OH Nucleophile Research Articles

Exploring the catalytic mechanism of the 10-23 DNAzyme: insights from pH-rate profiles.

The 10-23 DNAzyme, a catalytic DNA molecule with RNA-cleaving activity, has garnered significant interest for its potential therapeutic applications as a gene-silencing agent. However, the lack of a detailed understanding about its mechanism has hampered progress. A recent structural analysis has revealed a highly organized conformation thanks to the stabilization of specific interactions within the catalytic core of the 10-23 DNAzyme, which facilitate the cleavage of RNA. In this configuration, it has been shown that G14 is in good proximity to the cleavage site which suggests its role as a general base, by activating the 2'-OH nucleophile, in the catalysis of the 10-23 DNAzyme. Also, the possibility of a hydrated metal acting as a general acid has been proposed. In this study, through activity assays, we offer evidence of the involvement of general acid-base catalysis in the mechanism of the 10-23 DNAzyme by analyzing its pH-rate profiles and the role of G14, and metal cofactors like Mg2+ and Pb2+. By substituting G14 with its analogue 2-aminopurine and examining the resultant pH-rate profiles, we propose the participation of G14 in a catalytically relevant proton transfer event, acting as a general base. Further analysis, using Pb2+ as a cofactor, suggests the capability of the hydrated metal ion to act as a general acid. These functional results provide critical insights into the catalytic strategies of RNA-cleaving DNAzymes, revealing common mechanisms among nucleic acid enzymes that cleave RNA.

Mechanistic insights into the conversion of flavin adenine dinucleotide (FAD) to 8-formyl FAD in formate oxidase: a combined experimental and in-silico study

Formate oxidase (FOx), which contains 8-formyl flavin adenine dinucleotide (FAD), exhibits a distinct advantage in utilizing ambient oxygen molecules for the oxidation of formic acid compared to other glucose-methanol-choline (GMC) oxidoreductase enzymes that contain only the standard FAD cofactor. The FOx-mediated conversion of FAD to 8-formyl FAD results in an approximate 10-fold increase in formate oxidase activity. However, the mechanistic details underlying the autocatalytic formation of 8-formyl FAD are still not well understood, which impedes further utilization of FOx. In this study, we employ molecular dynamics simulation, QM/MM umbrella sampling simulation, enzyme activity assay, site-directed mutagenesis, and spectroscopic analysis to elucidate the oxidation mechanism of FAD to 8-formyl FAD. Our results reveal that a catalytic water molecule, rather than any catalytic amino acids, serves as a general base to deprotonate the C8 methyl group on FAD, thus facilitating the formation of a quinone-methide tautomer intermediate. An oxygen molecule subsequently oxidizes this intermediate, resulting in a C8 methyl hydroperoxide anion that is protonated and dissociated to form OHC-RP and OH−. During the oxidation of FAD to 8-formyl FAD, the energy barrier for the rate-limiting step is calculated to be 22.8 kcal/mol, which corresponds to the required 14-hour transformation time observed experimentally. Further, the elucidated oxidation mechanism reveals that the autocatalytic formation of 8-formyl FAD depends on the proximal arginine and serine residues, R87 and S94, respectively. Enzymatic activity assay validates that the mutation of R87 to lysine reduces the kcat value to 75% of the wild-type, while the mutation to histidine results in a complete loss of activity. Similarly, the mutant S94I also leads to the deactivation of enzyme. This dependency arises because the nucleophilic OH− group and the quinone-methide tautomer intermediate are stabilized through the noncovalent interaction provided by R87 and S94. These findings not only explain the mechanistic details of each reaction step but also clarify the functional role of R87 and S94 during the oxidative maturation of 8-formyl FAD, thereby providing crucial theoretical support for the development of novel flavoenzymes with enhanced redox properties.

Hydrolytic Mechanism of a Metalloenzyme Is Modified by the Nature of the Coordinated Metal Ion.

