ABSTRACT
A TMSOTf-catalyzed C2-sulfenylation of indole alkaloids with N-sulfenylsuccinimides has been developed. This straightforward, metal-free, and cost-effective catalytic system produces valuable 2-thioindole derivatives with yields ranging from moderate to excellent. The synthetic applicability demonstrated includes the total syntheses of isatindigotindolosides I-IV.
ABSTRACT
We herein report the copper-catalyzed C-S bond coupling reaction of indoles with N-thiosuccinimides, resulting in moderate to excellent yields of mono- and bis-sulfenylated compounds such as arylthioindoles, alkylthioindoles, selenylated indoles, and cysteine-substituted indoles. Thioarylation and thioglycosylation at the C2 position of indole alkaloids in the Radix Isatidis were achieved via structural modification. The first total syntheses of isatindigotindolosides III and IV have been successfully carried out. The electrophilic sulfenyl bromides generated in situ can play an important role in the catalytic cycle.
ABSTRACT
Despite the importance of nucleosides and nucleotides for drug discovery, only a few practical methods to prepare tricyclic nucleosides have been reported. Here, we describe a synthetic strategy for late-stage functionalization of nucleosides and nucleotides via chemo- and site-selective acid-promoted intermolecular cyclization. The nucleoside analogs with an additional ring were obtained in moderate-to-high yields, including some antiviral drugs (acyclovir, ganciclovir, and penciclovir) derivatives, endogenous fused ring nucleoside (M1 dG) and its derivatives, and nucleotide derivatives. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of tricyclic acyclovir analogs (3a-3c) Basic Protocol 2: Synthesis of tricyclic nucleosides M1 dG (6) and M1 G (9) Basic Protocol 3: Synthesis of tricyclic nucleotide (12).
Subject(s)
Acyclovir , Nucleosides , Cyclization , Guanine , NucleotidesABSTRACT
The cycloaddition reaction of N-hydroxysuccinimide ester and isocyanatoacetate catalyzed by copper was described. A series of 4,5-disubstituted oxazole compounds, including ones derived from natural fatty acids, drugs, amino acids, and peptides, were obtained in moderate to high yields. The derivatization reaction was explored. The reaction mechanism was discussed.
ABSTRACT
Isatindigotindolosides, indoles containing a 1-S-ß-glucopyranosyl unit at position C2, show promising bioactivity. Here, we report a copper-catalyzed C2- or C3-thioglycosylation of indoles with N-(thioglycosides)succinimides to construct indole alkaloid glucosides. This reaction is widely tolerant of functional groups, as various indoles and thioglycosides are suitable. It also provides a reliable method for performing late-stage modifications of natural products, such as gramine and melatonin. Total syntheses of isatindigotindolosides I and II were successfully accomplished using the C2-thioglycosylation reaction as a key step.
ABSTRACT
3-(2-Deoxy-ß-d-erythropentofuranosyl)pyrimido[1,2-a]purin-10(3H)-one (M1dG) is an endogenous DNA adduct in bacterial and mammalian cells that could be explored as a biomarker for oxidative stress. Nonetheless, the lack of an efficient methodology for the preparation of M1dG hampers the deep investigation of its biosynthesis and biorelevant processes. In this project, we aimed to address this issue by developing a highly efficient method to synthesize M1dG and its analogues. This method has wide functional group tolerance, as various guanine-based nucleosides and nucleotides are suitable for the reaction. Furthermore, large-scale and derivatization reactions were carried out to showcase the possibility for biochemists to study DNA damage and repair processes in the future.
Subject(s)
Nucleosides , Nucleotides , Animals , Guanine , Cyclization , Purine Nucleosides , Mammals/metabolismABSTRACT
Herein, we report dialkoxylation of N-substituted indoles through a hypervalent iodine-mediated umpolung strategy, affording trans-2,3-dimethoxyindolines with up to 95% yield. In addition, C5-selective bromination of 2,3-dialkoxyindoline via NBS-mediated rearomatization was achieved. DFT calculation of the sequence of electrophilic addition and nucleophilic substitution pathway of N-substituted indoles has also been investigated.
