Methylene Linker Research Articles

Hypervalent iodine mediated synthesis of imidazo[1,2-a]pyridine ethers: consecutive methylene linkage and insertion of ethylene glycol

Hypervalent iodine mediated selective synthesis of imidazo[1,2-a]pyridine ethers using ethylene glycol as a methoxy ethanol source as well as solvent under metal-free conditions is described.

Molecular Engineering through Control of Structural Deformation for Highly Efficient Ultralong Organic Phosphorescence.

It is an enormous challenge to achieve highly efficient organic room-temperature phosphorescence (RTP) with a long lifetime. We demonstrate that, by bridging the carbazole and halogenated phenyl ring with a methylene linker, RTP phosphors CzBX (X=Cl, Br) present high phosphorescence efficiency (ΦPh ). A ΦPh up to 38 % was obtained for CzBBr with a lifetime of 220 ms, which is much higher than that of compounds CzPX (X=Cl, Br) with a C-N bond as a linker (ΦPh <1 %). Single-crystal analysis and theoretical calculations revealed that, in the crystal phase, intermolecular π-Br interactions accelerate the intersystem crossing process, while tetrahedron-like structures induced by sp3 methylene linkers restrain the nonradiative decay channel, leading to the high phosphorescence efficiency in CzBBr. This research paves a new road toward highly efficient and long-lived RTP materials with potential applications in anti-counterfeiting or data encryption.

Molecular Engineering through Control of Structural Deformation for Highly Efficient Ultralong Organic Phosphorescence

AbstractIt is an enormous challenge to achieve highly efficient organic room‐temperature phosphorescence (RTP) with a long lifetime. We demonstrate that, by bridging the carbazole and halogenated phenyl ring with a methylene linker, RTP phosphors CzBX (X=Cl, Br) present high phosphorescence efficiency (ΦPh). A ΦPh up to 38 % was obtained for CzBBr with a lifetime of 220 ms, which is much higher than that of compounds CzPX (X=Cl, Br) with a C−N bond as a linker (ΦPh&lt;1 %). Single‐crystal analysis and theoretical calculations revealed that, in the crystal phase, intermolecular π‐Br interactions accelerate the intersystem crossing process, while tetrahedron‐like structures induced by sp3 methylene linkers restrain the nonradiative decay channel, leading to the high phosphorescence efficiency in CzBBr. This research paves a new road toward highly efficient and long‐lived RTP materials with potential applications in anti‐counterfeiting or data encryption.

Designing dual inhibitors for the treatment of Alzheimer’s disease as well as Type 2 diabetes mellitus via pharmacoinformatics approach: A step towards better medication for diabetes-associated neurological disorder

Purpose: To design dual inhibitors against Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) via pharmacoinformatics approach.Methods: Dual Drug Candidates (DDC) were designed and explored for their molecular interaction with several AD and T2DM targets. Pterostilbene, a natural anti-T2DM compound was coupled with different cholinesterase inhibitors to design DDC. Orisis Datawarrior online property calculator tools, Autock 4.2 and Hex 5.1 were used to investigate the potency of all DDC relative to positive controls.Results: The study found that DDC2 (pterostilbene - methylene linker -octa hydro amino phenothiazine), DDC3 (pterostilbene - ethylene linker - N-phthalimide) and DDC5 (pterostilbene - carbonyl linker - 2-methyl-4-aminoquinoline) were the most promising out of all the DDCs. DDC2 showed strong molecular interaction with most of the AD and T2DM targets, including acetylcholinesterase, butrylcholinesterase, β-secretase, receptor for advanced glycation end products and ATP sensitive potassium channel, dipeptidyl peptidase IV and sodium glucose transport protien 2. The findings also revealed the amyloid anti-aggregation potential of DDC.Conclusion: The results show that DDC3 and DDC5 significantly interfer with the primary nucleation process of β amyloid. Thus, DDC2, DDC3 and DDC5 have strong anti-T2DM and anti-AD potential.&#x0D; Keywords: Type 2 Diabetes Mellitus, Alzheimer’s disease, Dual drug candidate, Amyloid-beta, Pterostilbene

Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility.

Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains. Improved antitubercular and antitrypanosomal activity was observed with the biaryl side chains, with most analogs achieved 2- to 175-fold higher activity than the monoaryl parent compounds, with encouraging improvements in solubility when pyridyl groups were incorporated. This study has contributed to understanding the existing structure–activity relationship (SAR) of the nitroimidazopyrazinone scaffold against a panel of disease-causing organisms to support future lead optimization.