The nuclease domain of colicin E7 cleaves double-strand DNA non-specifically. Zn2+ ion was shown to be coordinated by the purified NColE7 as its native metal ion. Here, we study the structural and catalytic aspects of the interaction with Ni2+, Cu2+ and Cd2+ non-endogenous metal ions and the consequences of their competition with Zn2+ ions, using circular dichroism spectroscopy and intact protein mass spectrometry. An R447G mutant exerting decreased activity allowed for the detection of nuclease action against pUC119 plasmid DNA via agarose gel electrophoresis in the presence of comparable metal ion concentrations. It was shown that all of the added metal ions could bind to the apoprotein, resulting in a minor secondary structure change, but drastically shifting the charge distribution of the protein. Zn2+ ions could not be replaced by Ni2+, Cu2+ and Cd2+. The nuclease activity of the Ni2+-bound enzyme was extremely high in comparison with the other metal-bound forms, and could not be inhibited by the excess of Ni2+ ions. At the same time, this activity was significantly decreased in the presence of equivalent Zn2+, independent of the order of addition of each component of the mixture. We concluded that the Ni2+ ions promoted the DNA cleavage of the enzyme through a more efficient mechanism than the native Zn2+ ions, as they directly generate the nucleophilic OH- ion.

Preparation and performance of polypyrrole modified filter paper humidity sensor by in situ polymerization

Polypyrrole (PPy) has high electrical conductivity, good environmental stability, and reversible electrochemical redox characteristics, which makes PPy responsive to changes in environmental humidity values. In this work, a humidity sensor with a good response to humidity was prepared using in situ polymerization of PPy in filter paper doping with acetic acid. A possible sensing mechanism of conductive polymers is proposed and the conjecture is verified by experiments. The results demonstrated that the PPy/filter paper-based humidity sensor provides an electron migration channel with the capability of detecting the relative humidity. External humidity stimulation can regulate the electrochemical reaction of PPy. The reduction reaction occurs near the water side to generate the nucleophilic product OH–. The PPy system loses electrons to form carrier directional channels, resulting in changes in the output voltage measured between the two electrodes. The PPy/filter paper-based humidity sensor exhibits the moisture dependent voltage response over a wide range from a relative humidity of 11–98%, and a response/recovery time of 43/51 s as it was placed between relative humidity of 33% and 98%. In addition, unlike the traditional sensing mechanism, the voltage sensing mechanism raised here shows self-powered ability with no need for an additional power unit. This provides a new idea for self-powered sensor devices, and this sensor shows good performance in non-contact sensing applications such as breath detection.

Carbon Dioxide Capture at Nucleophilic Hydroxide Sites in Oxidation-Resistant Cyclodextrin-Based Metal-Organic Frameworks.

Carbon capture and sequestration (CCS) from industrial point sources and direct air capture are necessary to combat global climate change. A particular challenge faced by amine-based sorbents-the current leading technology-is poor stability towards O2 . Here, we demonstrate that CO2 chemisorption in γ-cylodextrin-based metal-organic frameworks (CD-MOFs) occurs via HCO3 - formation at nucleophilic OH- sites within the framework pores, rather than via previously proposed pathways. The new framework KHCO3 CD-MOF possesses rapid and high-capacity CO2 uptake, good thermal, oxidative, and cycling stabilities, and selective CO2 capture under mixed gas conditions. Because of its low cost and performance under realistic conditions, KHCO3 CD-MOF is a promising new platform for CCS. More broadly, our work demonstrates that the encapsulation of reactive OH- sites within a porous framework represents a potentially general strategy for the design of oxidation-resistant adsorbents for CO2 capture.

Carbon Dioxide Capture at Nucleophilic Hydroxide Sites in Oxidation‐Resistant Cyclodextrin‐Based Metal–Organic Frameworks**

AbstractCarbon capture and sequestration (CCS) from industrial point sources and direct air capture are necessary to combat global climate change. A particular challenge faced by amine‐based sorbents—the current leading technology—is poor stability towards O2. Here, we demonstrate that CO2 chemisorption in γ‐cylodextrin‐based metal–organic frameworks (CD‐MOFs) occurs via HCO3− formation at nucleophilic OH− sites within the framework pores, rather than via previously proposed pathways. The new framework KHCO3 CD‐MOF possesses rapid and high‐capacity CO2 uptake, good thermal, oxidative, and cycling stabilities, and selective CO2 capture under mixed gas conditions. Because of its low cost and performance under realistic conditions, KHCO3 CD‐MOF is a promising new platform for CCS. More broadly, our work demonstrates that the encapsulation of reactive OH− sites within a porous framework represents a potentially general strategy for the design of oxidation‐resistant adsorbents for CO2 capture.

