First atroposelective Chan-Lam coupling for the synthesis of C-N linked biaryls.

The first atroposelective Chan-Lam coupling for the synthesis of C-N axial enantiomers is reported with good yields and ee. MnO2 additive is crucial for the success of the coupling. The longstanding problem of the lack of enantioselective synthesis to make chiral C-N linked atropisomers is solved.

Syntheses of 25-Adamantyl-25-alkyl-2-methylidene-1α,25-dihydroxyvitamin D3 Derivatives with Structure-Function Studies of Antagonistic and Agonistic Active Vitamin D Analogs.

The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a major regulator of calcium homeostasis through activation of the vitamin D receptor (VDR). We have previously synthesized vitamin D derivatives with large adamantane (AD) rings at position 24, 25, or 26 of the side chain to study VDR agonist and/or antagonist properties. One of them-ADTK1, with an AD ring and 23,24-triple bond-shows a high VDR affinity and cell-selective VDR activity. In this study, we synthesized novel vitamin D derivatives (ADKM1-6) with an alkyl group substituted at position 25 of ADTK1 to develop more cell-selective VDR ligands. ADKM2, ADKM4, and ADKM6 had VDR transcriptional activity comparable to 1,25(OH)2D3 and ADTK1, although their VDR affinities were weaker. Interestingly, ADKM2 has selective VDR activity in kidney- and skin-derived cells-a unique phenotype that differs from ADTK1. Furthermore, ADKM2, ADKM4, and ADKM6 induced osteoblast differentiation in human dedifferentiated fat cells more effectively than ADTK1. The development of vitamin D derivatives with bulky modifications such as AD at position 24, 25, or 26 of the side chain is useful for increased stability and tissue selectivity in VDR-targeting therapy.

Microwave-assisted C-C bond formation of diarylacetylenes and aromatic hydrocarbons on carbon beads under continuous-flow conditions.

The synthesis of polycyclic aromatic compounds generally requires stoichiometric oxidants or homogeneous metal catalysts, however, the risk of contamination of inorganic residues can affect their properties. Here we present a microwave (MW)-assisted platinum on beaded activated carbon (Pt/CB)-catalyzed C-C bond formation of diarylacetylenes and aromatic hydrocarbons under continuous-flow conditions. Various fused aromatic compounds were continuously synthesized via dehydrogenative C(sp2)-C(sp2) and C(sp2)-C(sp3) bond formation with yields of up to 87% without the use of oxidants and bases. An activated, local reaction site on Pt/CB in the flow reaction channel reaching temperatures of more than three hundred degrees Celsius was generated in the catalyst cartridge by selective microwave absorption in CB with an absorption efficiency of > 90%. Mechanistic experiments of the transformation reaction indicated that a constant hydrogen gas supply was essential for activating Pt. This is an ideal reaction with minimal input energy and no waste production.

Enantiodivergent Chemoenzymatic Dynamic Kinetic Resolution: Conversion of Racemic Propargyl Alcohols into Both Enantiomers.

Natural lipases typically recognize enantiomers of alcohols based on the size differences of substituents near the carbinol moiety and selectively react with the R enantiomers of secondary alcohols. Therefore, lipase-catalyzed dynamic kinetic resolution (DKR) of racemic secondary alcohols produces only R enantiomers. We report herein a method for obtaining S enantiomers by DKR of secondary 3-(trialkylsilyl)propargyl alcohols by using a well-known R-selective Pseudomonas fluorescens lipase in combination with a racemization catalyst VMPS4, in which the silyl group reverses the size relationship of substituents near the carbinol moiety. We have already reported R-selective DKR of the corresponding propargyl alcohols without substituents on the ethynyl terminal carbon, and the presence of an easily removable silyl group has enabled us to produce both enantiomers of propargyl alcohols in high chemical yields and with high enantiomeric excess. In addition, immobilization of the lipase on Celite was found to be important for achieving a high efficiency of the DKR.

