TFA-Promoted Cascade Sulfonylation/Rearrangement/Cyclization of 1,5-Diynols and Sodium Sulfinates to Construct Sulfonylated Benzo[b]fluorenes.

A novel conversion of 1,5-diynols into sulfonylated benzo[b]fluorenes is reported by a TFA-promoted cascade cyclization with sodium sulfinates under mild conditions. This strategy provides an efficient and practical approach for accessing various sulfonated benzo[b]fluorenes in moderate to excellent yields under metal-free conditions. On the basis of the control experimental results and density functional theory calculations, a possible cascade transformation mechanism consisting of the dehydration of propargylic alcohols, sulfonylation, allenylation, and Schmittel-type cyclization is proposed. It is worth noting that TFA played an important role in this cascade cyclization, which promoted C-SO2R bond cleavage in a propargylic sulfone intermediate to form allenyl sulfones, followed by Schmittel-type cyclization to give the target product.

Synthesis of gem-dibromo 1,3-oxazines by NBS-mediated electrophilic cyclization of propargylic amides.

We present a highly efficient and practical method for synthesizing gem-dibromo 1,3-oxazines through 6-endo-dig cyclization of propargylic amides, using N-bromosuccinimide (NBS) as an electrophilic source. The metal-free reaction can be conducted under mild conditions with good functional group compatibility, delivering excellent yields of the desired products. Mechanistic studies suggest that the reaction proceeds via a double electrophilic attack by NBS on the propargylic amide substrate.

Electrochemically enabled decyanative C(sp3)-H oxygenation of N-cyanomethylamines to formamides.

Selective oxygenation of C(sp3)-H bonds adjacent to nitrogen atoms is a highly attractive strategy for synthesizing various formamide derivatives while preserving the substrate skeletons. Herein, an environmentally benign electrochemically enabled decyanative C(sp3)-H oxygenation of N-cyanomethylamines using H2O as a carbonyl oxygen atom source is described, leading to the synthesis of a large class of formamides in good to excellent yields with a broad substrate scope under metal- and oxidant-free conditions. This electrochemical technology highlights the facile incorporation of N-formyl into some important bioactive molecules.

The Association of Low Hemoglobin Levels with IgA Nephropathy Progression: A Two-Center Cohort Study of 1,828 Cases.

AIM: To investigate the relationship between hemoglobin levels and the progression of IgA nephropathy (IgAN). METHODS: In a two-center cohort of 1,828 cases with biopsy-proven IgAN, we examined the association of hemoglobin levels with the primary outcome of a composite of all-cause mortality or kidney failure defined as a 40% decline in eGFR, or ESKD (defined as eGFR <15 mL/min/1.73 m2 or need for kidney replacement therapy including hemodialysis, peritoneal dialysis, or kidney transplantation), or the outcome of kidney failure, assessed using Cox and logistic regression models, respectively, with adjustment for confounders. RESULTS: At baseline, mean age, eGFR, and hemoglobin levels were 33.75 ± 11.03 years, 99.70 ± 30.40 mL/min/1.73 m2, and 123.47 ± 18.36 g/L, respectively. During a median of approximately 7-year follow-up, 183 cases reached the composite outcome. After adjustment for demographic and IgAN-specific covariates and treatments, a lower quartile of hemoglobin was nonlinearly associated with an increased risk of the primary outcome or kidney failure in the Cox proportional hazards models (primary outcome: HR for quartile 3 vs. 4, 1.37; 95% CI, 0.83-2.25; HR for quartile 2 vs. 4, 1.18; 95% CI, 0.68-2.07; HR for quartile 1 vs. 4, 1.91; 95% CI, 1.15-3.17; kidney failure: HR for quartile 3 vs. 4, 1.39; 95% CI, 0.84-2.31; HR for quartile 2 vs. 4, 1.20; 95% CI, 0.68-2.11; HR for quartile 1 vs. 4, 1.83; 95% CI, 1.09-3.07) in the fully adjusted model. Then, hemoglobin levels were transformed to a binary variable for fitting the model according to the criteria for anemia of 110 g/L in the women and 120 g/L in men in China. The participants in the anemia group had an increased risk of developing outcomes compared with the nonanemia group in both genders (primary outcome: male: HR, 1.64; 95% CI, 1.01-2.68; female: HR, 1.68; 95% CI, 1.02-2.76; kidney failure: male: HR, 1.60; 95% CI, 0.97-2.64; female: HR, 1.58; 95% CI, 0.95-2.61) in the fully adjusted model. CONCLUSIONS: A low level of hemoglobin was nonlinearly associated with IgAN progression. The anemic IgAN patients presented a higher risk of developing poor outcomes compared with the nonanemic patients.