Structure of 3'-PO4/5'-OH RNA ligase RtcB in complex with a 5'-OH oligonucleotide.

RtcB enzymes comprise a widely distributed family of manganese- and GTP-dependent RNA repair enzymes that join 2′,3′-cyclic phosphate ends to 5′-OH ends via RtcB-(histidinyl-N)–GMP, RNA 3′-phosphate, and RNA3′pp5′G intermediates. RtcB can ligate either 5′-OH RNA or 5′-OH DNA strands in vitro. The nucleic acid contacts of RtcB are uncharted. Here we report a 2.7 Å crystal structure of Pyrococcus horikoshii RtcB in complex with a 6-mer 5′-OH DNA oligonucleotide HOA1pT2pG3pT4pC5pC6, which reveals enzymic contacts of Asn202 to the terminal 5′-OH nucleophile; Arg238 to the A1pT2 and T2pG3 phosphates; Arg190 and Gln194 to the T2pG3 phosphate; and an Arg190 π-cation interaction with the G3 nucleobase. The structural insights affirm functional studies of E. coli RtcB that implicated the conserved counterpart of Arg238 in engagement of the 5′-OH strand for ligation. The essential active site Cys98 that coordinates two manganese ions is oxidized to cysteine sulfonic acid in our structure, raising the prospect that RtcB activity might be sensitive to modulation during oxidative stress.

The mechanism studies of catalytic chemoselective conjugate addition of amino alcohols to α,β-unsaturated ester

The competing mechanisms of silver-/aminolithium-catalyzed hydrofunctionalization of α,β-unsaturated ester with an amino alcohol have been systematically studied with the DFT methods. Here, the acidity of a weaker nucleophile OH group of an amino alcohol is significantly higher than that of NH2 group, so it is easy to deprotonate by Ag(HMDS)/dppe. However, the generated Ag–O bond is more stable than the corresponding Ag–N bond. Therefore, the OH group shows higher reactivity than the NH2 group in the presence of a Lewis acid/Bronsted base pair catalyst. Then, α,β-unsaturated esters can be inserted into corresponding Ag–O bonds to obtain alkyl silver species. Alkyl silver can be protonated by bis(trimethylsilyl)amines to obtain hydrogen functionalized products and regenerate silver amino active compounds Ag(HMDS)/dppe.

1250. Novel Boronic Acid Transition State Analogs (BATSI) with in vitro inhibitory activity against class A, B and C β-lactamases

BackgroundCatalytic mechanisms of serine β-lactamases (SBL; classes A, C and D) and metallo-β-lactamases (MBLs) have directed divergent strategies towards inhibitor design. SBL inhibitors act as high affinity substrates that -as in BATSIs- form a reversible, dative covalent bond with the conserved active site Ser. MBL inhibitors bind the active-site Zn2+ ions and displace the nucleophilic OH-. Herein, we explore the efficacy of a series of BATSI compounds with a free-thiol group at inhibiting both SBL and MBL.MethodsExploratory compounds were synthesized using stereoselective homologation of (+) pinandiol boronates to introduce the amino group on the boron-bearing carbon atom, which was subsequently acylated with mercaptopropanoic acid. Representative SBL (KPC-2, ADC-7, PDC-3 and OXA-23) and MBL (IMP-1, NDM-1 and VIM-2) were purified and used for the kinetic characterization of the BATSIs. In vitro activity was evaluated by a modified time-kill curve assay, using SBL and MBL-producing strains.ResultsKinetic assays revealed that IC50 values ranged from 1.3 µM to >100 µM for this series. The best compound, s08033, demonstrated inhibitory activity against KPC-2, VIM-2, ADC-7 and PDC-3, with IC50 in the low μM range. Reduction of at least 1.5 log10-fold of viable cell counts upon exposure to sub-lethal concentrations of antibiotics (AB) + s08033, compared to the cells exposed to AB alone, demonstrated the microbiological activity of this novel compound against SBL- and MBL-producing E. coli (Table 1).Table 1 ConclusionAddition of a free-thiol group to the BATSI scaffold increases the range of these compounds resulting in a broad-spectrum inhibitor toward clinically important carbapenemases and cephalosporinases.DisclosuresRobert A. Bonomo, MD, Entasis, Merck, Venatorx (Research Grant or Support)

