Regio- and Enantioselective Nickel-Catalyzed Ipso- and Remote Hydroamination Utilizing Organic Azides as Amino Sources for the Synthesis of Primary Amines.

Primary amines serve as key synthetic precursors to most other N-containing compounds, which are important in organic and medicinal chemistry. Herein, we present a NiH-catalyzed mild ipso- and remote hydroamination technique that utilizes organic azides as deprotectable primary amine sources. This strategy offers a highly flexible platform for the efficient construction of α-chiral branched primary amines, as well as linear primary amines.

Direct Synthesis of α- and ß-2'-Deoxynucleosides with Stereodirecting Phosphine Oxide via Remote Participation.

2'-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on ß-2'-deoxynucleosides with the natural ß-configuration. In fact, their isomeric α-2'-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both α- and ß-2'-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare α-2'-deoxynucleosides with an easily accessible 3,5-di-ODPP donor. Instead of acting as a H-bond acceptor on a 2-(diphenylphosphinoyl)acetyl (DPPA) group in our previous studies for syn-facial O-glycosylation, the phosphine oxide moiety here acts as a remote participating group to enable highly antifacial N-glycosylation. This proposed remote participation mechanism is supported by our first characterization of an important 1,5-briged P-heterobicyclic intermediate via variable-temperature NMR spectroscopy. Interestingly, antiproliferative assays led to a α-2'-deoxynucleoside with IC50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its ß-anomer exhibited no inhibition at 100 µM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.

Synthesis and Structural Revision of a Natural Tetrasaccharide from Starfish Asterias rollestoni Bell.

Starfish provide important saponins with diverse bioactivities as the secondary metabolites, among which 2-O-glycosylated glycosides are commonly found. Preparation of those 1,2-trans 2-O-glycosylated glycosides usually relies on 2-O-acyl participation requiring the selective installation and cleavage of 2-O-acyl groups. A convergent synthesis using 2-O-glycosylated oligosaccharide donors would be more straightforward but also pose greater challenges. Herein, we report a convergent synthesis of a distinctive tetrasaccharide isolated from starfish Asterias rollestoni Bell. Dual 2-(diphenylphosphinoyl)acetyl (DPPA) groups at O3 and O4 on galactose moiety led to high ß-selectivities (ß/α=12/1 or ß only) in the challenging [2+2] glycosylation, giving the desired tetrasaccharides in >90 % yields from the 2-O-glycosylated disaccharide donors. These synthetic studies have also unambiguously revised the structure of these natural tetrasaccharides. This work would facilitate further studies on new inhibitors of α-glucosidase as hypoglycemic drugs.

Conformational Modulation of Efficient Macrocyclic Emitters Featuring Delayed Fluorescence by Conjugation Length and Cavity Dimensions.

The π-conjugated macrocyclic emitters with thermally activated delayed fluorescence (TADF) characteristics have attracted widespread attention in the field of organic electroluminescence (EL) materials due to their unique geometries and excellent luminescence performance. Despite the significant impact of conjugation length and cavity dimensions on molecular conformation, the influence of these factors on the excited-state properties remains understudied. Herein, we formulated a strategy aimed at modulating the conformation of TADF macrocyclic molecules containing aniline as the donor (D) unit, and triazine as the acceptor (A), linked in D-A and D-π-A alternative macrocyclic construction (MC-TNT and MC-TST). Corroborated by experimental and theoretical analyses, the compact and conformationally twisted MC-TNT exhibits efficient blue luminescence in crystalline state, facilitating EL at high doping concentrations with maximum external quantum efficiency (EQEmax) of 13.9%, leading the field of blue macrocyclic emitters. Notably, MC-TST with π-bridge and flat conformation, demonstrates diminished Coulombic repulsion, achieving nearly 100% photoluminescence quantum yield and superior horizontal dipole orientation of 85% in 5 wt% doped films, and the corresponding device's EQEmax reaches record-high 32.7% within the TADF macrocyclic domain.