Subject(s)
Iodine , Indoles , IodidesABSTRACT
A simple and efficient synthetic protocol for the preparation of acridinium esters and amides through the cyclization and esterification or amidation of isatins with alcohols or amines as nucleophiles in the presence of CF3SO3H is established. A series of polycyclic acridine derivatives bearing large π-conjugated systems were obtained in high yields, including some key intermediates for the synthesis of biologically active molecules. The photophysical properties of these synthesized acridines were investigated, demonstrating that the sulfur heterocyclic acridine 9w was obtained in a high quantum yield.
ABSTRACT
Environmentally friendly and highly regioselective C-3 dichlorination and C-2 oxidation of N-substituted indoles have been established using NaCl as a chlorine source and H2O as an oxygen source. A series of 3,3-dichloro-2-oxindoles were obtained in moderate to excellent yields. The gram-scale synthesis and derivatization reaction were explored. The possible mechanism for this reaction was elucidated.
Subject(s)
Lung/drug effects , Lung/metabolism , Secretory Leukocyte Peptidase Inhibitor/metabolism , Sulfur Dioxide/pharmacology , Animals , Blotting, Western , Electrophoresis, Polyacrylamide Gel , Humans , Interleukin-6/metabolism , Interleukin-8/metabolism , Rats , Tumor Necrosis Factor-alpha/metabolismABSTRACT
To investigate the effect of intravenous Vitamin C (VC) on hemorrhagic shock (HS)-associated rat renal injury and the involved mechanism. Thirty SD rats were randomly assigned to the sham surgery (sham), hemorrhagic shock (HS), HS+100 mg/kg VC (H + VL), HS+500 mg/kg VC (H + VH) and HS+100 mg/kg VC + EX527 (H + VL + E) groups. Tissue and blood samples were collected 6 h after surgery. Kidney pathological changes were scored. Creatinine (CRE), blood urea nitrogen (BUN), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) levels in serum and Vitamin C levels and superoxide dismutase (SOD) activity and the ability to suppress hydroxyl radical (RAFHR) in plasma were measured. The expression of Sirtuin1 (SIRT1), Acetyl-NF-κB (Ace-NF-κB), heme oxygenase-1 (HO-1), TNF-α, and IL-1ß in tissues was analyzed by ELISA or western-blot. In the HS group, the kidney pathological score and CRE, BUN, TNF-α, and IL-1ß levels in serum were significantly higher than in the Sham group (Pâ¯<â¯0.05), while SOD and RAFHR were significantly decreased in the plasma (Pâ¯<â¯0.05). SOD activity and SIRT1 expression were remarkably lower in the kidney in the HS group than in the Sham group (Pâ¯<â¯0.05), while MDA, TNF-α, and IL-1ß concentrations and Acetyl-NF-κB andHO-1 expression in the kidney showed a noteworthy increase compared to the Sham group (Pâ¯<â¯0.05). Compared to the HS group, VC treatment led to a remarkable reduction in the kidney pathological score and CRE,BUN,TNF-α, and IL-1ß levels (Pâ¯<â¯0.05), and a significant increase in Vitamin C, SOD, and RAFHR levels in the plasma (Pâ¯<â¯0.05). Additionally, MDA, TNF-α, IL-1ß and Acetyl-NF-κB expression levels were decreased in the kidney (P < 0.05), while SOD, SIRT1 and HO-1 levels were notably enhanced. There were no differences between the H + VL and H + VH groups aside from plasma Vitamin C levels. The effect of Vitamin C was decreased after the addition of EX527, which inhibits SIRT1. Intravenous Vitamin C might attenuate HS-related renal injury via the SIRT1 pathway, and it appears that there were no differences in the effects between the high and low doses.