(Industrial Electrochemistry and Electrochemical Engineering Division H. H. Dow Memorial Student Achievement Award Address) Anion Exchange and Bipolar Membranes for Electrochemical Energy Conversion and Storage

Ion-conducting membranes play a central role in electrochemical devices. The rise in anion exchange membrane fuel cell (AEMFC) research is attributed to the viability of using platinum-group-metal free electrocatalysts for hydrogen oxidation reaction (HOR) and oxygen reduction reaction (ORR).1 However, there are two major obstacles to apply anion exchange membranes (AEMs) as separators in alkaline electrochemical energy conversion devices. The first challenge is to develop the AEM with hydroxide ion conductivities above 100 mS/cm at 70 °C. The second challenge is to synthesize stable AEM (especially stable cationic head-groups) that exhibit high durability in strongly alkaline environments (e.g. in the presence of nucleophilic OH- ions). To solve the first problem, a triblock copolymer-based polymer backbone has been developed to synthesize AEMs with high ion conductivities by engineering a phase-separated morphology. To address the second problem, cycloaliphatic quaternary ammonium based AEM have been prepared that demonstrate excellent alkaline stability.Except for the performance of the separator, there are other factors including the design of electrocatalysts for HOR and ORR, and the structure of catalyst layer contributes to overall fuel cell performance. Herein, significant amount of effort has been made to better design the ionomer/electrocatalysts interface and to better understand the transport of the ionomer in confined regime. The use of a pH-gradient-enabled microscale bipolar interface (PMBI) to effectively separate the anolyte and catholyte of a direct borohydride/ hydrogen peroxide liquid fuel cell (DBFC) has been engineered and demonstrated, which enables record high DBFC performance. 2 The PMBI-type electrodes provide a new and fascinating design to engineer fuel-cell membrane electrode assemblies. Interdigitated electrode arrays (IDEs) have been developed as a platform for highly sensitive electrochemical measurements of polymer thin film with thickness of less than 100 nm.3 The IDEs coupled with electrochemical impedance spectroscopy (EIS) has been demonstrated as an effective platform to probe ion transport of polymer thin film, which provide direct translation to the design of the ionomer in fuel cell. References (1) Arges, C. G.; Zhang, L. Anion Exchange Membranes’ Evolution toward High Hydroxide Ion Conductivity and Alkaline Resiliency. ACS Applied Energy Materials 2018, 1 (7), 2991-3012, DOI: 10.1021/acsaem.8b00387.(2) Wang, Z.; Parrondo, J.; He, C.; Sankarasubramanian, S.; Ramani, V. Efficient pH-gradient-enabled microscale bipolar interfaces in direct borohydride fuel cells. Nature Energy 2019, DOI: 10.1038/s41560-019-0330-5.(3) Sharon, D.; Bennington, P.; Liu, C.; Kambe, Y.; Dong, B. X.; Burnett, V. F.; Dolejsi, M.; Grocke, G.; Patel, S. N.; Nealey, P. F. Interrogation of Electrochemical Properties of Polymer Electrolyte Thin Films with Interdigitated Electrodes. J Electrochem Soc 2018, 165 (16), H1028-H1039, DOI: 10.1149/2.0291816jes.

Copper Reactivity Can Be Tuned to Catalyze the Stereoselective Synthesis of 2-Deoxyglycosides from Glycals.

We demonstrate that tuning the reactivity of Cu by the choice of oxidation state and counterion leads to the activation of both "armed" and "disarmed" type glycals toward direct glycosylation leading to the α-stereoselective synthesis of deoxyglycosides in good to excellent yields. Mechanistic studies show that CuI is essential for effective catalysis and stereocontrol and that the reaction proceeds through dual activation of both the enol ether as well as the OH nucleophile.

