A Study of the Fluorine Effect in C-H Borylation

Iridium-catalysed C-H borylation of fluoroarenes represents a very powerful method for the synthesis of fluorinated aryl boronic esters, which are a range of versatile synthetic building blocks. Following a brief review of the developments of Ir-catalysed C-H borylation reactions and synthesis of fluoroaromatics, this thesis describes the investigation of the influence of fluorine substituents on selectivity and effectiveness of iridium-catalysed C-H borylation of polyfluorinated arenes. As observed through the reactions of 1-fluoro-4-methylbenzene, 1-bromo-4-fluorobenzene, and other related substrates, simple fluoroarenes react considerably faster than their non-fluorinated counterparts. Polyfluoroarenes and fluorinated pyridines are even more reactive substrates. The fluorine atom is of low steric bulk and this coupled with a strong inductive electron-withdrawing effect leads to the activation of the C-H bonds ortho to a fluorine atom. However, with 1,3-difluoro-2-substituted arenes, as the electron-withdrawing nature of the 2-substituent increases there is a corresponding increase in the formation of the 1,3-difluoro-5-Bpin product. The parent arene, 1,3-difluorobenzene, shows variable selectivity depending on the nature of the boron source (B2pin2 and HBpin) and this observation challenges the accepted catalytic cycle for these reagents for which the key C-H activation step is supposed to be common. The resulting fluorinated aryl boronic esters can be used in the synthesis of fluorinated biaryls through Suzuki-Miyaura cross-coupling reactions using CsF as an anhydrous base to circumvent protodeboronation observed with more classical aqueous base conditions

Effects of sitagliptin on blood glucose, lipids, pancreatic β cell secretory function and insulin resistance in patients with type 2 diabetes mellitus

Purpose: To study the influence of sitagliptin on blood glucose, lipid and pancreatic β cell function in type II diabetes mellitus (T2DM) patients.Methods: Two groups of T2DM patients (100/group) received either metformin only (control group), or metformin plus sitaglipin (study group) for 3 months. Blood lipid profiles, fasting blood glucose (FBG), indices of pancreatic function and insulin resistance were assayed using standard biochemical methods.Results: The metformin-sitaglipin combination resulted in significant decreases in FBG, 2-h PBG, HbAlc total cholesterol (TC), triacylglycerol, and low-density lipoprotein cholesterol (LDL-C), when compared with the metformin-only treatment (p < 0.05). Although there were significant decreases in pancreatic secretion of insulin, fasting insulin, and 2 h postprandial insulin in the two groups, these parameters were significantly lower in the metformin-only treated patients than in those with combination treatment (p < 0.05).Conclusion: Sitagliptin normalizes fasting blood glucose, lipid profiles and insulin secretion in type II diabetes mellitus (T2DM) patients.Keywords: Type 2 diabetes mellitus, Sitagliptin, Blood glucose, Pancreatic islet function, Insuli

Iridium‐Catalysed C−H Borylation of Fluoroarenes: Insights into the Balance between Steric and Electronic Control of Regioselectivity

The iridium catalysed C−H borylation of polyfluorinated arenes and heteroarenes occurs rapidly and efficiently. As with other borylation reactions, whilst steric parameters dominate, an underlying electronic influence on reaction selectivity can be observed. Notably borylation regioselectivity in fluorinated (hetero)arenes is determined by purely electronic effects except for ortho-borylation between two fluorine atoms where steric effects of fluorine substituents become apparent. Borylation at the para position with respect to fluorine is disfavoured whereas a strong electronic preference for borylation para to the azinyl nitrogen of pyridine is observed. When these features co-operate high selectivity can be expected. For these reactions, computations based on transition state, rather than intermediate, energies in iridium geometries showed excellent agreement between predicted and observed selectivities

Incremental value of non-invasive myocardial work for the evaluation and prediction of coronary microvascular dysfunction in angina with no obstructive coronary artery disease