Direct Synthesis of 2,6-Dideoxy-ß-glycosides and ß-Rhamnosides with a Stereodirecting 2-(Diphenylphosphinoyl)acetyl Group.

Anomeric stereocontrol is usually one of the major issues in the synthesis of complex carbohydrates, particularly those involving ß-configured 2,6-dideoxyglycoside and d/l-rhamnoside moieties. Herein, we report that 2-(diphenylphosphinoyl)acetyl is highly effective as a remote stereodirecting group in the direct synthesis of these challenging ß-glycosides under mild conditions. A deoxy-trisaccharide as a mimic of the sugar chain of landomycin E was prepared stereospecifically in high yield. The synthetic potential was also highlighted in the synthesis of Citrobacter freundii O-antigens composed of a [→4)-α-d-Manp-(1→3)-ß-d-Rhap(1→4)-ß-d-Rhap-(1→] repeating unit, wherein the convergent assembly up to a nonasaccharide was realized with a strongly ß-directing trisaccharide donor. Variable-temperature NMR studies indicate the presence of intermolecular H-bonding between the donor and the bulky acceptor as direct spectral evidence in support of the concept of hydrogen-bond-mediated aglycone delivery.

More than a Leaving Group: N-Phenyltrifluoroacetimidate as a Remote Directing Group for Highly α-Selective 1,2-cis Glycosylation.

The anomeric configuration can greatly affect the biological functions and activities of carbohydrates. Herein, we report that N-phenyltrifluoroacetimidoyl (PTFAI), a well-known leaving group for catalytic glycosylation, can act as a stereodirecting group for the challenging 1,2-cis α-glycosylation. Utilizing rapidly accessible 1,6-di-OPTFAI glycosyl donors, TMSOTf-catalyzed glycosylation occurred with excellent α-selectivity and broad substrate scope, and the remaining 6-OPTFAI group can be cleaved chemoselectively. The remote participation of 6-OPTFAI is supported by the first characterization of the crucial 1,6-bridged bicyclic oxazepinium ion intermediates by low-temperature NMR spectroscopy. These cations were found to be relatively stable and mainly responsible for the present stereoselectivities. Further application is highlighted in glycosylation reactions toward trisaccharide heparins as well as the convergent synthesis of chacotriose derivatives using a bulky 2,4-di-O-glycosylated donor.

Single-nucleotide polymorphism rs4142441 and MYC co-modulated long non-coding RNA OSER1-AS1 suppresses non-small cell lung cancer by sequestering ELAVL1.

Single-nucleotide polymorphisms (SNP) and long non-coding RNAs (lncRNAs) have been involved in the process of lung cancer. Following clues given by lung cancer risk-associated SNP, we aimed to find novel functional lncRNAs as candidate targets in lung cancer. We identified a lncRNA Oxidative Stress Responsive Serine Rich 1 Antisense RNA 1 (OSER1-AS1) through a lung cancer risk-associated SNP rs4142441. OSER1-AS1 was down-regulated in tumor tissue and its low expression was significantly associated with poor overall survival among non-smokers in non-small cell lung cancer (NSCLC) patients. Gain- and loss-of-function studies showed that OSER1-AS1 acted as a tumor suppressor by inhibiting lung cancer cell growth, migration and invasion in vitro. Xenograft tumor assays and a metastasis mouse model confirmed that OSER1-AS1 suppressed tumor growth and metastasis in vivo. The promoter of OSER1-AS1 was repressed by MYC, and the 3'-end of OSER1-AS1 was competitively targeted by microRNA hsa-miR-17-5p and RNA-binding protein ELAVL1. Our results indicated that OSER1-AS1 exerted tumor-suppressive functions by acting as an ELAVL1 decoy to keep it away from its target mRNAs. Our findings characterized OSER1-AS1 as a new tumor-suppressive lncRNA in NSCLC, suggesting that OSER1-AS1 may be suitable as a potential biomarker for prognosis, and a potential target for treatment.

