Atomically precise copper nanoclusters mediated Fenton-like reaction for cancer chemodynamic therapy.

We developed stable luminescent morpholine-appended copper nanoclusters CuNCs@MorMB with an ultra-small size (<3 nm) and a long emission lifetime (577 ns). They mediate a Fenton-like reaction to produce reactive hydroxyl radicals (˙OH), subsequently depleting antioxidant glutathione levels for cancer chemodynamic therapy (CDT).

Comparison and Determination of the Content of Mosapride Citrate by Different qNMR Methods.

As a salt-type compound, mosapride citrate's metabolism and side effects are correlated with its salt-forming ratio. Several techniques were developed in this work to compare various quantitative nuclear magnetic resonance (qNMR) methodologies and to quantitatively examine the content of raw materials. Among the qNMR techniques, methods for 1H NMR and 19F NMR were developed. Appropriate solvents were chosen, and temperature, number of scans, acquisition time, and relaxation delay parameter settings were optimized. Maleic acid was chosen as the internal standard in 1H NMR, and the respective characteristic signals of mosapride and citrate were selected as quantitative peaks. The internal standard in 19F NMR analysis was 4,4'-difluoro diphenylmethanone, and the distinctive signal peak at -116.15 ppm was utilized to quantify mosapride citrate. The precision, repeatability, linearity, stability, accuracy, and robustness of the qNMR methods were all validated according to the ICH guidelines. By contrasting the outcomes with those from high-performance liquid chromatography (HPLC), the accuracy of qNMR was assessed. As a result, we created a quicker and easier qNMR approach to measure the amount of mosapride citrate and evaluated several qNMR techniques to establish a foundation for choosing quantitative peaks for the qNMR method. Concurrently, it is anticipated that various selections of distinct quantitative objects will yield the mosapride citrate salt-forming ratio.

Late-Stage Radical C-H Alkylamination of Tyrosine Compounds and Phenol-Containing Drugs.

A modular site-selective iron-catalyzed radical amination of a number of phenol-containing biomolecules such as tyrosine-containing peptides, estrogens, and other phenol-based pharmaceuticals has been developed. The method features the use of the cost-efficient combination of FeBr3 as catalyst along with triflic acid as Brønsted acid, thereby enabling the predictable appendance of morpholine and related heterocycles at the ortho C-H bond of phenols in a late-stage fashion.

Synthesis and Biological Activity of New Hydrazones Based on N-Aminomorpholine.

The data on the synthesis of N-aminomorpholine hydrazones are presented. It is shown that the interaction of N-aminomorpholine with functionally substituted benzaldehydes and 4-pyridinaldehyde in isopropyl alcohol leads to the formation of corresponding hydrazones. The structure of the synthesized compounds was studied by 1H and 13C NMR spectroscopy methods, including the COSY (1H-1H), HMQC (1H-13C) and HMBC (1H-13C) methodologies. The values of chemical shifts, multiplicity, and integral intensity of 1H and 13C signals in one-dimensional NMR spectra were determined. The COSY (1H-1H), HMQC (1H-13C), and HMBC (1H-13C) results revealed homo- and heteronuclear interactions, confirming the structure of the studied compounds. The antiviral, cytotoxic, and antimicrobial activity of some synthesized hydrazones were investigated. It is shown that 2-((morpholinoimino)methyl)benzoic acid has a pronounced viral inhibitory property, comparable in its activity to commercial drugs Tamiflu and Remantadine. A docking study was performed using the influenza virus protein models (1930 Swine H1 Hemagglutinin and Neuraminidase of 1918 H1N1 strain). The potential binding sites that are complementary with 2-((morpholinoimino)methyl)benzoic acid were found.

A lysosome-located and rhodamine-based fluorescence probe for recognizing hydrogen polysulfide.