Aryl Boronic Esters Are Stable on Silica Gel and Reactive under Suzuki-Miyaura Coupling Conditions.

A wide range of aryl boronic 1,1,2,2-tetraethylethylene glycol esters [ArB(Epin)s] were readily synthesized. Purifying aryl boronic esters by conventional silica gel chromatography is generally challenging; however, these introduced derivatives are easily purified on silica gel and isolated in excellent yields. We subjected the purified ArB(Epin) to Suzuki-Miyaura couplings, which provided higher yields of the desired biaryl products than those obtained using the corresponding aryl boronic acids or pinacol esters.

Could London Dispersion Force Control Regioselective (2 + 2) Cyclodimerizations of Benzynes? YES: Application to the Synthesis of Helical Biphenylenes.

In recent years, London dispersion interactions, which are the attractive component of the van der Waals potential, have been found to play an important role in controlling the regio- and/or stereoselectivity of various reactions. Particularly, the dispersion interactions between substrates and catalysts (or ligands) are dominant in various selective catalyzes. In contrast, repulsive steric interactions, rather than the attractive dispersion interactions, between bulky substituents are predominant in most of the noncatalytic reactions. Herein, we demonstrate the first example of London dispersion-controlled noncatalytic (2 + 2) cyclodimerization of substituted benzynes to selectively afford proximal biphenylenes in high yields and regioselectivities, depending on the extent of dispersion interactions in the substituents. This method can be applied for the synthesis of novel helical biphenylenes, which would be fascinating for chemists as these compounds are potential skeletons for ligands, catalysts, and medicines.

One-Pot Generation of Functionalized Benzynes from Readily Available 2-Hydroxyphenylboronic Acids.

We developed a one-pot method for the generation of benzynes from a range of readily available 2-hydroxyphenylboronic acids. This method features the in situ activation of both boronic acid and hydroxyl groups of the substrate to enhance benzyne generation at 60 °C. Such mild conditions facilitate the generation of functionalized benzynes that immediately react with diverse arynophiles to produce multisubstituted fused benzenes.

One-Pot Generation of Benzynes from Phenols: Formation of Primary Anilines by the Deoxyamination of Phenols.

Benzynes were selectively generated in situ from phenols and trapped regioselectively with potassium hexamethyldisilazide to form primary anilines following acidic workup. The direct conversion of a phenolic hydroxyl group into a free amino group is a useful method for the preparation of primary aryl amines that are hard to synthesize by using coupling reactions involving phenol derivatives with ammonia. Whereas reactions of ortho- and meta-substituted phenols produced meta-substituted anilines exclusively, those of para-substituted phenols provided ortho-silylanilines.

Analysis of genes linked to depressive-like behaviors in interleukin-18-deficient mice: Gene expression profiles in the brain.

Interleukin (IL)-18 is an interferon γ-inducing inflammatory cytokine associated with function of the immune system and other physiological functions. IL-18-deficient (Il18 -/-) mice exhibit obesity, dyslipidemia, non-alcoholic steatohepatitis and depressive-like behavioral changes. Therefore, IL-18 has a number of important roles associated with immunity, energy homeostasis and psychiatric conditions. In the present study, gene expression in the brains of Il18 -/- mice was analyzed to identify genes associated with the depressive-like behaviors and other impairments displayed by Il18 -/- mice. Using whole genome microarray analysis, gene expression patterns in the brains of Il18 +/+ and Il18 -/- mice at 6 and 12 weeks of age were examined and compared. Subsequently, genes were categorized using Ingenuity® Pathway Analysis (IPA). At 12 weeks of age, 2,805 genes were identified using microarray analysis. Genes related to 'Major depression' and 'Depressive disorders' were identified by IPA core analysis, and 13 genes associated with depression were isolated. Among these genes, fibroblast growth factor receptor 1 (Fgfr1); protein tyrosine phosphatase, non-receptor type 1 (Ptpn1); and urocortin 3 (Ucn3) were classed as depression-inducing and the other genes were considered depression-suppressing genes. Subsequently, the interactions between the microarray results at 6 weeks of age and the above three depression-inducing genes were analyzed to search for effector genes of depression at 12 weeks of age. This analysis identified cyclin D1 (Ccnd1) and NADPH oxidase 4 (Nox4). The microarray analysis results were correlated with the results of reverse transcription-quantitative PCR (RT-qPCR). Overall, the results suggest that Fgfr1, Ptpn1 and Ucn3 may be involved in depression-like changes and Ccnd1 and Nox4 regulate these three genes in IL-18-deficient mice.