Cover Feature: Synergistic Self‐Assembly of Oxoanions and d‐Block Metal Ions with Heteroditopic Receptors into Triple‐Stranded Helicates (Chem. Eur. J. 63/2020)

In competitive extraction experiments, receptors functionalized with 2,2’-bipyridine (bpy) and o-phenylene-bis(urea) (pbu) binding sites that are interconnected with methylene linker exhibit very high affinity towards CuSO4 in the presence of other divalent first-row transition metal sulfates. Synergistic recognition of divalent d-block metal ions and tetrahedral oxoanions by these receptors induces self-assembly of triple-stranded helicates. More information can be found in the Communication by S. Jansone-Popova et al. on page 14290.

저온 플라즈마 처리된 녹차 유래의 최종당화산물 생성 억제물질의 동정

Green tea (Camellia sinensis) with abundant phenolic compounds is considered to a major dietary source of flavan 3-ols such as (−)-epigallocatechin gallate (EGCG). Here, we assessed the effects of non-thermal dielectric barrier discharge (DBD) plasma on green tea extract using spectroscopy and bioassays. Plasma-induced structural changes in EGCG in green tea resulted in the isolation of two methylene-bridge dimers, oolonghomobisflavan A (1) and B (2). The structures of these compounds were characterized using nuclear magnetic resonance and mass spectroscopy data. The symmetric dimer 1 connected by a methylene linkage was the most potent inhibitor of advanced glycation end products (AGEs) formation (IC50, 8.2±0.5 μM). The radical scavenging capacity of against hydroxyl, and stereoisomers 1 and 2 was more potent than that of the positive control ((+)-catechin). These major products purified by treating green tea with DBD plasma for 60 min were quantified by HPLC. Our results provide evidence that structural changes of EGCG in green tea extract induced by plasma might enhance biological efficacy.

Triphenylphosphonium conjugates of 1,2,3-triazolyl nucleoside analogues. Synthesis and cytotoxicity evaluation

A series of triphenylphosphonium (TPP) conjugates of 1,2,3-triazolyl analogues of several pyrimidine nucleosides was synthesized and evaluated for the in vitro cytotoxicity against human cancer cell lines M-HeLa, MCF-7, PANC-1, PC-3, DU145, SKOV-3, A275, and normal human cell line WI-38. In these TPP-conjugates triphenylphosphonium cation was attached via a tetramethylene chain to the N-3 atom of the heterocycle moiety (uracil, thymine, quinazoline-2,4-dione), which was coupled with the D-ribofuranosyl-1,2,3-triazol-4-yl fragment via methylene or tetramethylene linker. It was shown for the first time that the conjugation of 1,2,3-triazolyl derivatives of uridine, its analogues featuring quinazoline-2,4-dione fragment as well as uracil and thymine derivatives, having propargyl or a 1,2,3-triazolyl substituent at the N-1 atom, with a TPP-butyl cation endowed some of them with cytotoxic activity against human cancer cells. Among all human cancer cell lines used, DU-145 and A375 cells were the most sensitive to these TPP conjugates. At the same time, all tested compounds did not inhibit growth of normal cells WI-38. Propargyl containig TPP-conjugates of uracil 4f, 4j, and thymine 5f showed the highest cytotoxicity with IC50 values in the low micromolar concentration range. The present findings suggest that TPP-conjugates of uracil and thymine derivatives would be promising for further development as an anticancer agent.

Low-Symmetry β-Diketimine Aryloxide Rare-Earth Complexes: Flexible, Reactive, and Selective.

We report the synthesis, characterization, and reactivity of a new low-symmetry β-diketimine featuring a pendant amino(methyl)phenol donor and its corresponding heteroleptic rare-earth (RE) complexes. This includes the first structurally characterized examples of alcoholysis and insertion from an isolated REIII amide in a β-diketimine framework. The flexible methylene linkage leads to REIII complexes with tunable dynamic solution behavior that defines their stoichiometric and catalytic reactivity. The addition of a strong neutral donor ligand, tricyclohexylphosphine oxide, suppresses a prevalent catalyst degradation pathway (base-promoted elimination) and dramatically enhances the catalyst performance in the stereospecific ring-opening polymerization of rac-β-butyrolactone. Our results further demonstrate the importance of ligand reorganization in the stoichiometric and catalytic activity of REIII ions.