Hydrogen polysulfide (H2Sn, n≥2), as a kind of active sulfur species (RSS), has become a hot topic in RSS. It can regulate the biological activity of many proteins through S-sulfhydrylation of cysteine residues (protein Cys-SSH), and has a protective effect on cells. Although there have been some studies on hydrogen polysulfide, its production, degradation pathway and regulation mechanism still need further be researched. In presented study, an original lysosome-localized fluorescent probe for determining H2Sn was developed utilizing rhodamine as the fluorogen. The probe used morpholine as the locating unit of lysosomes and chose 2-fluoro-5-nitrobenzoate as the recognizing group. Before adding H2Sn, the proposed probe displayed a spironolactone structure and emitted very weak fluorescence. After adding H2Sn, a conjugated xanthene was formed and the probe demonstrated green fluorescence. When the H2Sn concentration was varied from 6.0×10-7 mol·L-1 to 10.0×10-5 mol·L-1, the fluorescence intensity of the probe was linearly dependent on the H2Sn concentration. And the detection limit was 1.5×10-7 mol·L-1. The presented probe owned a fast response speed, good selectivity, excellent sensitivity and broad pH work scope. In addition, the probe had been well utilized to sense endogenic and exogenic H2Sn in lysosomes.

Discovery of the DNA-PKcs inhibitor DA-143 which exhibits enhanced solubility relative to NU7441.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a vital role in DNA damage repair and lymphocyte function, presenting a significant target in cancer and immune diseases. Current DNA-PKcs inhibitors are undergoing Phase I/II trials as adjuncts to radiotherapy and chemotherapy in cancer. Nevertheless, clinical utility is limited by suboptimal bioavailability. This study introduces DNA-PKcs inhibitors designed to enhance bioavailability. We demonstrate that a novel DNA-PKcs inhibitor, DA-143, surpasses NU7441 in aqueous solubility as well as other available inhibitors. In addition, DA-143 displayed an improvement in DNA-PKcs inhibition relative to NU7441 achieving an IC50 of 2.5 nM. Consistent with current inhibitors, inhibition of DNA-PKcs by DA-143 resulted in increased tumor cell sensitivity to DNA-damage from chemotherapy and inhibition of human T cell function. The improved solubility of DA-143 is critical for enhanced efficacy at reduced doses and facilitates more effective evaluation of DNA-PKcs inhibition in both preclinical and clinical development.

Observation of polarity changes in Sjogren's syndrome mice using a targeting lysosomes and ratiometric fluorescent probe.

Utilizing non-invasive, real-time dynamic imaging and high-resolution detection tools to track polarity changes in Sjögren's syndrome (SS) contributes to a better understanding of the disease progression. Herein, a ratiometric polarity-sensitive fluorescent probe (DIM) was designed and synthesized, DIM consisted of dicyanoisophorone as the fluorophore and morpholine moiety as lysosome targeting. DIM showed a ratiometric response to polarity and high selectivity (unaffected by viscosity, pH, ROS, RNS, etc.), offering a more accurate analysis of intracellular polarity through a built-in internal reference calibration. The polarity abnormality of submandibular glands in non-obese diabetic (NOD) mice was revealed and verified by in vivo ratiometric fluorescence imaging of DIM, suggesting that fluorescent probe have great potential in the diagnosis of salivary gland abnormalities.

Morpholine, Piperazine, and Piperidine Derivatives as Antidiabetic Agents.

Diabetes mellitus is a severe endocrine disease that affects more and more people every year. Modern medical chemistry sets itself the task of finding effective and safe drugs against diabetes. This review provides an overview of potential antidiabetic drugs based on three heterocyclic compounds, namely morpholine, piperazine, and piperidine. Studies have shown that compounds containing their moieties can be quite effective in vitro and in vivo for the treatment of diabetes and its consequences.

A series of quinazolin-4(3H)-one-morpholine hybrids as anti-lung-cancer agents: Synthesis, molecular docking, molecular dynamics, ADME prediction and biological activity studies.

In this study, we synthesized 15 novel quinazoline-morpholinobenzylideneamino hybrid compounds from methyl anthranilate and we assessed their cytotoxicity via in vitro assays against A549 and BEAS-2B cell lines. Molecular docking studies were conducted to evaluate the protein-ligand interactions and inhibition mechanisms on nine different molecular targets, while molecular dynamics (MD) simulations were carried out to assess the stability of the best docked ligand-protein complexes. Additionally, ADME prediction was carried out to determine physicochemical parameters and drug likeness. According to the cytotoxicity assays, compound 1 (IC50 = 2.83 µM) was found to be the most active inhibitor against A549 cells. While the selectivity index (SI) of compound 1 is 29, the SI of the reference drugs paclitaxel and sorafenib, used in this study, are 2.40 and 4.92, respectively. Among the hybrid compounds, 1 has the best docking scores against VEGFR1 (-11.744 kcal/mol), VEGFR2 (-12.407 kcal/mol) and EGFR (-10.359 kcal/mol). During MD simulations, compound 1 consistently exhibited strong hydrogen bond interactions with the active sites of VEGFR1 and 2, and these interactions were maintained for more than 90% of the simulation time. Additionally, the RMSD and RMSF values of the ligand-protein complexes exhibited high stability at their minimum levels around 1-2 Å. In conclusion, these findings suggest that compound 1 may be a potent and selective inhibitor candidate for lung cancer treatment and inhibition of VEGFR2, especially.

