Changes in Autonomic Nervous System Activity in Children With Spina Bifida: A Case-Control Study.

PURPOSE: We compared heart rate variability parameters between patients with spina bifida and a control group during urodynamic studies, with the goal of evaluating the autonomic nervous system dysfunction present in spina bifida. METHODS: Continuous heart rate variability parameters were recorded during 3 successive periods (P0, the 2 minutes prior to the start of filling; P1, from the start of filling to the first desire to void; and P2, from P1 to the end of filling or the start of voiding). The control group consisted of children with vesicoureteral reflux who had undergone video-urodynamic studies. Our study included 11 patients with spina bifida and 9 control participants. RESULTS: At baseline, patients with spina bifida exhibited lower values for the root mean square of successive differences in NN intervals, the percentage of successive R-R interval differences exceeding 50 msec relative to the total number of intervals, and high frequency (HF). In contrast, the low frequency (LF)/HF ratio was elevated in these patients (5.04 ± 4.75 vs. 0.67 ± 0.42, P = 0.014). During bladder filling, LF/HF values increased in the control group (P0, 0.67 ± 0.42; P1, 0.89 ± 0.34; P2, 1.21 ± 0.64; P = 0.018), while they declined in patients with spina bifida (P0, 5.04 ± 4.75; P1, 3.96 ± 4.35; P2, 3.26 ± 4.03; P < 0.001). The HF values were significantly elevated in children with spina bifida during bladder filling (P = 0.002). In the time domain, the standard deviations of all NN intervals were elevated only in the control group during bladder filling. Parasympathetic activity domains were reduced in the children with spina bifida at the initial assessment. CONCLUSION: During the bladder filling phase, parasympathetic activity increased along with fixed sympathetic activity in the spina bifida group. In contrast, the control group exhibited a shift towards a sympathetic preponderance at the conclusion of bladder filling. These observations may be associated with the pathophysiology of neurogenic bladder in spina bifida.

Adsorption behavior of furan at Ge(100) surface.

The adsorption behavior of furan on the Ge(100) surface was studied using a combination of high-resolution photoemission spectroscopy (HRPES) and density functional theory (DFT) calculations. We identified the two adsorption species produced by the [4 + 2] cycloaddition and deoxygenation reactions of furan with the Ge(100) surface in a ratio of approximately 76:24 at the surveyed coverages, via an analysis of the binding energies and relative area proportions of all the peaks in the C 1s and O 1s core-level spectra. The DFT simulation results revealed that the [4 + 2] cycloaddition and deoxygenation adducts are thermodynamically preferred by the reaction of furan with the Ge(100) surface compared with others, which is consistent with the HRPES results. The findings will further our understanding of the surface reactions of five-membered heterocyclic molecules.

A Green Chemical Approach for Iodination of Pyrimidine Derivatives by Mechanical Grinding under Solvent-Free Conditions.

The iodination of pyrimidines is usually carried out by using toxic reagents under acidic conditions, such as with sulfuric acid and nitric acid. To avoid toxic reagents, we developed a simple and eco-friendly approach for the iodination of pyrimidine derivatives under solvent-free conditions using solid iodine and AgNO3 as an electrophilic iodinating reagent. The advantages of this method are the relatively short reaction time (20-30 min), simple set-up procedure, high yields (70-98%), and environmentally friendly reaction conditions. Our novel approach for the iodination of pyrimidines, as well as a variety of their derivatives, will contribute to the development of nucleobase-related drug candidates.

Novel Cinnamaldehyde Derivatives Inhibit Peripheral Nerve Degeneration by Targeting Schwann Cells.

Peripheral nerve degeneration (PND) is a preparative process for peripheral nerve regeneration and is regulated by Schwann cells, a unique glial cell in the peripheral nervous system. Dysregulated PND induces irreversible peripheral neurodegenerative diseases (e.g., diabetic peripheral neuropathy). To develop novel synthetic drugs for these diseases, we synthesized a set of new cinnamaldehyde (CAH) derivatives and evaluated their activities in vitro, ex vivo, and in vivo. The 12 CAH derivatives had phenyl or naphthyl groups with different substitution patterns on either side of the α,ß-unsaturated ketone. Among them, 3f, which had a naphthaldehyde group, was the most potent at inhibiting PND in vitro, ex vivo, and in vivo. To assess their interactions with transient receptor potential cation channel subfamily A member 1 (TRPA1) as a target of CAH, molecular docking studies were performed. Hydrophobic interactions had the highest binding affinity. To evaluate the underlying pharmacological mechanism, we performed bioinformatics analysis of the effect of 3f on PND based on coding genes and miRNAs regulated by CAH, suggesting that 3f affects oxidative stress in Schwann cells. The results show 3f to be a potential lead compound for the development of novel synthetic drugs for the treatment of peripheral neurodegenerative diseases.