Theoretical evaluation of EGFR kinase inhibition and toxicity of di-indol-3-yl disulphides with anti-cancer potency

Research aimed at developing potent di-indol-3-yl disulphides for cancer diseases makes use of various theoretical techniques to evaluate the drug-likeness parameters and the mode of action. A drug-likeness filter helps evaluate the therapeutic potency of four bis-indole derivatives, structurally related to 3,3′-methanediyl-bis-indole (DIM) but having the S-S instead of the methylene linker and showing a high inhibitory impact on the variants of cancer cell lines (among them HL-60 and DU-145). Based on in vitro experimental results for their close analogues, a correlation was found between the epidermal growth factor receptor kinase (EGFR) inhibition and the theoretical energy of complexation. Docking studies of ligands followed by molecular dynamics were performed at the ATP-binding site of EGFR tyrosine kinase to scrutinize the inhibition of the di-indol-3-yl disulphides at a molecular level. Derivatives with bromine or iodine substituents at C-5 positions of the indole moieties made strong complexes by interaction with the most important hinge region residues Met-793 and Cys-733. The inhibition model for EGFR kinase and the proposed procedures can be very informative in the biological testing of selected bis-indoles and may be useful for future research on effective inhibitors for the treatment of EGFR-related cancer. Communicated by Ramaswamy H. Sarma

Synthesis and Characterization of New Organosoluble and Thermally Stable Aromatic Polyamides Containing Flexible Ether, Ketone, and Methylene Linkages

AbstractA new aromatic diacid monomer, namely, 1,4‐phenylene‐bis‐[[4′‐(4″‐carboxy methylene) phenoxy phenyl] methanone] (PBCPPM) is successfully synthesized and characterized by physical constant, FT‐IR, NMR (1H and 13C) spectroscopy, and mass spectrometry. Synthesis of new series of polyamides with high thermal stability and improved solubility are performed by Yamazaki's direct phosphorylative polycondensation method from new PBCPPM with different aromatic diamines. The inherent viscosity of these polyamides is in the range 0.47–0.81 dL g−1. All these polyamides are amorphous or partly crystalline and reveal good solubility in polar aprotic solvents and exhibit glass transition temperatures between 201 and 232 °C. Initial decomposition temperatures are in the range 300–367 °C and T10 is in the range of 376–414 °C indicating good thermal stability of these polyamides. The present observations suggest that these polyamides can find potential applications as high performance polymers.

A computational study of effects on membrane recruitment of the polar linkers in Vitamin E derivatives

BackgroundPrevious studies found that Vitamin E (VE) could recruit protein kinase B (Akt1) to the membrane by targeting its unconventional lipid-binding site, which led to the dephosphorylation of Akt1 at Ser473, eventually deactivating the enzyme. MethodsA series of VE-like compounds with varying types and lengths of the linker groups are designed to study the VE-driven membrane recruitment of Akt1 using a combined molecular docking and molecular dynamics (MD) simulation approach. ResultsWe find that the linker groups with only one methylene linker and multiple hydrogen bond donors are optimal for achieving a balance between binding to the protein and partitioning into the membrane to form a stable protein-ligand-membrane ternary complex. These polar linkers are found to form stable hydrogen bonds with the lipid head groups during the MD simulations, which turns out critical for ensuring that the chromanol ring of the VE-like compounds resides above the membrane surface to fully engage in the protein. ConclusionsOur results reveal the molecular determinants of the linker groups for VE derivatives' ability to anchor Akt1 to the membrane. General significanceThese findings will facilitate the design of membrane interfacial compounds to recruit specific proteins to the membrane to modulate the protein function.

Efficient dimerization of (−)-epigallocatechin gallate using nonthermal plasma as potent melanogenesis inhibitors

(−)-Epigallocatechin gallate (EGCG), which is the most abundant bitter polyphenol in green tea (Camellia sinensis) leaves, is generally unstable under oxidative conditions. In this study, the efficient dimerization of EGCG was successfully achieved without changes in stereochemistry by treatment with nonthermal dielectric barrier discharge (DBD) plasma. The stereochemically pure dimers 2 and 3 connected by a methylene linkage exhibited significantly enhanced melanogenesis inhibitory activities compared to the parent EGCG and the active compounds 2 and 3 suppressed cellular tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2 expression in B16F10 melanoma cells, which could be considered one of the mechanisms of action. These results indicate a new method for efficient dimerization of stereochemically active depigment agent induced by DBD plasma treatment.