Subject(s)
Ascorbic Acid/administration & dosage , Renal Insufficiency/drug therapy , Shock, Hemorrhagic/complications , Sirtuin 1/metabolism , Administration, Intravenous , Animals , Ascorbic Acid/blood , Cytokines/blood , Cytokines/metabolism , Heme Oxygenase (Decyclizing)/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Kidney/metabolism , Kidney/pathology , Male , NF-kappa B/metabolism , Oxidative Stress/drug effects , Rats, Sprague-Dawley , Renal Insufficiency/etiology , Shock, Hemorrhagic/metabolism , Shock, Hemorrhagic/physiopathology , Up-RegulationABSTRACT
Mild, metal-free, highly regioselective hypervalent-iodine mediated C-2 acetoxylation and C-3 oxidations of N-substituted indoles with (diacetoxyiodo)benzene [PhI(OAc)2] have been reported. The reaction involves three cascade steps. The quantity of PhI(OAc)2 employed in this reaction plays a key role in the outcome of three types of products (2a-4a). Furthermore, the mild and highly regioselective C-2 oxidation and C-3 dichlorination of N-substituted indoles with PhICl2 have been developed. Extensive studies including in situ IR techniques and H2O18-labeling experiment were performed to gain insight into the possible reaction mechanism.
ABSTRACT
BACKGROUND: The prevalence of asthma and allergic diseases has risen in recent decades. The etiology of asthma and allergic diseases has not been entirely elucidated. OBJECTIVE: In this study, we investigated the possibility that programmed vaccination in China may have a potential role in asthma and allergic diseases. METHODS: In this animal model, newborn BALB/c mice were randomly divided into three groups: vaccine plus ovalbumin (OVA), OVA, and control. The mice of vaccine plus OVA only group were inoculated with vaccines by following the National Vaccines Inoculation Program in China. Mice of vaccine plus OVA and OVA only groups were sensitized and challenged with OVA. Airway hyperresponsiveness was assessed by lung function and serum interleukin (IL) 4 and interferon (IFN) γ were measured. RESULTS: The results of lung function showed that mice of the vaccine plus OVA group exhibited an increase in enhanced pause (Penh) compared with that in the OVA group at methacholine concentrations of 6.25 and 12.5 mg/mL (p < 0.05). Serum IL-4 in the vaccine plus OVA group was higher than that in the OVA group (p < 0.01). The serum IFN-γ level in the OVA group was lower than that in the control group (p < 0.01), and also lower than that in the vaccine plus OVA group (p < 0.05). The ratio of IFN-γ to IL-4 both in the OVA and vaccine plus OVA group was lower than that in the control group (p < 0.01). CONCLUSIONS: Results of our study indicated that programmed vaccination in China may have a potential role in the prevalence of asthma and allergic diseases by inducing T-helper 2 cytokine expression and may be responsible for the increasing prevalence of asthma and allergic diseases in China.
Subject(s)
Asthma/etiology , Hypersensitivity/etiology , Vaccination/adverse effects , Animals , Asthma/epidemiology , Hypersensitivity/epidemiology , Interferon-gamma/blood , Interleukin-4/blood , Mice , Mice, Inbred BALB C , Ovalbumin/immunology , Respiratory Hypersensitivity/etiology , Th1 Cells/immunology , Th2 Cells/immunologyABSTRACT
OBJECTIVE: To assess whether serum levels of S100A12 and soluble receptor for advanced glycation end products (sRAGE) could predict the severity of acute pancreatitis (AP). METHODS: We conducted a non-interventional pilot study, including 74 AP patients and 28 healthy volunteers serving as controls. AP patients were further divided into the mild (MAP, n = 22), moderately severe (MSAP, n = 30) and severe (SAP, n = 22) groups. Peripheral blood samples were collected within 72 h after the onset of AP for the determination of S100A12, sRAGE and C-reactive protein (CRP) levels. The acute physiology and chronic health evaluation II (APACHE II) score, Balthazar computed tomography severity index (CTSI) were calculated at admission. RESULTS: S100A12 and sRAGE levels in SAP patient were significantly higher than in controls, MAP and MSAP patients. The receiver operating characteristic (ROC) curve analysis demonstrated the predictive ability of S100A12 [sensitivity 91%, specificity 81%, the area under the ROC curve AUROC 0.9047] and sRAGE (sensitivity 57%, specificity 100%, AUROC 0.8304) for evaluating the severity of AP. S100A12 and sRAGE were correlated with APACHE II and CTSI but not with CRP. This combination of new and traditional indicators had higher accuracy than traditional indicators alone. Specifically, S100A12 and sRAGE were positively correlated with the type of organ failure (respiratory and renal failure) and might distinguish transient from persistent organ failure at admission. CONCLUSION: S100A12 and sRAGE could be used as efficient biomarkers for the early identification of SAP.