A new approach to identifying hypertension-associated genes in the mesenteric artery of spontaneously hypertensive rats and stroke-prone spontaneously hypertensive rats.

OBJECTIVE: Hypertension is one of the most prevalent diseases in humans who live a modern lifestyle. Alongside more effective care, clarification of the genetic background of hypertension is urgently required. Gene expression in mesenteric resistance arteries of spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP) and two types of renal hypertensive Wistar Kyoto rats (WKY), two kidneys and one clip renal hypertensive rat (2K1C) and one kidney and one clip renal hypertensive rat (1K1C), was compared using DNA microarrays. METHODS: We used a simultaneous equation and comparative selection method to identify genes associated with hypertension using the Reactome analysis tool and GenBank database. RESULTS: The expression of 298 genes was altered between SHR and WKY (44 upregulated and 254 downregulated), while the expression of 290 genes was altered between SHRSP and WKY (83 upregulated and 207 downregulated). For SHRSP versus SHR, the expression of 60 genes was altered (36 upregulated and 24 downregulated). Several genes expressed in SHR and SHRSP were also expressed in the renovascular hypertensive 2K1C and 1K1C rats, indicative of the existence of hyper-renin and/or hypervolemic pathophysiological changes in SHR and SHRSP. CONCLUSION: The overexpression of Kcnq1, Crlf1, Alb and Xirp1 and the inhibition of Galr2, Kcnh1, Ache, Chrm2 and Slc5a7 expression may indicate that a relationship exists between these genes and the cause and/or worsening of hypertension in SHR and SHRSP.

Microflow Fluorinations of Benzynes: Efficient Synthesis of Fluoroaromatic Compounds.

Fluorinated aromatic compounds are found in a variety of biologically active compounds, including clinical drugs and agrochemicals. Therefore, the synthesis of aryl fluorides is particularly important in the medicinal and process chemistry fields. In this paper, we report a method for the synthesis of aryl fluorides by benzyne fluorination under microflow conditions using the efficient Comet X-01 micromixer. In comparison to our previously reported method under ordinary batch conditions, this approach facilitates a significant reduction in reaction times, to ca. 10 s, as well as increases in the yields of fluoroarenes (by up to 51%).

Inflamed site-specific drug delivery system based on the interaction of human serum albumin nanoparticles with myeloperoxidase in a murine model of experimental colitis.

To develop a new strategy for inflamed site-specific drug delivery in the colon for the treatment of ulcerative colitis (UC), we leveraged on the interaction between myeloperoxidase (MPO) and human serum albumin (HSA) and prepared nanoparticles (HSA NPs) conjugated with 5-aminosalicylic acid (5-ASA). The 5-ASA-HSA NPs (nine molecules of 5-ASA per HSA molecule) were uniform particles with an average particle size of 190 nm, a zeta potential of --11.8 mV, and a polydispersity index of 0.35. This was considered a suitable particle characteristic to pass through the mucus layer and accumulate into the mucosa. The specific interaction between the 5-ASA-HSA NPs and MPO was observed using quartz crystal microbalance analysis in vitro. In addition, the 5-ASA-HSA NPs group containing one thousandth of the dose of the 5-ASA (75 µg/kg) showed significantly lower disease activity index values and colon weight/length ratios in UC model mice as similar to large amount of neat 5-ASA group (75 mg/kg), indicating that the therapeutic effect of the 5-ASA-HSA NP formulation was confirmed in vivo. Microscopic images of tissue sections of colon extracted from UC model mice demonstrated that HSA NPs and MPO were both localized in the colon, and this specific interaction between HSA NPs and MPO would be involved the in the therapeutic effect in vivo. Furthermore, in the 5-ASA and 5-ASA-HSA NPs groups, some inflammatory damage was observed in the colon, but the degree of damage was mild compared with the control and HSA NPs groups, suggesting mucosal repair and replacement with fibrous granulation tissue had occurred. Therefore, these data demonstrated that an HSA NP formulation has the potential to specifically deliver 5-ASA to an inflamed site where MPO is highly expressed.