New morpholine-containing pyrimidinones act on α-adrenoceptors.

Drugs that act on α-adrenoceptors may contain morpholine and pyrimidinone heterocycles. The aim of this study was to synthesize a series of pyrimidinones (S6a-e and S8) and characterize their α-adrenoceptor activity. Cytotoxicity assays (MTT and LDH) were performed in A7r5 and HUVECs. Concentration-effect curves to phenylephrine (Phe) were performed in rat aortic rings in the presence of compounds S6a-e and S8 or vehicle. Nitric oxide (NO) production and NO stable metabolic products, nitrite and nitrate, expressed as total nitrogen oxides (NOx) were assessed in HUVECs by confocal microscopy with the DAF-2DA probe and by the Griess reaction, respectively. Molecular docking simulations were performed using the 6a compound and α2A-adrenoceptor. In the evaluated conditions, the percentage of viable cells and the release of LDH were similar between control cells and cells exposed to the tested pyrimidinones. S6d, S6e, S8, and the positive control prazosin (but not S6a, S6b, and S6c) decreased Phe-induced contractions in endothelium-denuded aortic rings. S6a, S6b, and S6c decreased Phe-induced contractions in endothelium-intact aortic rings. The effect of S6a was abolished by L-NAME. NO production and NOx levels were inhibited in the presence of the α2 receptor antagonist yohimbine and the NOS inhibitor L-NAME. The 6a docking simulation estimated that the mean binding free energy of the compound was lower than the estimated value for yohimbine. These data suggest that S6d, S6e, and S8 may be α1-adrenoceptor antagonists while S6a acts as an agonist of α2-adrenoceptors.

Development of an extended action fostemsavir lipid nanoparticle.

An extended action fostemsavir (FTR) lipid nanoparticle (LNP) formulation prevents human immunodeficiency virus type one (HIV-1) infection. This FTR formulation establishes a drug depot in monocyte-derived macrophages that extend the drug's plasma residence time. The LNP's physicochemical properties improve FTR's antiretroviral activities, which are linked to the drug's ability to withstand fluid flow forces and levels of drug cellular internalization. Each is, in measure, dependent on PEGylated lipid composition and flow rate ratios affecting the size, polydispersity, shape, zeta potential, stability, biodistribution, and antiretroviral efficacy. The FTR LNP physicochemical properties enable the drug-particle's extended actions.

N-methylmorpholine incorporation into the structure of biphenyl leads to the bioactive inhibitor of PD-1/PD-L1 interaction.

We present new small-molecular probes targeting the human PD-L1 protein. The molecules were designed by incorporating a newly discovered N-methylmorpholine substituent into a known biphenyl-based structure. Four prototype derivatives of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (STD4), comprising a morpholine substituent fused with a biphenyl core at different orientations were first verified for their potential binding to PD-L1 using the molecular docking method. A more favorable 7-phenyl derivative of STD4 was then equipped with an amide bond, pyridine, and either a tris(hydroxymethyl)aminomethane or serinol tail leading to two final molecules. Among them, compound 1c showed activity in three bioassays, i.e., the homogenous time-resolved fluorescence (HTRF) assay, immune checkpoint blockade (ICB) assay, and T-cell activation (TCA) assay. Our work shows that morpholine can substitute for dioxane and becomes a promising component in PD-L1-targeting molecules. This finding unlocks new avenues for optimizing PD-L1-targeting compounds, presenting exciting prospects for future developments in this field.

Stereoselective Synthesis of Baloxavir Marboxil Using Diastereoselective Cyclization and Photoredox Decarboxylation of l-Serine.