Conformational exchange of the Zα domain of human RNA editing enzyme ADAR1 studied by NMR spectroscopy.

Z-DNA binding proteins (ZBPs) play important roles in RNA editing, innate immune responses, and viral infections. Numerous studies have implicated a role for conformational motions during ZBPs binding upon DNA, but the quantitative intrinsic conformational exchanges of ZBP have not been elucidated. To understand the correlation between the biological function and dynamic feature of the Zα domains of human ADAR1 (hZαADAR1), we have performed the 15N backbone amide Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion experiments on the free hZαADAR1 at two different magnetic fields at 35 °C. The robust inter-dependence of parameters in the global fitting process using multi-magnetic field CPMG profiles allows us characterizing the dynamic properties of conformational changes in hZαADAR1. This study found that free hZαADAR1 exhibited the conformational exchange with a kex of 5784 s-1 between the states "A" (89% population) and "B" (11% population). The different hydrophobic interactions among helices α1, α2, and α3 between these two states might correlate with efficient Z-DNA binding achieved by the hydrogen bonding interactions between its side-chains and the phosphate backbone of Z-DNA.

Non-Canonical Helical Structure of Nucleic Acids Containing Base-Modified Nucleotides.

Chemically modified nucleobases are thought to be important for therapeutic purposes as well as diagnosing genetic diseases and have been widely involved in research fields such as molecular biology and biochemical studies. Many artificially modified nucleobases, such as methyl, halogen, and aryl modifications of purines at the C8 position and pyrimidines at the C5 position, are widely studied for their biological functions. DNA containing these modified nucleobases can form non-canonical helical structures such as Z-DNA, G-quadruplex, i-motif, and triplex. This review summarizes the synthesis of chemically modified nucleotides: (i) methylation, bromination, and arylation of purine at the C8 position and (ii) methylation, bromination, and arylation of pyrimidine at the C5 position. Additionally, we introduce the non-canonical structures of nucleic acids containing these modifications.

Enantioselective organocatalytic Michael reactions using chiral (R,R)-1,2-diphenylethylenediamine-derived thioureas.

Although the Michael addition is a very well-known and widely applied reaction, cost-effective, metal-free, and readily prepared organic catalysts remain rare. A chiral, bifunctional, (R,R)-1,2-diphenylethylenediamine-derived thiourea organic catalyst was developed and applied to asymmetric Michael additions of nitroalkenes under neutral conditions. Generally, fluorine-substituted thiourea catalysts exhibited high chemical yields and enantioselectivities under neutral conditions. The mild reactions were tolerant of many functional groups and afforded good-to-excellent yields, as well as high diastereo- and enantioselectivities for the Michael adducts. The utility of the transformation was demonstrated by the synthesis of a bioactive compound, (R)-Phenibut.

A Simple Procedure for the Synthesis of ß-Hydroxyallenamides via Homoallenylation of Aldehydes.

A simple one-pot synthesis of ß-hydroxyallenamides is reported. This procedure entails chemo- and regioselective hydroboration of 3-en-1-ynyl-sulfonylamides with Cy2BH followed by homoallenylation of aldehydes to yield ß-hydroxyallenamides (up to 94% yield and >20:1 dr). Controlled synthesis of up to three continuous stereochemical elements was realized. Density functional theory (DFT) calculations suggest a concerted Zimmerman-Traxler chair-like transition state. Initial results suggest that enantio- and diastereoselective synthesis of ß-hydroxyallenamides with optically active hydroboration reagents is viable.

Synthesis of Diarylated 4-Pyridylmethyl Ethers via Palladium-Catalyzed Cross-Coupling Reactions.