DMSO/t-BuONa/O2-Mediated Aerobic Dehydrogenation of Saturated N-Heterocycles.

Aromatic N-heterocycles such as quinolines, isoquinolines, and indolines are synthesized via sodium tert-butoxide-promoted oxidative dehydrogenation of the saturated heterocycles in DMSO solution. This reaction proceeds under mild reaction conditions and has a good functional group tolerance. Mechanistic studies suggest a radical pathway involving hydrogen abstraction of dimsyl radicals from the N-H bond or α-C-H of the substrates and subsequent oxidation of the nitrogen or α-aminoalkyl radicals.

First Total Synthesis of 5'-O-α-d-Glucopyranosyl Tubercidin.

The first total synthesis of 5'-O-α-d-glucopyranosyl tubercidin was successfully developed. It is a structurally unique disaccharide 7-deazapurine nucleoside exhibiting fungicidal activity, and was isolated from blue-green algae. The total synthesis was accomplished in eight steps with 27% overall yield from commercially available 1-O-acetyl-2,3,5-tri-O-benzoyl-ß-d-ribose. The key step involves stereoselective α-O-glycosylation of the corresponding 7-bromo-6-chloro-2',3'-O-isopropylidene-ß-d-tubercidin with 2,3,4,6-tetra-O-benzyl-glucopyranosyl trichloroacetimidate. All spectra are in accordance with the reported data for natural 5'-O-α-d-glucopyranosyl tubercidin. Meanwhile, 5'-O-ß-d-glucopyranosyl tubercidin was also prepared using the same strategy.

The protective effect of Phellinus linteus decoction on podocyte injury in the kidney of FSGS rats.

BACKGROUND: This study aimed to investigate the effect of the Phellinus linteus (Mesima) decoction on podocyte injury in a rat model of focal and segmental glomerulosclerosis (FSGS) and evaluate the potential mechanisms. METHODS: FSGS resembling primary FSGS in humans was established in rats by uninephrectomy and the repeated injection of doxorubicin. The FSGS rats were randomly divided into the model group, low-dose group of P. linteus decoction (PLD-LD), medium-dose group of P. linteus decoction (PLD-MD), and high-dose group of P. linteus decoction (PLD-HD). Blood and urine analysis were performed after 12 weeks and the molecular indicators of renal function and the renal pathological changes were examined. RESULTS: FSGS developed within 12 weeks in the test group and showed progressive proteinuria and segmental glomerular scarring. Urinary protein, serum creatinine, urea nitrogen, triglycerides and cholesterol were significantly reduced following the 12-week intervention with P.linteus decoction, especially in the PLD-LD group. Renal nephrin and podocin were markedly increased. Moreover, the pathological damage in the renal tissue was alleviated by the PLD-LD intervention. CONCLUSION: The P. linteus decoction alleviated the podocyte injury in the FSGS rat model, thus minimizing the progression of glomerular sclerosis and improving renal function.

TMSBr-Promoted Cascade Cyclization of ortho-Propynol Phenyl Azides for the Synthesis of 4-Bromo Quinolines and Its Applications.

Difficult-to-access 4-bromo quinolines are constructed directly from easily prepared ortho-propynol phenyl azides using TMSBr as acid-promoter. The cascade transformation performs smoothly to generate desired products in moderate to excellent yields with good functional groups compatibility. Notably, TMSBr not only acted as an acid-promoter to initiate the reaction, and also as a nucleophile. In addition, 4-bromo quinolines as key intermediates could further undergo the coupling reactions or nucleophilic reactions to provide a variety of functionalized compounds with molecular diversity at C4 position of quinolines.

An Efficient Approach to Phosphorylated Isoindoline Fused with Triazoles via Zn-Catalyzed Cascade Cyclization of 2-Propynol Benzyl Azides and Diarylphosphine Oxides.

An efficient approach for the synthesis of phosphorylated isoindoline fused with triazoles via Zn(OTf)2-catalyzed cascade cyclization of easily prepared ortho-propynol benzyl azides and diarylphosphine oxides is developed. The transformation occurred smoothly in moderate to excellent yields and tolerated various propargylic alcohol substrates.