Baloxavir marboxil (1; BXM) is a potent drug used for treating influenza infections. The current synthetic route to BXM (1) is based on optical resolution; however, this method results in the loss of nearly 50% of the material. This study aimed to describe an efficient and simpler method for the synthesis of BXM. We achieved a stereoselective synthesis of BXM (1). The tricyclic triazinanone core possessing a chiral center was prepared via diastereoselective cyclization utilizing the readily available amino acid l-serine. The carboxyl moiety derived from l-serine was removed via photoredox decarboxylation under mild conditions to furnish the chiral tricyclic triazinanone core ((R)-14). The synthetic route demonstrated herein provides an efficient and atomically economical method for preparing this potent anti-influenza agent.

Biological and structural investigation of tetrahydro-ß-carboline-based selective HDAC6 inhibitors with improved stability.

Our previously reported HDAC6 inhibitor (HDAC6i) Marbostat-100 (4) has provided many arguments for further clinical evaluation. By the substitution of the acidic hydrogen of 4 for different carbon residues, we were able to generate an all-carbon stereocenter, which significantly improves the hydrolytic stability of the inhibitor. Further asymmetric synthesis has shown that the (S)-configured inhibitors preferentially bind to HDAC6. This led to the highly selective and potent methyl-substituted derivative S-29b, which elicited a long-lasting tubulin hyperacetylation in MV4-11 cells. Finally, a crystal structure of the HDAC6/S-29b complex provided mechanistic explanation for the high potency and stereoselectivity of synthesized compound series.

Rationalizing Diverse Binding Mechanisms to the Same Protein Fold: Insights for Ligand Recognition and Biosensor Design.

The engineering of novel protein-ligand binding interactions, particularly for complex drug-like molecules, is an unsolved problem, which could enable many practical applications of protein biosensors. In this work, we analyzed two engineered biosensors, derived from the plant hormone sensor PYR1, to recognize either the agrochemical mandipropamid or the synthetic cannabinoid WIN55,212-2. Using a combination of quantitative deep mutational scanning experiments and molecular dynamics simulations, we demonstrated that mutations at common positions can promote protein-ligand shape complementarity and revealed prominent differences in the electrostatic networks needed to complement diverse ligands. MD simulations indicate that both PYR1 protein-ligand complexes bind a single conformer of their target ligand that is close to the lowest free-energy conformer. Computational design using a fixed conformer and rigid body orientation led to new WIN55,212-2 sensors with nanomolar limits of detection. This work reveals mechanisms by which the versatile PYR1 biosensor scaffold can bind diverse ligands. This work also provides computational methods to sample realistic ligand conformers and rigid body alignments that simplify the computational design of biosensors for novel ligands of interest.

Fouling behavior of nanofiltration membrane during the refining treatment of morphlines-dominant reverse osmosis concentrate.

Nanofiltration (NF) has been proven to be with great potential for the separation of morpholines with molecular weight less than 200 Da in refining reverse osmosis concentrate (ROC), but its application is significantly restricted by the membrane fouling, which can reduce the rejection and service time. To enable the long-term operation stability of nanofiltration, this work focuses on the fouling behavior of each substance in the hydrosaline organic solution on nanofiltration membrane, aiming to give insight into the fouling mechanism. To this end, in this work, the effects of salts (i.e NaCl and Na2SO4), organic substances (including N-(2-hydroxypropyl)morpholine(NMH) and 4-morpholineacetate(MHA)) and representative divalent ions (Ca2+ and Mg2+) on the performance and physicochemical properties of DK membrane were systematically investigated. The results show that both salts and organics can induce DK membrane swelling, leading to an increase of the mean effective pore size. After the filtration of Na2SO4-NaCl-H2O, the mean pore size increased by 0.002 nm, resulting in the decrease of the removal ratio of NMH and MHA for 3.82% and 13.10%, respectively. With static adsorption of NMH and MHA, the mean pore size of DK membrane increased by 0.005 and 0.003 nm. The swelling slowed the entrance of more organic molecules into membrane pores. Among them, MHA led to the terrible irreversible pore blocking. As the concentration of Ca2+ increased, gypsum scaling was formed on the membrane surface. During this process, NMH and MHA played different roles, i.e. NMH accelerated the CaSO4 crystallization while MHA inhibited. As a conclusion, the fouling behavior of substances in the high saline organic wastewater on DK membrane were systematically revealed with the fouling mechanisms proposed, which could provide an insightful guidance for membrane fouling control and cleaning in the treatment of high salinity and organic wastewater.