Regioselective Rearrangement of 4,4-Disubstituted 2-Hydroxycyclohexa-2,5-Dienones under Deoxyfluorination Conditions.

The dienone-phenol rearrangement is a useful tool for the synthesis of highly substituted phenols. In our previous study of the rearrangement of 4,4-disubstituted 2-hydroxycyclohexa-2,5-dienone under deoxyfluorination conditions, bond migration proceeded with very poor regioselectivity. In this paper, an acid-mediated rearrangement of O-perfluoroalkylsulfonyl difluorides with regioselective migration toward the ß'-carbon is reported. This method allowed the synthesis of a fluorinated analog of allocolchicinoids with improved total yield. Successful application to other substrates was also demonstrated.

2-(Trimethylsilyl)phenyl Trimethylsilyl Ethers as Stable and Readily Accessible Benzyne Precursors.

Stable 2-(trimethylsilyl)phenyl trimethylsilyl ethers, readily obtained from the corresponding halogenated phenols in two steps, were identified as novel benzyne precursors. These species were converted to benzynes by a domino reaction of O-desilylation, O-nonaflylation, and ß-elimination under mild conditions using nonafluorobutanesulfonyl fluoride (NfF) and tetrabutylammonium triphenyldifluorosilicate (TBAT). The generated benzynes were trapped by various arynophiles to afford a wide variety of benzo-fused heterocycles.

Postabsorptive hyperglucagonemia in patients with type 2 diabetes mellitus analyzed with a novel enzyme-linked immunosorbent assay.

AIMS/INTRODUCTION: The aims of the present study were to investigate the performance of a novel sandwich enzyme-linked immunosorbent assay (ELISA) for measuring glucagon (1-29) with monoclonal antibodies against both the C- and N-terminal regions of glucagon (1-29), and to analyze the differences in plasma levels and responses of glucagon (1-29) to oral glucose loading in normal glucose tolerance (NGT) subjects and patients with type 2 diabetes mellitus. MATERIALS AND METHODS: The cross-reactivity against proglucagon fragments using the ELISA kit and two types of conventional radioimmunoassay (RIA) kits was evaluated. A 75-g oral glucose tolerance test was carried out with NGT subjects and patients with type 2 diabetes mellitus, and the glucagon (1-29) concentration was measured using three types of kit. RESULTS: The ELISA kit clearly had the lowest cross-reactivity against miniglucagon (19-29) and glicentin (1-61). The oral glucose tolerance test was carried out with 30 NGT and 17 patients with type 2 diabetes mellitus. The glucagon (1-29) levels measured by the ELISA kit after glucose loading were significantly higher at all time-points in the type 2 diabetes mellitus group than in the NGT group. However, the glucagon (1-29) levels measured by one RIA kit were significantly higher in the NGT group, and those measured with the other RIA kit were approximately the same among the groups. CONCLUSIONS: The novel sandwich ELISA accurately determines plasma glucagon (1-29) concentrations with much less cross-reactivity against other proglucagon fragments than conventional RIA kits.

1,3- and 1,4-Benzdiyne equivalents for regioselective synthesis of polycyclic heterocycles.

