vitro effects of two fatty ethanolamides (FAA1 and FAA2), synthetized via direct amidation from andiroba oil (Carapa guianensis Aublet), on C6 glioma cells. FAA1 and FAA2 reduced C6 cell viability, proliferation and migratory potential in a dose-dependent manner and were not toxic to normal retina glial cells. Both FAAs caused apoptotic cell death through the loss of mitochondrial integrity (ΔΨm), probably by activating cannabinoid receptors, and inhibiting the PI3K/Akt pathway. In conclusion, FAAs derived from natural products may have the potential to treat glioma-type brain cancer.
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Biodegradable and biocompatible biomaterials have several important applications in drug delivery. The biomaterial family known as poly(ester amide)s (PEAs) has garnered considerable interest because it exhibits the benefits of both polyester and polyamide, as well as production from readily available raw ingredients and sophisticated synthesis techniques. Specifically, α-amino acid-based PEAs (AA-PEAs) are promising carriers because of their structural flexibility, biocompatibility, and biodegradability. Herein, we summarize the latest applications of PEAs in drug delivery systems, including antitumor, gene therapy, and protein drugs, and discuss the prospects of drug delivery based on PEAs, which provides a reference for designing safe and efficient drug delivery carriers.
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Typically catalysed by transition metals, alkene isomerisation is a powerful methodology for preparation of internal olefins. In contrast, the use of more earth abundant main group reagents is limited to activated substrates, requiring high temperatures and excess stoichiometric amounts. Opening a new avenue for progressing this field, here we report applications of bulky sodium amide NaTMP (TMP=2,2,6,6-tetramethylpiperidide) when partnered with tridentate Lewis donor PMDETA (N,N,N',N'',N''-pentamethyldiethylenetriamine) in catalytic alkene isomerisation of terminal olefins under mild reaction conditions. An array of distinct olefins could successfully be isomerised, including unactivated olefins, allylamines, and allylethers, showing the high activity of this partnership. In-depth mechanistic insights provided by X-ray crystallography, real-time nuclear magnetic resonance (NMR) monitoring, and density functional theory (DFT) calculations have unveiled the crucial role of in situ-generated TMP(H) in facilitating efficient isomerisation, and the choice of alkali-metal. Additionally, theoretical studies shed light on the observed E/Z selectivity, particularly accounting for the selective formation of Z-vinyl ethers. The versatility of our method is further demonstrated through the isomerisation of unactivated cycloalkenes, which undergo hydrogen isotope exchange to produce deuterated compounds.
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This study investigates the in vitro activity of Nα-aroyl-N-aryl-phenylalanine amides (AAPs), previously identified as antimycobacterial RNA polymerase (RNAP) inhibitors, against a panel of 25 non-tuberculous mycobacteria (NTM). The compounds, including the hit compound MMV688845, were selected based on their structural diversity and previously described activity against mycobacteria. Bacterial strains, including the M. abscessus complex, M. avium complex, and other clinically relevant NTM, were cultured and subjected to growth inhibition assays. The results demonstrate significant activity against the most common NTM pathogens from the M. abscessus and M. avium complexes. Variations in activity were observed against other NTM species, with for instance M. ulcerans displaying high susceptibility and M. xenopi and M. simiae resistance to AAPs. Comparative analysis of RNAP ß and ß' subunits across mycobacterial species revealed strain-specific polymorphisms, providing insights into differential compound susceptibility. While conservation of target structures was observed, differences in compound activity suggested influences beyond drug-target interactions. This study highlights the potential of AAPs as effective antimycobacterial agents and emphasizes the complex interplay between compound structure, bacterial genetics, and in vitro activity.
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To aid valorisation of beer brewing by-products, more insight into their composition is essential. We have analysed the phenolic compound composition of four brewing by-products, namely barley rootlets, spent grain, hot trub, and cold trub. The main phenolics detected were hydroxycinnamoylagmatines and dimers thereof. Barley rootlets contained the highest hydroxycinnamoylagmatine content and cold trub the highest dimer content. Additionally, variations in (dimeric) hydroxycinnamoylagmatine composition and content were observed in fourteen barley rootlet samples. The most abundant compound in all rootlets was the glycosylated 4-O-7'/3-8'-linked heterodimer of coumaroylagmatine and feruloylagmatine, i.e. CouAgm-4-O-7'/3-8'-(4'Hex)-DFerAgm. Structures of glycosylated and hydroxylated derivatives of coumaroylagmatine were elucidated by NMR spectroscopy after their purification from a rootlet extract. An MS-based decision tree was developed, which aids in identifying hydroxycinnamoylagmatine dimers in complex mixtures. In conclusion, this study shows that the diversity of phenolamides and (neo)lignanamides in barley-derived by-products is larger than previously reported.
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Cerveza , Hordeum , Hordeum/química , Cerveza/análisis , Dimerización , Residuos/análisis , Fenoles/química , Fenoles/análisis , Ácidos Cumáricos/química , Ácidos Cumáricos/análisis , Estructura MolecularRESUMEN
Amidations employing mixed (carbonic) anhydrides have long been favoured in peptide synthesis because of their cost-effectiveness and less waste generation. Despite their long history, no study has compared the effects of additives on the activation of mixed anhydrides and carbonic anhydrides. In this study, we investigated the amidation of mixed (carbonic) anhydride in the presence of a base and/or Brønsted acids. The use of NMIâ HCl significantly improved the conversion of the mixed carbonic anhydride, while expediting nucleophilic attacks on the desired carbonyl group. In contrast, in the case of mixed anhydrides, neither the conversion nor the desired nucleophilic attack improved significantly. We developed a C-terminus-free N-methylated peptide synthesis method using mixed carbonic anhydrides in a micro-flow reactor. Fourteen N-alkylated peptides were synthesized in moderate to high yields (55-99 %) without severe racemization (<1 %). Additionally, a significant enhancement in the amidation between mixed carbonic anhydrides and bis-TMS-protected N-methyl amino acids with the inclusion of NMIâ HCl was observed for the first time. In addition, we observed unexpected C-terminal epimerization of the C-terminus-free N-methyl peptides.
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Anhídridos , Péptidos , Péptidos/química , Anhídridos/química , Metilación , Ácidos/química , AlquilaciónRESUMEN
A series of benzoxazole-based amides and sulfonamides were synthesized and evaluated for their human peroxisome proliferator-activated receptor (PPAR)α and PPARγ activity. All tested compounds showed a dual antagonist profile on both PPAR subtypes; based on transactivation results, seven compounds were selected to test their in vitro antiproliferative activity in a panel of eight cancer cell lines with different expression rates of PPARα and PPARγ. 3f was identified as the most cytotoxic compound, with higher potency in the colorectal cancer cell lines HT-29 and HCT116. Compound 3f induced a concentration-dependent activation of caspases and cell-cycle arrest in both colorectal cancer models. Docking experiments were also performed to shed light on the putative binding mode of this novel class of dual PPARα/γ antagonists.