2-Aryladenine Derivatives as a Potent Scaffold for Adenosine Receptor Antagonists: The 6-Morpholino Derivatives.

A set of 2-aryl-9-H or methyl-6-morpholinopurine derivatives were synthesized and assayed through radioligand binding tests at human A1, A2A, A2B, and A3 adenosine receptor subtypes. Eleven purines showed potent antagonism at A1, A3, dual A1/A2A, A1/A2B, or A1/A3 adenosine receptors. Additionally, three compounds showed high affinity without selectivity for any specific adenosine receptor. The structure-activity relationships were made for this group of new compounds. The 9-methylpurine derivatives were generally less potent but more selective, and the 9H-purine derivatives were more potent but less selective. These compounds can be an important source of new biochemical tools and/or pharmacological drugs.

Insight into the inhibitory potential of metal complexes supported by (E)-2-morpholino-N-(thiophen-2-ylmethylene)ethanamine: synthesis, structural properties, biological evaluation and docking studies.

A thiophene-derived Schiff base ligand (E)-2-morpholino-N-(thiophen-2-ylmethylene)ethanamine was used for the synthesis of M(II) complexes, [TEM(M)X2] (M = Co, Cu, Zn; X = Cl; M = Cd, X = Br). Structural characterization of the synthesized complexes revealed distorted tetrahedral geometry around the M(II) center. In vitro investigation of the synthesized ligand and its M(II) complexes showed considerable anti-urease and leishmanicidal potential. The synthesized complexes also exhibited a significant inhibitory effect on urease, with IC50 values in the range of 3.50-8.05 µM. In addition, the docking results were consistent with the experimental results. A preliminary study of human colorectal cancer (HCT), hepatic cancer (HepG2), and breast cancer (MCF-7) cell lines showed marked anticancer activities of these complexes.

Total Synthesis and Stereochemical Assignment of Enteropeptin A.

The total synthesis and structural elucidation of the antimicrobial sactipeptide enteropeptin A is reported. Enteropeptin A contains a thioaminoketal group with an unassigned stereochemical configuration that is embedded in a highly unusual thiomorpholine ring. In this synthesis, a linear peptide containing a dehydroamino acid and a pendant cysteine residue is subjected to Markovnikov hydrothiolation by a dithiophosphoric acid catalyst. This cyclization reaction forms the central thiomorpholine ring found in the enteropeptins. Both diastereomers at the unassigned thioaminoketal stereocenter of enteropeptin A were prepared, and their comparison to an authentic standard allowed for the unambiguous stereochemical assignment of the natural product to be of the D configuration. This inaugural total synthesis of enteropeptin A represents the first total synthesis of a sactipeptide reported to date. Moreover, the strategy disclosed herein serves as a general platform for the synthesis of stereochemically defined thiomorpholine-containing peptides, which may enable the discovery of new cyclic peptide antibiotics.

Synergistic antifungal effect and potential mechanism of Dimethomorph combined with Pyrimethanil against Phytophthora capsici.

Synergistic effect of dimethomorph (DIM) and pyrimethanil (PYM) was evaluated using the Wadley method and the molecular mechanism of the antifungal effects of the combined treatment was systematically investigated. DIM+PYM had a synergistic effect on Phytophthora capsici, with the synergistic effect being observed at 5:1, at which the synergy coefficient was 1.8536. The mycelia of the pathogen treated with DIM+PYM were branched, uneven in thickness, and swollen. Moreover, scanning electron microscopy (SEM) revealed that DIM+PYM caused mycelium breaks, swelling, and apex enlargement, while transmission electron microscopy (TEM) revealed structural damage, cavities, and cell membrane morphological abnormalities. DIM+PYM inhibited the growth of mycelia, destroyed the cell membrane, interfered with energy metabolism, reduced protein and sugar content. Additionally, the transcriptome and metabolome of fungi treated with DIM+PYM changed significantly; specifically, there were 1571 differentially expressed genes and 802 differential metabolites. DIM+PYM may mainly damage the cell membrane, energy, protein, soluble sugar pathways.