We have devised a novel 1,3-benzdiyne equivalent, capable of quadruple functionalization by sequential benzyne generation and reaction with arynophiles. The key features of this method include the chemoselective generation of two triple bonds in a single benzene ring under fluoride-mediated mild conditions, and the regiocontrol of each benzyne reaction by the substituent next to the triple bond. This method produced various benzo-fused heteroaromatic compounds via reactions with arynophiles, such as furans, azides, and diazo compounds. A validation of the method is given in the convergent synthesis of the antipsychotic drug risperidone. A similar strategy has also been applied to a 1,4-benzdiyne equivalent to construct linearly benzo-fused heteroaromatics.

Asymmetric dimethylarginine, a biomarker of cardiovascular complications in diabetes mellitus.

Cardiovascular (CV) complications are an essential causal element of prospect in diabetes mellitus (DM), with carotid atherosclerosis being a common risk factor for prospective crisis of coronary artery diseases and/or cerebral infarction in DM subjects. From another point of view, asymmetric dimethylarginine (ADMA) has been established as an inhibitor of endogenous nitric oxide synthesis and the relationship between ADMA and arteriosclerosis has been reported. In our study with 87 type 2 DM (T2DM) patients, we have examined whether ADMA and other CV risk factors are the useful predictors of DMCV complications. After the measurement of the respective CV risk factors, we have followed the enrolled T2DM patients for 5 years. We have finally analyzed 77 patients. DMCV complications developed in 15 cases newly within 5 years, and 4 cases recurred. The concentrations of ADMA in plasma were markedly more elevated in 19 DM patients with CV complications than in 58 DM patients without CV complications. Urinary albumin (U-Alb), mean intimal-medial thickness (IMT) and ankle brachial index (ABI) were also higher in patients with CV complications. Multiple regression analyses showed that U-Alb had an influence on the high level of ADMA (standardized ß = 6.59, P = 0.00014) independently of age, systolic BP, fibrinogen, mean IMT, plaque score, and ABI. The review indicates what is presently known regarding plasma ADMA that might be a new and meaningful biomarker of CV complications in DM subjects.

Trifluoromethanesulfonyloxy-group-directed regioselective (3 + 2) cycloadditions of benzynes for the synthesis of functionalized benzo-fused heterocycles.

Highly regioselective (3 + 2) cycloadditions of (trifluoromethanesulfonyloxy)benzynes [(triflyloxy)benzynes] with 1,3-dipoles followed by cross-coupling reactions provided multisubstituted benzo-fused heterocycles. The triflyloxy group at the 3-position of benzynes, and even that at the remote 4-position, greatly affected the regiocontrol of the cycloaddition. These groups also served to install other substituents at their ipso-positions.

[Efficient synthesis of multisubstituted aromatic compounds from phenol derivatives].

Phenols are abundant in nature and diverse phenols are readily available commercially at low cost. Thus, phenols can be used as the raw materials for the synthesis of valuable multisubstituted aromatic compounds by the direct activation of phenolic hydroxyl groups (C-O bond activation), followed by substitutions with other substituents. Although the derivatization of phenolic hydroxyl groups to sulfonates, such as triflates, nonaflates, tosylates and mesylates, followed by the transition-metal-catalyzed coupling reactions has been extensively investigated for this purpose, the direct C-O bond activation of phenols for subsequent functional group transformation has been a long-standing challenge in modern organic synthesis. In this review, I have summarized my recent studies on the formal direct C-O bond activation of phenols using nonafluorobutanesulfonyl fluoride (NfF) for the synthesis of multisubstituted aromatics. I have focused on the dual use of NfF, a less expensive commercially available reagent, including the tentative formation of highly reactive nonaflates from phenols and the use of the liberated fluoride ion as a nucleophile to promote the reactions of nonaflates. The following four topics are discussed: 1) palladium-catalyzed coupling reactions of phenols, 2) novel preparation of benzynes from 2-silylphenols, 3) synthesis of fluorinated aromatic compounds via the formation of benzynes, and 4) Hiyama coupling of (tert-butyldimethylsilyl)arenes activated by internal phenolic hydroxyl groups.