Bone marrow mesenchymal stem cells attenuate the progression of focal segmental glomerulosclerosis in rat models.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is the most common glomerular etiology of end-stage kidney disease (ESKD). Increasing evidence has indicated the reparative potential of mesenchymal stem cells (MSCs) in damaged diseased kidneys. However, the effect of bone marrow mesenchymal stem cells (BMSCs) on the FSGS progression remains unclear. This study aimed to investigate the protective effects of BMSCs on FSGS progression. METHODS: A rat model of FSGS was generated via unilateral nephrectomy plus adriamycin injection. Rat BMSCs were isolated and characterized on the basis of their differentiative potential towards adipocytes and osteoblasts and via flow cytometry analysis. Thereafter, rat BMSCs were transplanted into FSGS recipients through the caudal vein. After 8 weeks, 24-h proteinuria, serum creatinine, and urea nitrogen levels were determined. Renal morphology was assessed using a light and transmission electron microscope. MMP9 and TIMP-1 positive cells were detected via immunohistochemical analysis. Expression levels of proinflammatory cytokines IL-6 and TNF-α were examined via RT-PCR. RESULTS: The isolated adherent cells from the bone marrow of rats were phenotypically and functionally equivalent to typical MSCs. Clinical examination revealed that BMSC transplantation reduced the 24-h urinary protein excretion, and serum creatinine and urea nitrogen levels. Renal morphology was ameliorated in BMSCs-transplanted rats. Mechanistically, BMSC transplantation significantly downregulated TIMP-1 and upregulated MMP9, thereby increasing the renal MMP9/TIMP-1 ratio. Moreover, BMSC transplantation also downregulated IL-6 and TNF-α. CONCLUSIONS: BMSC transplantation can attenuate FSGS progression in a rat model of FSGS, thereby providing a theoretical foundation for the application of autologous BMSCs in clinical FSGS therapy.

Decarboxylative Halogenation and Cyanation of Electron-Deficient Aryl Carboxylic Acids via Cu Mediator as Well as Electron-Rich Ones through Pd Catalyst under Aerobic Conditions.

Simple strategies for decarboxylative functionalizations of electron-deficient benzoic acids via using Cu(I) as promoter and electron-rich ones by employing Pd(II) as catalyst under aerobic conditions have been established, which lead to smooth synthesis of aryl halides (-I, Br, and Cl) through the decarboxylative functionalization of benzoic acids with readily available halogen sources CuX (X = I, Br, Cl), and easy preparation of benzonitriles from decarboxylative cyanation of aryl carboxylic acids with nontoxic and low-cost K4Fe(CN)6 under an oxygen atmosphere for the first time.

(2R,3S,4R,5R)-5-(4-Amino-5-iodo-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)-4-fluoro-2-(hy-droxy-meth-yl)tetra-hydro-furan-3-ol.

The title compound, C11H12FIN4O3, is composed of a 7-carbapurine moiety connected via an N atom to 2-de-oxy-2-fluoro-ß-d-ribose. The conformation about the N-glycosydic bond is -anti with χ = -129.0 (11)°. The glycosydic N-C bond length is 1.435 (14) Å. The sugar ring adopts an Nconformation with an unsymmetrical twist O-endo-C-exo ((o)T4). The conformation around the C-C bond is +sc, with a torsion angle of 53.0 (12)°. In the crystal, mol-ecules are linked by N-H⋯O hydrogen bonds, forming chains propagating along the a axis. These chains are linked via O-H⋯I and C-H⋯O hydrogen bonds, forming layers lying parallel to the c axis.

Concise total synthesis of two marine natural nucleosides: trachycladines A and B.

We report the first total synthesis of trachycladines A (10 steps, 34.2% overall yield) and B (11 steps, 35.0% overall yield) by using 5-deoxy-1,2,3-tri-O-acetyl-ß-D-ribofuranose as the starting material. The critical step was the SnCl4 assisted regio- and steroselective deprotection of perbenzylated 1-O-methyl-5-deoxyribofuranose. The enzyme adenylate deaminase (EC 3.5.4.6) was successfully applied to the chemoenzymatic synthesis of trachycladines B.

Association between renal α-klotho and renal pathology among patients with chronic kidney disease.