The direct arylation of weakly acidic sp3-hybridized C-H bonds via deprotonated cross-coupling processes (DCCP) is a challenge. Herein, a Pd(NIXANTPHOS)-based catalyst for the mono arylation of 4-pyridylmethyl 2-aryl ethers to generate diarylated 4-pyridyl methyl ethers is introduced. Furthermore, under similar conditions, the diarylation of 4-pyridylmethyl ethers with aryl bromides has been developed. These methods enable the synthesis of new pyridine derivatives, which are common in medicinally active compounds and in application in materials science.

Palladium-catalysed synthesis of triaryl(heteroaryl)methanes.

Tetraarylmethane derivatives are desirable for a variety of applications, but difficult to access with modern C-C bond-forming reactions. Here we report a straightforward method for palladium-catalysed arylation of aryl(heteroaryl)methanes and diaryl(heteroaryl)methanes with aryl chlorides. This reaction enables introduction of various aryl groups to construct triaryl(heteroaryl)methanes via a C-H functionalization in good to excellent yield, and represents the first step towards a general transition metal catalysed synthesis of tetraarylmethanes.

Nickel-Catalyzed Arylation of Heteroaryl-containing Diarylmethanes: Exceptional Reactivity of the Ni(NIXANTPHOS)-based Catalyst.

Nickel(0)-catalyzed cross-coupling of heteroaryl-containing diarylmethanes with both aryl bromides and chlorides has been achieved. The success of this reaction relies on the introduction of a unique nickel/NIXANTPHOS-based catalyst system, which provides a direct route to triarylmethanes from heteroaryl-containing diarylmethanes. Reactivity studies indicate the Ni(NIXANTPHOS)-based catalyst exhibits enhanced reactivity over XANTPHOS derivatives and other Ni(phosphine)-based catalysts in the reactions examined.

Palladium-Catalyzed Selective α-Alkenylation of Pyridylmethyl Ethers with Vinyl Bromides.

An efficient palladium-catalyzed α-alkenylation of pyridylmethyl ethers with vinyl bromides is presented. A Pd/NIXANTPHOS-based catalyst system enables a mild and chemoselective coupling between a variety of pyridylmethyl ethers and vinyl bromides in good to excellent yields. Under the mild conditions, ß,γ-unsaturated products are obtained without isomerization or Heck byproducts observed.

Chemoselective Palladium-Catalyzed Deprotonative Arylation/[1,2]-Wittig Rearrangement of Pyridylmethyl Ethers.

Control of chemoselectivity is one of the most challenging problems facing chemists and is particularly important in the synthesis of bioactive compounds and medications. Herein, the first highly chemoselective tandem C(sp3)-H arylation/[1,2]-Wittig rearrangement of pyridylmethyl ethers is presented. The efficient and operationally simple protocols enable generation of either arylation products or tandem arylation/[1,2]-Wittig rearrangement products with remarkable selectivity and good to excellent yields (60-99%). Choice of base, solvent, and reaction temperature play a pivotal role in tuning the reactivity of intermediates and controlling the relative rates of competing processes. The novel arylation step is catalyzed by a Pd(OAc)2/NIXANTPHOS-based system via a deprotonative cross-coupling process. The method provides rapid access to skeletally diverse aryl(pyridyl)methanol core structures, which are central components of several medications.

Palladium-Catalyzed Benzylic Arylation of Pyridylmethyl Silyl Ethers: One-Pot Synthesis of Aryl(pyridyl)methanols.

An efficient palladium-catalyzed direct arylation of pyridylmethyl silyl ethers with aryl bromides is described. A Pd(OAc)2/NIXANTPHOS-based catalyst provides aryl(pyridyl)methyl alcohol derivatives in good to excellent yields (33 examples, 57-100% yield). This protocol is compatible with different silyl ether protecting groups, affording either the protected or the free alcohols in an effective one-pot process. The scalability of the reaction is demonstrated.

Tandem C(sp3)-H Arylation/Oxidation and Arylation/Allylic Substitution of Isoindolinones.

Isoindolinones comprise an important class of medicinally active compounds. Herein we report a straightforward functionalization of the isoindolinones with aryl bromides (22 examples) using a Pd(OAc)2/NIXANTPHOS-based catalyst system. Additionally 3-aryl 3-hydroxy isoindolinone derivatives, which exhibit anti-tumor activity, can be accessed via a tandem reaction. Thus, when the arylation product is exposed to air under basic conditions, in situ oxidation takes place to install the 3-hydroxyl group. Furthermore, a tandem arylation/allylic substitution reaction is advanced in which both the arylation and allylic substitution are catalyzed by the same palladium catalyst. Finally, a tandem arylation/alkylation procedure is presented. These tandem reactions enable the synthesis of a variety of structurally diverse isoindolinone derivatives from common starting materials.