Calcium Hydroxide Effect in Degradation of Aqueous Naphthalene: Nucleophilic Substitution of Hydrogen at the C(sp2)–H Bond

The degradation of naphthalene in aqueous solutions containing submerged calcium peroxide-based and calcium hydroxide pellets was examined by using UV–vis and IR spectroscopy and mass spectrometry. The observed products are one-ring and fused rings quinoid and aromatic compounds containing OH and C(H)O groups. Their formation is explained in terms of a Ca2+ cation–π interaction and a nucleophilic OH– attack at the aromatic ring ensued by a departure of H– anion. Such process has not been so far observed in aqueous phase. Its recognition may become a challenge for further studies on applications of alkaline substances in remediation of wastewater and soil contaminated with polycyclic hydrocarbons.

Gold(I)-catalyzed intermolecular dioxolane addition to alkynes: the role of water

Density functional theory (DFT) calculations have been performed on a homogeneous gold-catalyzed reaction between acetylene/propyne and the cyclic ketal 2,2-dimethyl-1,3-dioxolane, DMDO, in the presence of water, with the aim of understanding the actual role played by water. After the addition of DMDO to the alkyne, hydrolysis may happen through two possible reaction routes. In the so-called H-route (previously proposed for similar intramolecular reactions), a water proton is initially added to the alkyne C atom still linked to gold and, afterwards, an OH group adds to a DMDO C atom to allow the release of acetone, whereas in the newly proposed OH-route, a water OH group firstly adds to the most substituted DMDO C atom with simultaneous addition of H to the alkyne C atom linked to gold. A 1,3-H transposition from the just added OH group allows the release of acetone. An intramolecular nucleophilic OH addition to the gold-activated alkene intermediate formed from both hydrolysis paths drives the system to the corresponding 1,3-dioxolane product. The H-route is unable to explain the formation of the dioxolane addition products (observed in similar intramolecular reactions) instead of those coming from the direct addition of water to the alkyne, since it is energetically more demanding than the direct hydration. However, OH-route goes through structures that are more stable than those in the water addition, so, it is the one actually happening for the reaction under study. The regioselective addition of DMDO to the internal C atom of propyne is predicted on the basis of the large polarity of the structures formed in this approach, which makes them capable of strong interactions with water.

Spontaneous advent of genetic diversity in RNA populations through multiple recombination mechanisms.

There are several plausible abiotic synthetic routes from prebiotic chemical materials to ribonucleotides and even short RNA oligomers. However, for refinement of the RNA World hypothesis to help explain the origins of life on the Earth, there needs to be a manner by which such oligomers can increase their length and expand their sequence diversity. Oligomers longer than at least 10–20 nucleotides would be needed for raw material for subsequent natural selection. Here, we explore spontaneous RNA–RNA recombination as a facile means by which such length and diversity enhancement could have been realized. Motivated by the discovery that RNA oligomers stored for long periods of time in the freezer expand their lengths, we systematically investigated RNA–RNA recombination processes. In addition to one known mechanism, we discovered at least three new mechanisms. In these, one RNA oligomer acts as a splint to catalyze the hybridization of two other oligomers and facilitates the attack of a 5′-OH, a 3′-OH, or a 2′-OH nucleophile of one oligomer onto a target atom of another. This leads to the displacement of one RNA fragment and the production of new recombinant oligomers. We show that this process can explain the spontaneous emergence of sequence complexity, both in vitro and in silico.

Editors' Choice—Control of Si3N4 Etching Kinetics and Selectivity to SiO2 by the Additives in Superheated Water

Selective etching of Si3N4 to SiO2 is essential in the semiconductor fabrication process. In particular, as the number of alternating Si3N4/SiO2 multi-layered stacks increases, selective removal of Si3N4 without loss of SiO2 becomes difficult. In this study, the dissolution of Si3N4 was demonstrated in superheated water without addition of H3PO4, which has been widely used to etch Si3N4. The dissolution rates of Si3N4 and SiO2 in the superheated water depended strongly on the concentration of OH−, and the activation energy obtained for the dissolution of Si3N4 was 72.65 ± 0.95 kJ/mol. It is believed that the attack of the partially δ+ charged Si atoms in the Si3N4 by nucleophilic OH− was the key step in the dissolution of Si3N4 in the superheated water. Because a tradeoff between the dissolution rate of Si3N4 and the Si3N4-to-SiO2 etching selectivity was observed, H2SiO3 and HF were added to HCl-based superheated water for optimization. The HCl-based superheated water with the addition of 0.005 vol% HF and 0.01 M H2SiO3 allowed successful fabrication of a horizontal SiO2 trench structure on a patterned Si3N4/SiO2 15 pair-layered stack through selective etching of Si3N4 without thinning of the SiO2 layer.