Early kidney injury predicts disease progression in patients with COVID-19: a cohort study.

BACKGROUND: The receptor of severe respiratory syndrome coronavirus 2 (SARS-CoV-2), angiotensin-converting enzyme 2, is more abundant in kidney than in lung tissue, suggesting that kidney might be another important target organ for SARS-CoV-2. However, our understanding of kidney injury caused by Coronavirus Disease 2019 (COVID-19) is limited. This study aimed to explore the association between kidney injury and disease progression in patients with COVID-19. METHODS: A retrospective cohort study was designed by including 2630 patients with confirmed COVID-19 from Huoshenshan Hospital (Wuhan, China) from 1 February to 13 April 2020. Kidney function indexes and other clinical information were extracted from the electronic medical record system. Associations between kidney function indexes and disease progression were analyzed using Cox proportional-hazards regression and generalized linear mixed model. RESULTS: We found that estimated glomerular filtration rate (eGFR) and creatinine clearance (Ccr) decreased in 22.0% and 24.0% of patients with COVID-19, respectively. Proteinuria was detected in 15.0% patients and hematuria was detected in 8.1% of patients. Hematuria (HR 2.38, 95% CI 1.50-3.78), proteinuria (HR 2.16, 95% CI 1.33-3.51), elevated baseline serum creatinine (HR 2.84, 95% CI 1.92-4.21) and blood urea nitrogen (HR 3.54, 95% CI 2.36-5.31), and decrease baseline eGFR (HR 1.58, 95% CI 1.07-2.34) were found to be independent risk factors for disease progression after adjusted confounders. Generalized linear mixed model analysis showed that the dynamic trajectories of uric acid was significantly related to disease progression. CONCLUSION: There was a high proportion of early kidney function injury in COVID-19 patients on admission. Early kidney injury could help clinicians to identify patients with poor prognosis at an early stage.

Association between short-term ambient air pollution and outpatient visits of anxiety: A hospital-based study in northwestern China.

Anxiety, a common and devastating mental disorder, has raised widespread interests. The impacts of air pollution on physical health are well known, whereas few studies have explored the association of atmospheric pollution, especially short-term air pollution exposure, with the risk of anxiety disorders. In addition, there are increasing concerns in emerging evidence supporting a possible etiological link. Therefore, our aim was to evaluate the relationship between short-term exposure to atmospheric pollutants and anxiety outpatient visits in Xi'an, a city of northwestern China and a metropolis with relatively heavy air pollution. We collected the data of both daily outpatient visits and daily air pollution (SO2, NO2, and PM10) between January 1, 2010 and January 31, 2016 (2222 days). To clarify the association between short-term ambient atmospheric pollution exposure and anxiety outpatient visits, an over-dispersed Poisson generalized additive model was applied by adjusting the day of the week and weather conditions (including temperature, humidity, sunlight hours, and rainfalls). Positive association between gaseous air pollutants (SO2 and NO2) and anxiety daily outpatient visits was observed. Moreover, the largest estimated values of both SO2 and NO2 were evidence at lag 03 (4-day moving average lag), with 10 µg/m3 increase corresponded to the increase of outpatient anxiety visits at 4.11% (95% CI: 2.15%, 6.06%) for SO2 and 3.97% (95% CI: 1.90%, 6.06%) for NO2. However, there was no differences in susceptibility to air pollutants between different genders as well as different ages. Taken together, short-term exposure to ambient air pollutants, especially gaseous air pollutants (NO2 and SO2), can be related to higher risk of anxiety outpatient visits.

Recent Progress in the Construction of Natural De-O-Sulfonated Sulfonium Sugars with Antidiabetic Activities.