Subject(s)
Pancreatitis/diagnosis , Receptor for Advanced Glycation End Products/blood , S100A12 Protein/blood , APACHE , Acute Disease , Adult , Aged , Biomarkers/blood , C-Reactive Protein/analysis , Case-Control Studies , Early Diagnosis , Female , Humans , Male , Middle Aged , Multiple Organ Failure/etiology , Pancreatitis/complications , Pilot Projects , Prognosis , Sensitivity and Specificity , Young AdultABSTRACT
An efficient C(sp(3))-H bond activation and intramolecular amination reaction via palladium catalysis at the ß-position of carboxyamides to make ß-lactams was described. The investigation of the substrate scope showed that the current reaction conditions favored activation of the ß-methylene group. Short sequences were developed for preparation of various diazabicyclic ß-lactam compounds with this method as the key step from chiral proline and piperidine derivatives.
ABSTRACT
The concise building of the spiroketal core of acortatarin-type alkaloids as potential therapeutic agents in diabetic nephropathy was established in four steps, through a tandem N-alkylation/hemiacetalization between pyrrole units and the corresponding halo alcohols generated by convenient halomethylation of chiral lactones from natural aldoses.
ABSTRACT
An efficient method to synthesize the ß-lactams with high regioselectivity via Pd-catalyzed C(sp(3))-H bond activation and intramolecular amination of simple and readily available aminoquinoline carboxamides was demonstrated. C6F5I plays a significant role in the formation of the C-N bond of the four-membered ring ß-lactams. High yield along with wide substrate scope and functional group tolerance makes this reaction applicable to build natural-product-derived ß-lactams. This method has been applied to the efficient synthesis of the ß-lactamase inhibitor MK-8712.
Subject(s)
Amides/chemistry , Monobactams/chemical synthesis , Palladium/chemistry , beta-Lactamase Inhibitors , beta-Lactams/chemical synthesis , Amination , Aminoquinolines/chemistry , Catalysis , Molecular Structure , Monobactams/chemistry , Monobactams/pharmacology , beta-Lactams/chemistryABSTRACT
Synoviocyte hyperplasia is critical for rheumatoid arthritis, therefore, potentially an important target for therapeutics. It was found in this work that a TRPV1 agonist capsaicin, and acidic solution (pH 5.5) induced increases in cytosolic calcium concentration ([Ca(2+)](c)) and reactive oxygen species (ROS) production in synoviocytes isolated from a rat model of collagen-induced arthritis. The increases in both [Ca(2+)](c) and ROS production were completely abolished in calcium-free buffer or by a TRPV1 antagonist capsazepine. Further experiments revealed that capsaicin and pH 5.5 solution caused mitochondrial membrane depolarization and reduction in cell viability; such effects were inhibited by capsazepine, or the NAD(P)H oxidase inhibitor diphenylene iodonium. Both capsaicin and pH 5.5 buffer induced apoptosis as shown by nuclear condensation and fragmentation. Furthermore, RT-PCR readily detected TRPV1 mRNA expression in the isolated synoviocytes. Taken together, these data indicated that TRPV1 activation triggered synoviocyte death by [Ca(2+)](c) elevation, ROS production, and mitochondrial membrane depolarization.