The ordered side chain imidazole functionalized cross-linked anion exchange membrane

In recent years, the development of alkaline anion exchange membrane fuel cells (AEMFCs) has received widespread attention. On the one hand, non-noble metals can be used as catalysts in alkaline anion exchange membrane fuel cells (AEMFCs), such as silver and nickel which reduced the cost of fuel cell devices. On the other hand, the hydroxide ions move in the opposite direction with the fuel, which reduce fuel permeability and the cost on other aspects. Therefore, the development prospect of alkaline fuel cells is good, while anion exchange membrane, as the core component of alkaline fuel cells, has problems such as the insufficient ion conductivity and alkaline stability, which hinder the successful realization of AEMFCs technology. Until now, many cationic groups have been widely investigated, such as quaternary ammonium, imidazolium, guanidinium and phosphonium. Quaternary ammonium group and imidazolium group are the most commonly used cationic group. The experimental results suggest that imidazole-type anion exchange membrane have better performance. Due to the existence of the conjugated π bond in the unique N -heterocyclic structure, imidazolium grafted membranes exhibit not only high ionic conductivity, but also excellent chemical and thermal stability. The formation of cross-linked network structure is advantageous in suppressing the swelling of the membrane, thereby improving the dimensional stability of the membrane. Meantime, we introduce 1-vinylimidazole to improve the performance of the 1-methylimidazole grafted membrane. This monomer contains not only imidazolium cation groups, but also double bonds can be cross-linked. The imidazole group can transfer OH- ions. The dense network structure formed by double bonds cross-linking makes membranes have good mechanical properties and dimensional stability, and conducive to defense strong nucleophile OH- attack. First, a benzylmethyl-containing poly ether (ether ether ketone) (PEEK) copolymer was synthesized through condensation polymerization of 4,4′-difluorobenzopheno and methylhydroquinone. Then, dissolved the PEEK by 1,1,2,2-tetra- chloroethane, the yellow precipitate bromination of polyether ether ketone (BPEEK) was synthesized by adding NBS and BPO into the solution and reacted at 80°C for 5 h under the nitrogen atmosphere. The BPEEK was chosen to react directly with the functional reagent, 1-methyl imidazole and 1-vinylimidazole and obtained poly (ether ether ketone) crosslinked anion exchange membranes. The structure was characterized by 1H NMR spectroscopy. The morphology and microstructure of the resulting samples were characterized using transmission electron microscopy (TEM). The ion conductivity of the Im-PEEK- x membrane was measured by four-probe alternating current (AC) impedance technique. The thermal stability was tested by thermogravimetric analysis (TGA). The alkaline solution stability of the Im-PEEK- x membrane was evaluated by measuring the changes in IEC values after immersed in 1 mol/L NaOH for a certain time. Water uptake, swelling ratio and mechanical properties of the membranes were also measured. The results indicated that the Im-PEEK- x membrane had been synthesized. After grafting of 1-vinylimidazole, for the membrane of Im-PEEK-0.7, the maximum stress is 60.03 MPa, and the swelling rate is 18.2% at 80°C. After soaking in 1 mol L–1 NaOH solution for 200 h at 80°C, the IEC value was about 81.5% of the initial, which exhibited excellent alkaline stability.

Exploring the Role of the Third Active Site Metal Ion in DNA Polymerase η with QM/MM Free Energy Simulations.

The enzyme human DNA polymerase η (Pol η) is critical for bypassing lesions during DNA replication. In addition to the two Mg2+ ions aligning the active site, experiments suggest that a third Mg2+ ion could play an essential catalytic role. Herein the role of this third metal ion is investigated with quantum mechanical/molecular mechanical (QM/MM) free energy simulations of the phosphoryl transfer reaction and a proposed self-activating proton transfer from the incoming nucleotide to the pyrophosphate leaving group. The simulations with only two metal ions in the active site support a sequential mechanism, with phosphoryl transfer followed by relatively fast proton transfer. The simulations with three metal ions in the active site suggest that the third metal ion may play a catalytic role through electrostatic interactions with the leaving group. These electrostatic interactions stabilize the product, making the phosphoryl transfer reaction more thermodynamically favorable with a lower free energy barrier relative to the activated state corresponding to the deprotonated 3'OH nucleophile, and also inhibit the subsequent proton transfer. The possibility that Mg2+-bound hydroxide acts as the base deprotonating the 3'OH nucleophile is also explored.