(Invited) Photoluminescent Property Modulation of Locally Functionalized Single-Walled Carbon Nanotubes Based on Molecular Factors in Bis-Aryl Functionalization

Photoluminescence (PL) in the near infrared (NIR) region is applicable to bioimaging and telecommunication devices. Single-walled carbon nanotubes (SWNTs) with semiconducting features show NIR PL whose properties are governed by photogenerated excitons in the one-dimensional nanostructures. Defect doping to SWNTs is gathering great attentions due to enhance the contribution of the excitons to PL. The doped sites work as emissive sites with narrower bandgaps and exciton trapping features. As a result, additional PL (E 11*) with red-shifted wavelengths and enhanced quantum yields newly appears compared to original PL (E 11) of pristine SWNTs.[1-9]Local chemical modification for the defect creation achieves molecular functionalization of the defect-doped sites of the tubes, providing locally functionalized SWNTs (lf-SWNTs). They are found to show PL modulation based on the functionalized molecules. Here, we report bis-aryl functionalization for proximal defect doping of lf-SWNTs, in which molecular structure effects of bis-aryl diazonium modifiers and microenvironmental effects of the doped sites are discussed.Bis-arydiazonium salts (bAs) that had two reactive aryldiazonium groups connected with a methylene linker were synthesized and reacted with solubilized SWNTs for local functionalization. For PL wavelength modulation, the linker effects were examined by changing the connected positions on the aryl groups (pbAs for para and mbAs for meta) and the length of methylene chains.[5,8] In PL spectra of the synthesized lf-SWNTs (lf-SWNTs-pbA and lf-SWNTs-mbA), peaks appearing over 1200 nm (E 11 2*) changed sensitively depending on the chemical structures of bAs. In addition, the E 11 2* PL showed unique wavelength shifting behaviors by microenvironment changes using various organic solvents, which was different from those of E 11 PL and E 11* PL.[9]Thus, bis-aryl functionalization in lf-SWNTs creates the doped sites whose properties are different from typical doped sites showing E 11* PL and would be useful for fundamental understanding of this material and developing modulation techniques of the longer wavelength NIR PL.[1] B. Weisman et al. Science, 330, 1656 (2010). [2] Y. Miyauchi et al. Nat. Photon., 7, 715 (2013). [3] Y. Wang et al. J. Am. Chem. Soc., 138, 6878 (2016). [4] S. Doorn et al. Nat. Photon., 11, 577 (2017). [5] T. Shiraki et al. Sci. Rep., 6, 28393 (2016). [6] Y. Maeda et al. Nanoscale, 8, 16916 (2016) [7] T. Shiraki et al. Chem. Commun., 53, 12544 (2017). [8] T. Shiraki et al. Chem. Lett., 48, 791 (2019). [9] T. Shiraki et al. Chem. Commun., 55, 3662 (2019). Figure 1

Copolymerization of Nonpolar Olefins and Allyl Acetate Using Nickel Catalysts Bearing a Methylene-Bridged Bisphosphine Monoxide Ligand

Bisphosphine monoxide ligand 1 with a methylene linker was applied to the nickel catalyzed olefin polymerization. In situ generated phenylnickel chloride complex 2 and NaBArF4 mediated the homopoly...

Structural Characterization of Cure Bio-based Phenol Formaldehyde Wood Adhesive

Bio-phenol formaldehyde (BPF) resole resins were characterized by liquid-state 13C Nuclear Magnetic Resonance (NMR) spectroscopy. The liquid 13C NMR analysis indicated that the condensation reactions between the bark phenolic compounds and the formaldehyde occurred during the synthesis of the resins. Methylene ether bridges in the resins were more pronounced in the BPF resin when compared to the PF resin system. The liquid-state 13C NMR study revealed significant differences in the resins structures induced by the inclusion of bark-phenolic components. The bark-phenolic components favored the formation of para-ortho methylene linkages in the BPF resins and also enhanced the cure rate of the BPF resin system.

