N‐Acyl Derivatives of 4‐Phenoxyaniline as Neuroprotective Agents

Neuronal cell death is the main cause behind the progressive loss of brain function in age‐related neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Despite the differing etiologies of these neurological diseases, the underlying neuronal damage is triggered by common mechanisms such as oxidative stress, impaired calcium homeostasis, and disrupted mitochondrial integrity and function. In particular, mitochondrial fragmentation, mitochondrial membrane permeability, and the release of death‐promoting factors into the cytosol have been revealed as the “point of no return” in programmed cell death in neurons. Recent studies revealed a pivotal role for the pro‐apoptotic Bcl‐2‐family protein Bid in models of neuronal cell death, which confirmed Bid as a potential drug target. Herein, we present N‐acyl‐substituted derivatives of 4‐phenoxyaniline that were screened for their potential to attenuate Bid‐mediated neurotoxicity. These compounds provided significant protection against glutamate‐ and Bid‐induced toxicity in cultured neurons. Substitution of the amino group in the 4‐phenoxyaniline scaffold with 4‐piperidine carboxylic acid and N‐hydroxyethyl‐4‐piperidine carboxylic acid yielded compounds that displayed significant neuroprotective activity at concentrations as low as 1 μM . Furthermore, findings of a tBid‐overexpression assay and real‐time measurements of cell impedance support the hypothesis that these compounds indeed address the Bid protein.     

Synthesis and Properties of N‐Alkyl–N,N‐Dimethyl‐N‐(o‐Hydroxymethyl)Benzylammonium Chlorides

A series of N‐alkyl–N,N‐dimethyl‐N‐(o‐hydroxymethyl)benzylammonium chlorides surfactants (DHBA‐m) were synthesized using o‐chloromethylbenzyl alcohol and N‐alkyl–N,N‐dimethyl tertiary amine as raw materials. The structure of the products was confirmed by FT‐IR, ¹H NMR, ¹³C NMR and MS. DHBA‐m surfactants exhibit low Krafft points and high surface activities. The process of micellization of DHBA‐m is spontaneous, exothermic, and entropy‐driven. The hydroxymethyl substitution increases hydrophobicity of DHBA‐m, thus making micellization more favorable compared with that of N‐dodecyl–N,N‐dimethyl‐N‐benzylammonium chlorides (DDBAC‐m). The bactericidal activity of DHBA‐m is stronger on E. coli than that of DDBAC‐12, and DHBA‐16 shows strong bactericidal activity on Salmonella, S. aureus, and Streptococcus.     

N‐Alkyl‐, 1‐C‐Alkyl‐, and 5‐C‐Alkyl‐1,5‐dideoxy‐1,5‐imino‐(l)‐ribitols as Galactosidase Inhibitors

A series of 1,5‐dideoxy‐1,5‐imino‐(l )‐ribitol (DIR) derivatives carrying alkyl or functionalized alkyl groups were prepared and investigated as glycosidase inhibitors. These compounds were designed as simplified 4‐epi‐isofagomine (4‐epi‐IFG) mimics and were expected to behave as selective inhibitors of β‐galactosidases. All compounds were indeed found to be highly selective for β‐galactosidases versus α‐glycosidases, as they generally did not inhibit coffee bean α‐galactosidase or other α‐glycosidases. Some compounds were also found to be inhibitors of almond β‐glucosidase. The N‐alkyl DIR derivatives were only modest inhibitors of bovine β‐galactosidase, with IC₅₀ values in the 30–700 μm range. Likewise, imino‐l ‐ribitol substituted at the C1 position was found to be a weak inhibitor of this enzyme. In contrast, alkyl substitution at C5 resulted in enhanced β‐galactosidase inhibitory activity by a factor of up to 1000, with at least six carbon atoms in the alkyl substituent. Remarkably, the ‘pseudo‐anomeric’ configuration in this series does not appear to play a role. Human lysosomal β‐galactosidase from leukocyte lysate was, however, poorly inhibited by all iminoribitol derivatives tested (IC₅₀ values in the 100 μm range), while 4‐epi‐IFG was a good inhibitor of this enzyme. Two compounds were evaluated as pharmacological chaperones for a GM1‐gangliosidosis cell line (R301Q mutation) and were found to enhance the mutant enzyme activity by factors up to 2.7‐fold.     

Synthesis and Surface Active Properties of tri[(N‐alkyl‐N‐ethyl‐N‐Sodium carboxymethyl)‐2‐Ammonium bromide ethylene] Amines

Trimeric betaine surfactants tri[(N‐alkyl‐N‐ethyl‐N‐sodium carboxymethyl)‐2‐ammonium bromide ethylene] amines were prepared with raw materials containing tris(2‐aminoethyl) amine, alkyloyl chloride, lithium aluminium hydride, sodium chloroacetate, and bromoethane by alkylation, Hoffman degradation reaction, carboxymethylation and quaternary amination reaction. The chemical structures of the prepared compounds were confirmed by FTIR, ¹H NMR, MS and elemental analysis. With the increasing length of the carbon chain, the values of their critical micelle concentration initially decreased. Surface active properties of these compounds were superior to general carboxylate surfactants C₁₀H₂₁CHN⁺(CH₃)₂COONa. The minimum cross‐sectional area per surfactant molecule (A_min), standard Gibbs free energy adsorption (ΔG_ads) and standard Gibbs free energy micellization (ΔG_mic) are notably influenced by the chain length n, and the trimeric betaine surfactants have greater ability to adsorb at the air/water interface than form micelles in solution. The efficiency of adsorption at the water/air interface (pC₂₀) of these surfactants increased with the increasing length of the alkyl chain. Their foaming properties, wetting ability of a felt chip, and lime‐soap dispersing ability were also investigated.     