BackgroundEvidence suggests that patients suffering from angina with no obstructive coronary artery disease (ANOCA) experience coronary microvascular dysfunction (CMD). We aimed to understand the diagnosis value of noninvasive myocardial work indices (MWIs) with left ventricular pressure-strain loop (LV PSL) by echocardiography in ANOCA patients with CMD.Methods97 patients with ANOCA were recruited. All subjects underwent standard echocardiography with traditional ultrasound parameters, two-dimensional speckle-tracking echocardiography with global longitudinal strain (GLS), LV PSL with MWIs include global work index (GWI), global constructive work (GCW), global waste work (GWW) and global work efficiency (GWE). In addition, all enrolled cases underwent high-dose adenosine stress echocardiography (SE) with coronary flow velocity reserve (CFVR). CMD was defined as CFVR <2.0.ResultsOf the 97 patients with ANOCA, 52 were placed in the CMD group and 45 in the control group. GWI and GCW were decreased significantly in the CMD group compared with the control group (P < 0.001 for both). GWI and GCW were moderately correlated with CFVR (r = 0.430, P < 0.001 and r = 0.538, P < 0.001, respectively). In the multiple logistic regression analyses, GCW was identified as the only independent echocardiography parameter associated with CMD after adjusting for age and baseline APV [OR (95%CI) 1.009 (1.005–1.013); P < 0.001]. Moreover, the best predictor of CMD in patients with ANOCA using receiver operating characteristic (ROC) curve was GWI and GCW, with an area under the curve (AUC) of 0.800 and 0.832, sensitivity of 67.3% and 78.8%, specificity of 80.0% and 75.6%, respectively.ConclusionMWIs with LV PSL is a new method to detect LV systolic function noninvasively in ANOCA patients with CMD

Fabrication of Asymmetric Polysaccharide Composite Membranes as Guided Bone Regeneration Materials

Periodontal regeneration can be achieved by guided tissue and guided bone regeneration (GTR/GBR) membranes, which act as a physical barrier to exclude migration of connective and epithelium, favoring the repopulation of periodontal ligament cells. Asymmetric polysaccharide GBR membranes with two different surfaces were developed in this study. Positive chitosan (CS), negative hyluronaic acid (HA) and konjac glucomannan (KGM) were composited by electrostatic interaction, forming smooth and dense membranes as upper surface to inhibit the ingrowth of cells from gingiva. The lower porous and coarse surface was obtained by gel freeze-drying and mineralization to improve the regeneration of the bone tissue. The performance of the membranes was characterized by Infrared Radiation (IR), X-ray diffraction (XRD), scanning electron microscope (SEM), tensile strength and biological evaluation. It was found that the composite membranes with chitosan content of 56.7 wt%in the dry state possess the highest tensile strength, with elongation 10 times more higher than that of the pure CS ones. Additionaly, open pores with diameter of 10-100 µm and homogenouse distributed nano-hydroxyapatite (HAP) were investigated on the coarse part. Cell studies demonstrated that the porous surface promoted the growth of the preosteoblast. Overall, the composite membranes may be useful for regeneration of periodontal regeneration

Fstl1 Antagonizes BMP Signaling and Regulates Ureter Development

Bone morphogenetic protein (BMP) signaling pathway plays important roles in urinary tract development although the detailed regulation of its activity in this process remains unclear. Here we report that follistatin-like 1 (Fstl1), encoding a secreted extracellular glycoprotein, is expressed in developing ureter and antagonizes BMP signaling activity. Mouse embryos carrying disrupted Fstl1 gene displayed prominent hydroureter arising from proximal segment and ureterovesical junction defects. These defects were associated with significant reduction in ureteric epithelial cell proliferation at E15.5 and E16.5 as well as absence of subepithelial ureteral mesenchymal cells in the urinary tract at E16.5 and E18.5. At the molecular level, increased BMP signaling was found in Fstl1 deficient ureters, indicated by elevated pSmad1/5/8 activity. In vitro study also indicated that Fstl1 can directly bind to ALK6 which is specifically expressed in ureteric epithelial cells in developing ureter. Furthermore, Sonic hedgehog (SHH) signaling, which is crucial for differentiation of ureteral subepithelial cell proliferation, was also impaired in Fstl1-/- ureter. Altogether, our data suggest that Fstl1 is essential in maintaining normal ureter development by antagonizing BMP signaling

Upregulation of UCP2 by Adiponectin: The Involvement of Mitochondrial Superoxide and hnRNP K