INTRODUCTION: This study was designed to investigate whether renal α-klotho levels are associated with renal pathology. This is the first report on patients with chronic kidney disease (CKD). METHODS: We conducted a retrospective observational study. A total of 65 CKD patients were enrolled. Serum and renal biopsy samples were collected. Estimated glomerular filtration rate (eGFR) was examined by biochemical test. And α-klotho expressions were assessed by RT-PCR and immunohistochemistry. In addition, detailed microscopic findings were reviewed. RESULTS: Renal α-klotho levels are associated positively with eGFR, and negatively with renal pathology, including interstitial fibrosis, inflammatory cell infiltration, and tubular atrophy. CONCLUSIONS: The renal α-klotho is related to renal pathology.

Para-selective nitrobenzene amination lead by C(sp2)-H/N-H oxidative cross-coupling through aminyl radical.

Arylamines, serving as crucial building blocks in natural products and finding applications in multifunctional materials, are synthesized on a large scale via an electrophilic nitration/reduction sequence. However, the current methods for aromatic C-H amination have not yet attained the same level of versatility as electrophilic nitration. Here we show an extensively investigated transition metal-free and regioselective strategy for the amination of nitrobenzenes, enabling the synthesis of 4-nitro-N-arylamines through C(sp2)-H/N-H cross-coupling between electron-deficient nitroarenes and amines. Mechanistic studies have elucidated that the crucial aspects of these reactions encompass the generation of nitrogen radicals and recombination of nitrobenzene complex radicals. The C(sp2)-N bond formation is demonstrated to be highly effective for primary and secondary arylamines as well as aliphatic amines under mild conditions, exhibiting exceptional tolerance towards diverse functional groups in both nitroarenes and amines (>100 examples with yields up to 96%). Notably, this C(sp2)-H/N-H cross-coupling exhibits exclusive para-selectivity.

[Study of resveratrol suppressing TGF-beta1 induced transdifferentiation of podocytes].

OBJECTIVE: To explore the effect of resveratrol on transforming growth factor-beta1 (TGF-beta1) induced transdifferentiation of podocytes. METHODS: Mouse podocytes in vitro cultured under differentiating conditions for 10 days were divided into the normal group, the model group, the high dose resveratrol group, and the low dose resveratrol group. The podocytes in the high and low dose resveratrol groups were intervened with 5 micromol/L and 2 micromol/L resveratrol respectively for 30 min. Those in the model group and the two resveratrol treated groups were continually incubated with 5 ng/mL TGF-beta1 for 72 h. Those in the normal group were routinely cultured. The protein expression of podocyte phenotypic protein molecules such as E-cadherin, P-cadherin, zonula occludens-1 (ZO-1), NEPH1, and alpha-smooth muscle-actin (alpha-SMA) were detected by immunocytochemistry, flow cytometry (FCM), and Western blot. A simple albumin influx assay was used to evaluate the filtration barrier function of podocyte monolayer. RESULTS: Compared with the normal control group, E-cadherin (+) percentage rate, the protein expression of P-cadherin, ZO-1, and NEPH1 significantly decreased in the model group (P < 0.05), but the expression of alpha-SMA and albumin permeability across podocyte monolayers increased significantly (P < 0.05). Compared with the model group, E-cadherin (+) percentage rate significantly increased (P < 0.05) and albumin permeability across podocyte monolayers decreased significantly (P < 0.05) in the high and low dose resveratrol groups. In the low dose resveratrol group, the expression of P-cadherin and NEPH1 significantly increased (P < 0.05). In the high dose resveratrol group, the expression of P-cadherin, ZO-1, and NEPH1 increased significantly, and the expression of alpha-SMA decreased significantly (P < 0.05). The correlations between resveratrol concentrations and the expression of E-cadherin (+), P-cadherin, and NEPH1 were significantly positive (r(E-cadherin (+)) = 0.772, r(P-cadherin) = 0.756, r(NEPH1) = 0.809, P < 0.05). CONCLUSION: The role of resveratrol in inhibiting TGF-beta1 induced phenotype abnormality might be an important mechanism for preserving the integrality of glomerular filtration barrier and decreasing proteinuria.

Celastrol attenuates diabetic nephropathy by upregulating SIRT1-mediated inhibition of EZH2related wnt/ß-catenin signaling.