New Route to Synthesize Fluorine Substituted Lamotrigine Drug Analogues as an Anti-Inflammatory Agent

Aim and Objective: Lamotrigine antiepileptic drug, 3,5-diamino-6-(2',3'-dichlorophenyl)-1,2,4- triazine is used to treat epilepsy and bipolar disorder, lamotrigine is also effective in treating some diabetic neuropath. Recently, interest has focused on the synthesis of new lamotrigine analogues in view of their biocidal effects. This investigation focused on synthesis of novel fluorine substituted lamotrigine drug analogues using an efficient and environmental friendly process. Materials and Methods: Synthetic route to fluorinated lamotrigine analogues was furnished by aminolysis and ammionlysis of 6-(2'-amino-5'-fluorophenyl)-3-thioxo-1,2,4-triazin-5(2H,4H)one. The structures of the targets compounds have been deduced upon their elemental analysis and spectral data (UV, IR, 1HNMR, 13CNMR and Mass spectroscopy). The anti-inflammatory activities of the synthesized compounds are also evaluated. Results: The acute anti-inflammatory activity of the synthesis fluorine substituted lamotrigine analogues was evaluated and showed various anti-inflammatory effects at tested condition. Thus, compounds rich in fluorine showed higher activity in comparison with compounds lethal of fluorine atoms. In addition, compound with - COCF3 exhibited a higher activity over compounds with aromatic –CF. Furthermore, the higher number of fluorine atoms tend to a higher number of enzyme receptors involved in the inflammatory process. Conclusion: The present study described a simple and new route to synthesize some new fluorine substituted lamotrigine analogues starting from 3-thioxo-1,2,4-triazin-5-one through a simple nucleophilic displacement of SH and OH by amino groups. In addition, this study tends to search for new fluorinated lamotrigine analogues as anti-inflammatory agents. The obtained results revealed that compounds binding to -CF3 are more active in comparison with compound with aromatic –CF.

Gold(I)-Catalyzed Direct Stereoselective Synthesis of Deoxyglycosides from Glycals

Au(I) in combination with AgOTf enables the unprecedented direct and α-stereoselective catalytic synthesis of deoxyglycosides from glycals. Mechanistic investigations suggest that the reaction proceeds via Au(I)-catalyzed hydrofunctionalization of the enol ether glycoside. The room temperature reaction is high yielding and amenable to a wide range of glycal donors and OH nucleophiles.

The First Triple-Decker Complex with a Carbenium Center, [CpCo(μ-C3 B2 Me5 )RuC5 Me4 CH2 ]+ : Synthesis, Reactivity, X-Ray Structure, and Bonding.

The first derivative of the methylium cation with the triple-decker substituent, [CpCo(C3 B2 Me5 )RuC5 Me4 CH2 ]PF6 (2PF6 ), was synthesized from the reaction of the triple-decker complex CpCo(C3 B2 Me5 )RuCp* (1) with the salt of the trityl cation [CPh3 ]+ . The X-ray crystal structure of 2PF6 reveals that the methylium carbon is bound to the ruthenium with Ru-C bond length of 2.259 Å and corresponds to the description of its structure as η6 -fulvene-ruthenium. Reactions of 2PF6 with nucleophiles OH- , Ph3 P, Et3 N led to the corresponding derivatives of 1 in high yields. Aromatic amines PhNEt2 and 4-MeC6 H4 NH2 react with 2PF6 to give the electrophilic aromatic substitution products quantitatively. Chemical reduction of 2PF6 with Zn powder in tetrahydrofuran leads to the formation of the bis(triple-decker) derivative (CpCo(C3 B2 Me5 )RuC5 Me4 CH2 )2 (10) with a CH2 CH2 -bridge. The structures of complexes 4, 7-10 were determined by X-ray diffraction. Density functional calculations support the crystallographically determined geometry of 2 and allow rationalization of some characteristics of its structure, spectroscopy, and reactivity.