A group of sulfonium salts equipped with a polyhydroxylated side-chain structure have been isolated and identified as potent α-glycosidase inhibitors. Consequently, they have become an attractive target in diverse research disciplines, including organic synthesis, drug discovery, and chemical biology. To this end, the development of practical and effective synthetic strategies, especially for more bioactive de-O-sulfonated sulfonium salts, is a significant research area in organic synthesis. An ideal synthetic methodology should provide easily accessible intermediates with high chemical stability for the key coupling reaction to diastereoselectively construct the sulfonium cation center. This minireview summarizes recently developed strategies applied in the construction of natural de-O-sulfonated sulfonium sugars: 1) acid-catalyzed de-O-sulfonation of sulfonium sulfate inner salts, 2) a coupling reaction between side-chain fragments containing leaving groups and a thiosugar, 3) a coupling reaction between side-chain fragments containing epoxide structures and a thiosugar, and 4) a two-step sequential SN 2 nucleophilic substitution between side-chain fragments containing thiol groups and a diiodide derivative.

Melatonin attenuates expression of cyclooxygenase-2 (COX-2) in activated microglia induced by lipopolysaccharide (LPS).

Lipopolysaccharide (LPS) is a known neurotoxin and utilized most extensively as a microglial activator for induction of inflammatory neurodegeneration. Melatonin (MEL) is the main secretory product of pineal gland reported to be responsible for a variety of physiological functions. However, the molecular mechanisms underlying the influence of MEL on microglia activation remain unclear. The aim of this study was to investigate the effect of MEL on cyclooxygenase-2 (COX-2) levels in LPS-induced microglia. The results of RT-PCR and Western blot analysis showed that MEL significantly inhibited LPS-mediated upregulation of COX-2 in microglia. Data from ELISA demonstrated that prostaglandin E2 (PGE2), the downstream effector of COX-2, concentrations were also reduced. In addition, MEL was found to decrease activation of ERK1/2, JNK, p38 MAPK, and NF-κB, the upstream signal pathways of COX-2. Taken together, evidence indicates that MEL may attenuate upregulation of COX-2 by blocking the MAPK/NF-κB signaling pathway in LPS-stimulated microglia.

Design, Synthesis and Biological Evaluation of Nitrate Derivatives of Sauropunol A and B as Potent Vasodilatory Agents.

A group of nitrate derivatives of naturally occurring sauropunol A and B were designed and synthesized. Nitric oxide (NO) releasing capacity and vasodilatory capacity studies were performed to explore the structure-activity relationship of resulted nitrates. Biological evaluation of these compounds revealed that most of the synthesized mononitrate derivatives demonstrated superior releasing capacity than isosorbide mononitrate (ISMN), and 2MNS-6 even demonstrated stronger NO releasing capacity than isosorbide dinitrate (ISDN). Two dinitrates, DNS-1 and DNS-2, showed higher NO releasing capacity than ISDN. Evaluation of inhibitory activities to the contractions in mesenteric artery rings revealed that 2MNS-8 and DNS-2 showed stronger vasorelaxation activities than ISDN. High level of NO and soluble guanylyl cyclase (sGC) may be essential for the potent vasodilatory effect of DNS-2. The vasodilatory effects of DNS-2 may result from cellular signal transduction of NO-sGC-cGMP. DNS-2 was found to be the most potent sauropunol-derived nitrate vasodilatory agent for further pharmaceutical investigation against cardiovascular diseases.

Practical Route to Neokotalanol and Its Natural Analogues: Sulfonium Sugars with Antidiabetic Activities.

An efficient and divergent approach toward the synthesis of all four de-O-sulfonated sulfonium type α-glucosidase inhibitors, originally isolated from plants of genus Salacia, is reported for the first time. The key strategy features a coupling reaction between thiol derivatives and a diiodide counterpart. The newly designed thiol coupling partner presents high chemical stability, while the diiodide partner could be easily obtained with increased overall yields compared with conventional routes. The intermolecular nucleophilic substitution reaction followed by a diastereoselective intramolecular cyclization provided the target five-member sulfonium salt structure, which was connected in an α-orientation to a polyhydroxylated side-chain moiety.