Proteinuria is an independent risk factor for the progression of diabetic nephropathy (DN) and an imbalance in podocyte function aggravates proteinuria. Celastrol is the primary active ingredient of T. wilfordii, effective in treating DN renal injury; however, the mechanisms underlying its effect are unclear. We explored how celastrol prevents DN podocyte damage using in vivo and in vitro experiments. We randomly divided 24 male C57BLKS/J mice into three groups: db/m (n = 8), db/db (n = 8), and celastrol groups (db/db + celastrol, 1 mg/kg/d, gavage administration, n = 8). In vivo experiments lasted 12 weeks and intervention lasted ten weeks. Serum samples and kidney tissues were collected for biochemical tests, pathological staining, transmission electron microscopy, fluorescencequantitation polymerase chain reaction, and western blotting analysis. In vitro experiments to elaborate the mechanism of celastrol protection were performed on high glucose (HG)-induced podocyte injury. Celastrol reduced blood glucose levels and renal function index in db/db mice, attenuated renal histomorphological injury and glomerular podocyte foot injuries, and induced significant anti-inflammatory effects. Celastrol upregulated silent information regulator 2 related enzyme 1(SIRT1) expression and downregulated enhancer of zeste homolog (EZH2), inhibiting the wnt/ß-catenin pathway-related molecules, such as wnt1, wnt7a, and ß-catenin. SIRT1 repressed the promoter activity of EZH2, and was co-immunoprecipitated with EZH2 in mouse podocyte cells (MPC5). SIRT1 knockdown aggravated the protective effects of celastrol on MPC5 cells. Celastrol protected podocyte injury via SIRT1/EZH2, which participates in the wnt/ß-catenin pathway. Overall, celastrol-mediated SIRT1 upregulation inhibited the EZH2-related wnt/ß-catenin signaling pathway to attenuate DN and podocyte injury, providing a theoretical basis for celastrol clinical application.

One-Pot Hydrothermal Synthesis of mSiO2-N-CDs with High Solid-State Photoluminescence as a Fluorescent Probe for Detecting Dopamine.

An effective fluorescent probe (mSiO2-N-CDs) was prepared by embedding N-CDs into mesoporous silica via a simple one-pot hydrothermal reaction and applied to the detection of dopamine (DA). Mesoporous silica not only provided a skeleton to prevent the aggregation of N-CDs but also a medium for the centrifugal collection of N-CDs, avoiding the need for dialysis and freeze-drying. The formation process, phase composition, morphology, and luminescence properties of the composite were studied in detail. The synthesized mSiO2-N-CDs possessed spherical morphology, a smooth surface, and a diameter of approximately 150 nm. The fluorescence results indicated that mSiO2-N-CDs emitted intense blue color fluorescence at 465 nm under the optimal excitation of 370 nm. Because the mesoporous silica effectively inhibited the self-quenching caused by the aggregation of N-CDs, the quantum yield of solid mSiO2-N-CDs powder reached 32.5%. Furthermore, the emission intensity of the solid mSiO2-N-CDs remained constant for 28 days. The good sensitivity and selectivity of mSiO2-N-CDs for DA enabled the establishment of a rapid, simple, and sensitive DA detection method. The linear range was 0-50 µM and the limit of detection was calculated to be 107 nM. This method was used for the determination of DA in urine, with recovery rates ranging between 98% and 100.8%. In addition, the sensing mechanism was characterized by fluorescence lifetime decay and UV-VIS spectral analysis.

NBS-mediated bromination and dehydrogenation of tetrahydro-quinoline in one pot: scope and mechanistic study.

A facile and general approach was developed for the efficient construction of functionalized bromoquinolines by the dehydrogenation of tetrahydroquinolines using NBS as the electrophile and as oxidant. The cascade transformation proceeded with good functional group tolerance under metal-free conditions with a short reaction duration. Various tetrahydroquinolines bearing either electron-rich or electron-deficient groups at different positions were successfully converted into the corresponding target products in moderate to high yields under mild conditions. It is worth noting that the obtained polybromoquinolines could further undergo classic metal-catalyzed cross-coupling reactions with good regioselectivity. The Sonagashira coupling reaction occurred regioselectively in the C-6 position of the obtained products followed by a Suzuki coupling reaction to give multifunctionalized quinolines. The mechanism indicated that electrophilic bromination/radical dehydrogenation sequences occurred in one pot.

Direct Synthesis of Benzo[b]fluorenyl Thiophosphates via Tandem Cyclization of Diynols with (RO)2P(O)SH.

A general and metal-free protocol for the construction of benzo[b]fluorenyl thiophosphates was developed through the cascade cyclization of easily prepared diynols and (RO)2P(O)SH, with water as the only byproduct. The novel transformation involved the allenyl thiophosphate as the key intermediate, followed by Schmittel-type cyclization to achieve the desired products. Notably, (RO)2P(O)SH acted not only as a nucleophile but also as an acid-promoter to initiate the reaction.