Background: The adipocyte-derived hormone adiponectin elicits protective functions against fatty liver diseases and hepatic injuries at least in part by stimulating the expression of a mitochondrial inner membrane transporter, uncoupling protein 2 (UCP2). The present study was designed to investigate the cellular and molecular mechanisms underlying adiponectin-induced UCP2 expression. Methodology/Principal Findnigs: Mice were treated with adiponectin and/or different drug inhibitors. Parenchymal (PCs) and nonparenchymal (NPCs) cells were fractionated from the liver tissues for mitochondria isolation, Western blotting and quantitative PCR analysis. Mitochondrial superoxide production was monitored by MitoSOX staining and flow cytometry analysis. Compared to control mice, the expression of UCP2 was significantly lower in NPCs, but not PCs of adiponectin knockout mice (AKO). Both chronic and acute treatment with adiponectin selectively increased the mRNA and protein abundance of UCP2 in NPCs, especially in the enriched endothelial cell fractions. The transcription inhibitor actinomycin D could not block adiponectin-induced UCP2 expression, whereas the protein synthesis inhibitor cycloheximide inhibited the elevation of UCP2 protein but not its mRNA levels. Mitochondrial content of heterogeneous nuclear ribonucleoprotein K (hnRNP K), a nucleic acid binding protein involved in regulating mRNA transportation and stabilization, was significantly enhanced by adiponectin, which also evoked a transient elevation of mitochondrial superoxide. Rotenone, an inhibitor of mitochondrial respiratory complex I, abolished adiponectin-induced superoxide production, hnRNP K recruitment and UCP2 expression. Conclusions/Significance: Mitochondrial superoxide production stimulated by adiponectin serves as a trigger to initiate the translocation of hnRNP K, which in turn promotes UCP2 expressions in liver. © 2012 Zhou et al.published_or_final_versio

New methods for the synthesis of sulfur functional groups

Sulfur(VI) functionalities exhibit promising properties for both pharmaceutical and agrochemical applications. Described in this thesis are new methodologies for the synthesis of a range of S(VI) containing compounds, including sulfonimidamides, sulfondiimidoyl fluorides, and sulfondiimidoates. The developed methods exploit sulfinylamine reagents as synthetic linchpins, using organometallic reagents and amines/alcohols as key building blocks, that provide rapid and modular access to these demanding aza-sulfur scaffolds. Chapter 1 is a review introducing sulfur(VI) functional groups, with a focus on the current synthetic methods for accessing sulfonimidamides, sulfondiimidoyl fluorides, and sulfondiimidoates. The properties and applications of these compounds are also considered. Chapter 2 details the discovery of several novel N-silyl sulfinylamines. Notably, a stable sulfinylamine reagent, N-sulfinyltriisopropylsilylamine (TIPS-NSO), enables rapid preparation of primary sulfinamides. A hypervalent iodine-mediated amination of these primary sulfinamides then delivers a diverse range of sulfonimidamides, including a medicinally relevant sulfonimidamide-derivative. Chapter 3 describes the development of a practical synthesis of sulfondiimidoyl fluorides. The route employs organometallic reagents and pre-generated sulfurdiimides as starting materials, proceeding via sulfinamidines, and generating sulfondiimidoyl fluorides with broad structural variation. Divergent syntheses of sulfondiimines and sulfondiimidamides through subsequent SuFEx (sulfur-fluoride exchange) reactions are achieved. Chapter 4 documents a two-step synthetic approach towards sulfondiimidoates, using organometallic reagents, a sulfurdiimide reagent, and alcohols as key components. An iodine(III)-mediated oxidative reaction of primary sulfinamidines directly forms sulfondiimidoates. Variation of the nitrogen substituents of sulfondiimidoates through controlled manipulation is well-tolerated, allowing for the preparation of a series of N-functionalised derivatives. Chapter 5 summaries the research and discusses potential areas for future work. Chapter 6 provides experimental procedures and data for this research

The modular synthesis of sulfondiimidoyl fluorides and their application to sulfondiimidamide and sulfondiimine synthesis

A modular synthesis of sulfondiimidoyl fluorides - the double aza-analogues of sulfonyl fluorides - allowing variation of the carbon and both nitrogen-substituents is reported. The chemistry uses readily available organometallic reagents, commercial sulfinylamines, simple electrophiles, and N-fluorobenzenesulfonimide (NFSI), as the starting materials. The reactions are broad in scope, efficient, and scalable. We show that the sulfondiimidoyl fluoride products can be combined with amines to provide sulfondiimidamides, and with organolithium reagents to provide sulfondiimines, and that reactivity in these transformations can be modulated by variation of the N-substituents