Predicting obstructive coronary artery disease using carotid ultrasound parameters: A nomogram from a large real-world clinical data.

BACKGROUND: Carotid ultrasound is a noninvasive tool for risk assessment of coronary artery disease (CAD). There is no consensus on which carotid ultrasound parameter constitutes the best measurement of atherosclerosis. We investigated which model of carotid ultrasound parameters and clinical risk factors (CRF) has the highest predictive value for CAD. MATERIALS AND METHODS: We enrolled 2431 consecutive patients who have suspected CAD and underwent coronary angiography and carotid ultrasound with measurements of carotid intima-media thickness (CIMT), total number of plaques and areas of different types of plaques classified by echogenicity. RESULTS: Total number of plaques demonstrated the highest incremental prediction ability to predict CAD over CRF (area under the curve [AUC] 0.752 vs 0.701, net reclassification index [NRI] = 0.514, P < .001), followed by area of maximum mixed and soft plaques. CIMT had no significant incremental value over CRF (AUC 0.704 vs 0.701, P = .241; NRI = 0.062, P = .168). The model comprising total number of plaques, areas of maximum soft, hard and mixed plaques plus CRF had the highest discriminatory (AUC = 0.757) and reclassification value (NRI = 0.567) for CAD. A nomogram based on this model was developed to predict CAD. For subjects at low and intermediate risk, the model comprising total number of plaques plus CRF was the best. CONCLUSIONS: Total number of plaques, area of maximum soft, hard and mixed plaques showed significantly incremental prediction ability over CRF. A nomogram based on these factors provided an intuitive and practical method in detecting CAD.

Diastereoselective Synthesis of Salacinol-Type α-Glucosidase Inhibitors.

A facile and highly diastereoselective approach toward the synthesis of potent salacinol-type α-glucosidase inhibitors, originally isolated from plants of the genus "Salacia", was developed using the S-alkylation of thiosugars with epoxides in HFIP (∼90%, dr, α/ß = ∼ 26/1). The dr ratio of the product was significantly improved by the protocol as compared to that of the conventional S-alkylation of thiosugars (dr, α/ß = ∼ 8/1). The protocol could be used for gram scale synthesis of the desired compounds. The 3'-O-benzylated salacinol analogs, which are the most potent in vitro inhibitors to date, were synthesized and evaluated in vivo; all analogs suppressed blood glucose levels in maltose-loaded mice, at levels comparable to those of the antidiabetic agent, voglibose.

Association of Systemic Inflammation Score With Atrial Fibrillation: A Case-Control Study With Propensity Score Matching.

BACKGROUND: Inflammation plays a key role in the initiation and progression of atrial fibrillation (AF). We developed a novel systemic inflammation score (SIS) based on integration of biomarkers used routinely in clinical settings. We aim to explore the association between SIS and AF. METHODS: A matched case-control study with 376 pairs of AF cases and controls was performed using a propensity score matching system. The SIS was developed by integrating albumin (ALB), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocytes to monocytes ratio (LMR). Univariate and multivariate analyses were performed to examine the association of each marker and SIS with AF. RESULTS: The conditional multivariate logistic regression analysis showed that elevated levels of ALB and LMR were significantly associated with decreased risk of AF with an OR of 0.74 (95% CI: 0.65, 0.85) and 0.73 (95% CI: 0.64, 0.83), respectively. Patients with elevated SIS had a significantly higher risk of AF. Compared to the patients with SIS equal to 1, the patients with SIS equal to 3 and 4 had an OR of 2.16 (95% CI: 1.40 3.32), and 2.55 (95% CI: 1.66, 3.92), respectively. The SIS was positively correlated with left atrial diameter and right atrial diameter in patients with AF. CONCLUSIONS: In conclusion, this study provides further clinical epidemiological evidence that systemic inflammatory status was correlated with AF. The SIS, as an index to evaluate the intensity of systemic inflammatory status, could be useful for early prediction of AF development and understanding of AF mechanism.