Palladium-Catalyzed Benzylic C-H Arylation of Azaarylmethylamines.

A direct C-H functionalization approach to produce aryl(azaaryl)methylamines from azaarylmethylamines without directing groups is described. Under conditions where the azaarylmethylamines' C-H is reversibly deprotonated, a Pd(OAc)(2)/NIXANTPHOS-based catalyst couples the resulting carbanions with various aryl halides to provide aryl(azaaryl)methylamines. This umpolung strategy directly provides tertiary amines without protecting or activating groups.

Palladium-catalyzed C(sp(3))-H Arylation of N-Boc benzylalkylamines via a deprotonative cross-coupling process.

Diarylmethylamines are key intermediates and products in the pharmaceutical industry. Herein we disclose a novel method toward the synthesis of these important compounds via CH functionalization. Presented is a reversible deprotonation of N-Boc benzylalkylamines at the benzylic CH with in situ arylation by a NiXantPhos-based palladium catalyst (50-93 % yield, 29 examples). The method is also successful with N-Boc-tetrahydroisoquinolines. The advantages of this method are it avoids strong bases, low temperatures, and the need to transmetallate to main group metals for the coupling.

Room-temperature palladium-catalyzed direct 2-arylation of benzoxazoles with aryl and heteroaryl bromides.

An efficient room-temperature palladium-catalyzed direct 2-arylation of benzoxazoles with aryl bromides is presented. The Pd(OAc)2/NiXantphos-based catalyst enables the introduction of various aryl and heteroaryl groups, via a deprotonative cross-coupling process (DCCP) in good to excellent yields (60-99%).

Palladium-catalyzed chemoselective allylic substitution, Suzuki-Miyaura cross-coupling, and allene formation of bifunctional 2-B(pin)-substituted allylic acetate derivatives.

A formidable challenge at the forefront of organic synthesis is the control of chemoselectivity to enable the selective formation of diverse structural motifs from a readily available substrate class. Presented herein is a detailed study of chemoselectivity with palladium-based phosphane catalysts and readily available 2-B(pin)-substituted allylic acetates, benzoates, and carbonates. Depending on the choice of reagents, catalysts, and reaction conditions, 2-B(pin)-substituted allylic acetates and derivatives can be steered into one of three reaction manifolds: allylic substitution, Suzuki-Miyaura cross-coupling, or elimination to form allenes, all with excellent chemoselectivity. Studies on the chemoselectivity of Pd catalysts in their reactivity with boron-bearing allylic acetate derivatives led to the development of diverse and practical reactions with potential utility in synthetic organic chemistry.

Breaking Conjugation: Unusual Regioselectivity with 2-Substituted Allylic Substrates in the Tsuji-Trost Reaction.

η3-Allyl palladium complexes are key intermediates in Tsuji-Trost allylic substitution reactions. It is well known that (η3-1-aryl-3-alkyl substituted allyl)Pd intermediates result in nucleophilic attack at the alkyl substituted terminus. In contrast, the chemistry of (η3-1,2,3-trisubstituted allyl)Pd intermediates is relatively unexplored. Herein we probe the regioselectivity with 1,2,3-trisubstituted allylic substrates in Tsuji-Trost allylic substitution reactions. DFT investigation of cationic (η3-1-Ph-2-B(pin)-3-alkyl-allyl)Pd(PPh3)2 intermediates predict that nucleophilic attack should occur preferentially on anti-allyls rather than the syn-isomers to generate benzylic substitution products under Curtin-Hammett conditions. Experimentally, systematic studies with 1,2,3-trisubstituted allylic substrates revealed that a Linear Free Energy Relationship (LFER) is observed when Charton steric parameters of the C-2 substituents are plotted against the log of the ratio of regioisomers. Bulkier C-2 substituents in 1,2,3-trisubstituted η3-allyl palladium intermediates provide stronger preference for nucleophilic attack at anti-oriented benzylic termini. Additionally, the geometry of 1,4-elimination products supports the presence of anti-allyl palladium intermediates.