Assessment of the electrochemical behaviour of silicon@carbon nanocomposite anode for lithium-ion batteries

Abstract Silicon nanocomposites have great potential applications in lithium-ion batteries. However, huge mechanical strain, capacity retention and unstable solid electrolyte interface formation weaken their applications in the real world. To overcome the above challenges, a novel facile route was adopted to design nanostructured silicon core carbon shell composites (Si@C), where the carbonization of phenolic resins led to a uniform porous thin interfacial layer of carbon. The phenolic resin precursor endowed mesoporous morphology with the carbon layer due to the carbonization of aromatic carbon, methylene linkages and hydroxyl groups. The mesoporous conductive carbon helped effectively to control the mechanical strain of silicon nanoparticles which maintained the integrity of Si@C nanocomposites and provided effective channels to easy access of electrolyte and short lithium ions transport. This novel Si@C anode offered a stable specific capacity of ∼868 mAh g−1 at 0.1 Ag-1 up to 500 cycles with ≥99% columbic efficiency.

Characterization of microstructures and reaction mechanisms of Tröger's base polymers of intrinsic microporosity.

Tröger's base polymers of intrinsic microporosity (PIMs) are receiving increasing attention for applications such as polymer molecular sieve membranes. Development of novel membrane materials requires microstructure analysis in order to overcome processing and applications challenges. This study aims to address these challenges and overcome some of the solubility/aggregation issues that hinder the analysis of these materials. A combination of matrix-assisted laser desorption/ionization mass spectrometry and collision-induced dissociation was used to examine the reaction products of unfunctionalized Tröger's base PIMs. Enhanced data mining, using ultrahigh-resolution mass spectrometry and statistical analysis, yielded a wealth of information on the molecular mass, chemical connectivity, and end groups of species generated during synthesis. Modifications of interest include N-methyl, N-methanimine, N-formyl, and N-methylol end-capping moieties, as well as incomplete backbone methanodiazocine rings with missing bridging methylene linkages. Most importantly, a general fragmentation mechanism, supported by computational modeling, was developed to assist in the rapid identification of main-chain and end-group modifications in Tröger's base PIMs. Unfunctionalized Tröger's base polymers were selected as a model system, to thoroughly study their end-group modification chemistry. This model system could then be used to gain insights into complex hydroxy-functional PIM materials.

Spiroxatrine derivatives towards 5-HT1A receptor selectivity.

In our previous work, spiroxatrine was taken as reference compound to develop selective NOP ligands. Therefore, several triazaspirodecanone derivatives were synthesized. Here, we verify their selectivity towards other 5-HT1 receptor subtypes and with respect to α2-AR (Adrenergic Receptors). Binding affinities were determined on cells expressing human cloned receptors for 5-HT1A/B/D and α2A/B/C subtypes. The Ki values were determined for those with at least 50% radioligand inhibition. All our derivatives show a moderate affinity for α2 subtypes, spanning from 5 to 7.5 pKivalues. Moreover, they show affinity values in a μM-nM range at the 5-HT1A receptor, while they are practically inactive at 5-HT1B and 5-HT1D subtypes. Compound 11, the best of the series, has a 5-HT1A pKi value of 8.43 similar to spiroxatrine but, notably, it has a 5-HT1A favorable selectivity ratio of 52, 8 and 29, respectively over α2A, α2B and α2C adrenoceptor subtypes. In this SAR study, a 5-HT1A selective ligand has been identified in which a tetralone moiety replaced the 1,4-benzodioxane of spiroxatrine and the methylene linker to the triazaspirodecanone portion was maintained in position 2.

Selective Formation of S4- and T-Symmetric Supramolecular Tetrahedral Cages and Helicates in Polar Media Assembled via Cooperative Action of Coordination and Hydrogen Bonds.

We report on the synthesis and self-assembly study of novel supramolecular monomers encompassing quadruple hydrogen-bonding motifs and metal-coordinating 2,2'-bipyridine units. When mixed with metal ions such as Fe2+ or Zn2+, the tetrahedron cage complexes are formed in quantitative yields and full diastereoselectivity, even in highly polar acetonitrile or methanol solvents. The symmetry of the complexes obtained has been shown to depend critically on the flexibility of the ligand. Restriction of the rotation of the hydrogen-bonding unit with respect to the metal-coordinating site results in a T-symmetric cage, whereas introducing flexibility either through a methylene linker or rotating benzene ring allows the formation of S4-symmetric cages with self-filled interior. In addition, the possibility to select between tetrahedral cages or helicates and to control the dimensions of the aggregate has been demonstrated with a three-component assembly using external hydrogen-bonding molecular inserts or by varying the radius of the metal ion (Hg2+ vs Fe2+). Self-sorting studies of individual Fe2+ complexes with ligands of different sizes revealed their inertness toward ligand scrambling.