6,7-Seco-ent-Kauranoids Derived from Oridonin as Potential Anticancer Agents.

Structurally unique 6,7-seco-ent-kaurenes, which are widely distributed in the genus Isodon, have attracted considerable attention because of their antitumor activities. Previously, a convenient conversion of commercially available oridonin (1) to 6,7-seco-ent-kaurenes was developed. Herein, several novel spiro-lactone-type ent-kaurene derivatives bearing various substituents at the C-1 and C-14 positions were further designed and synthesized from the natural product oridonin. Moreover, a number of seven-membered C-ring-expanded 6,7-seco-ent-kaurenes were also identified for the first time. It was observed that most of the spiro-lactone-type ent-kaurenes tested markedly inhibited the proliferation of cancer cells, with an IC50 value as low as 0.55 µM. An investigation on its mechanism of action showed that the representative compound 7b affected the cell cycle and induced apoptosis at a low micromolar level in MCF-7 human breast cancer cells. Furthermore, compound 7b inhibited liver tumor growth in an in vivo mouse model and exhibited no observable toxic effects. Collectively, the results warrant further preclinical investigations of these spiro-lactone-type ent-kaurenes as potential novel anticancer agents.

A central role for GRB10 in regulation of islet function in man.

Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.

Next-generation sequencing reveals deep intronic cryptic ABCC8 and HADH splicing founder mutations causing hyperinsulinism by pseudoexon activation.

Next-generation sequencing (NGS) enables analysis of the human genome on a scale previously unachievable by Sanger sequencing. Exome sequencing of the coding regions and conserved splice sites has been very successful in the identification of disease-causing mutations, and targeting of these regions has extended clinical diagnostic testing from analysis of fewer than ten genes per phenotype to more than 100. Noncoding mutations have been less extensively studied despite evidence from mRNA analysis for the existence of deep intronic mutations in >20 genes. We investigated individuals with hyperinsulinaemic hypoglycaemia and biochemical or genetic evidence to suggest noncoding mutations by using NGS to analyze the entire genomic regions of ABCC8 (117 kb) and HADH (94 kb) from overlapping ~10 kb PCR amplicons. Two deep intronic mutations, c.1333-1013A>G in ABCC8 and c.636+471G>T HADH, were identified. Both are predicted to create a cryptic splice donor site and an out-of-frame pseudoexon. Sequence analysis of mRNA from affected individuals' fibroblasts or lymphoblastoid cells confirmed mutant transcripts with pseudoexon inclusion and premature termination codons. Testing of additional individuals showed that these are founder mutations in the Irish and Turkish populations, accounting for 14% of focal hyperinsulinism cases and 32% of subjects with HADH mutations in our cohort. The identification of deep intronic mutations has previously focused on the detection of aberrant mRNA transcripts in a subset of disorders for which RNA is readily obtained from the target tissue or ectopically expressed at sufficient levels. Our approach of using NGS to analyze the entire genomic DNA sequence is applicable to any disease.

Total synthesis, structural elucidation and anti-inflammatory activity evaluation of 2-deoxy-3,6-anhydro hexofuranoside derivatives isolated from Sauropus rostratus.

The first total synthesis of four 2-deoxy-3,6-anhydro hexofuranoside derivatives, namely sauropunols (A-D), isolated from the traditional Chinese medicinal plant Sauropus rostratus was accomplished. Structures of sauropunols A and B were clearly elucidated and reassigned. The anti-inflammatory activities of sauropunols (A-D) as well as the synthetic intermediates were evaluated, which is valuable for further structure-activity relationship (SAR) studies on this class of natural products.