Effect of Partially Fluorinated N‐Alkyl‐Substituted Piperidine‐2‐carboxamides on Pharmacologically Relevant Properties

The modulation of pharmacologically relevant properties of N‐alkyl‐piperidine‐2‐carboxamides was studied by selective introduction of 1–3 fluorine atoms into the n‐propyl and n‐butyl side chains of the local anesthetics ropivacaine and levobupivacaine. The basicity modulation by nearby fluorine substituents is essentially additive and exhibits an exponential attenuation as a function of topological distance between fluorine and the basic center. The intrinsic lipophilicity of the neutral piperidine derivatives displays the characteristic response noted for partially fluorinated alkyl groups attached to neutral heteroaryl systems. However, basicity decrease by nearby fluorine substituents affects lipophilicities at neutral pH, so that all partially fluorinated derivatives are of similar or higher lipophilicity than their non‐fluorinated parents. Aqueous solubilities were found to correlate inversely with lipophilicity with a significant contribution from crystal packing energies, as indicated by variations in melting point temperatures. All fluorinated derivatives were found to be somewhat more readily oxidized in human liver microsomes, the rates of degradation correlating with increasing lipophilicity. Because the piperidine‐2‐carboxamide core is chiral, pairs with enantiomeric N‐alkyl groups are diastereomeric. While little response to such stereoisomerism was observed for basicity or lipophilicity, more pronounced variations were observed for melting point temperatures and oxidative degradation.     

Recognition and Excision Properties of 8‐Halogenated‐7‐Deaza‐2′‐Deoxyguanosine as 8‐Oxo‐2′‐Deoxyguanosine Analogues and Fpg and hOGG1 Inhibitors

Cellular DNA continuously suffers various types of damage, and unrepaired damage increases disease progression risk. 8‐Oxo‐2′‐deoxyguanine (8‐oxo‐dG) is excised by repair enzymes, and their analogues are of interest as inhibitors and as bioprobes for study of these enzymes. We have developed 8‐halogenated‐7‐deaza‐2′‐deoxyguanosine derivatives that resemble 8‐oxo‐dG in that they adopt the syn conformation. In this study, we investigated their effects on Fpg (formamidopyrimidine DNA glycosylase) and hOGG1 (human 8‐oxoguanine DNA N‐glycosylase 1). Relative to 8‐oxo‐dG, Cl‐ and Br‐deaza‐dG were good substrates for Fpg, whereas they were less efficient substrates for hOGG1. Kinetics and binding experiments indicated that, although hOGG1 effectively binds Cl‐ and Br‐deaza‐dG analogues with low K_m values, their lower k_cat values result in low glycosylase activities. The benefits of the high binding affinities and low reactivities of 8‐oxo‐dG analogues with hOGG1 have been successfully applied to the competitive inhibition of the excision of 8‐oxoguanine from duplex DNA by hOGG1.     

An Energetic N‐Oxide and N‐Amino Heterocycle and its Transformation to 1,2,3,4‐Tetrazine‐1‐oxide

This study reports the preparation of 1‐amino‐1,2,3‐triazole‐3‐oxide (DPX2) and its transformation to 1,2,3,4‐tetrazine‐1‐oxide. DPX‐2 provides insight into a novel N‐oxide/N‐amino high‐nitrogen system, being the first energetic material in this class. The ability of this material to undergo a nitrene insertion forming 1,2,3,4‐tetrazine‐1‐oxide was also studied, and evidence for this material, the first non‐benzoannulated 1,2,3,4‐tetrazine‐1‐oxide, is presented. The existence of both of these materials opens new strategies in energetic materials design. DPX2 was characterized chemically (Infrared, Raman, NMR, X‐ray) and as a high explosive in terms of energetic performances (detonation velocity, pressure, etc.) and sensitivities (impact, friction, electrostatic). DPX‐2 was found to possess good thermal stability and moderate sensitivities, indicating the viability of N‐amino N‐oxides as a strategy for the preparation of new energetic materials.     

5‐(Piperidin‐4‐yl)‐3‐Hydroxypyrazole: A Novel Scaffold for Probing the Orthosteric γ‐Aminobutyric Acid Type A Receptor Binding Site

A series of bioisosteric N₁‐ and N₂‐substituted 5‐(piperidin‐4‐yl)‐3‐hydroxypyrazole analogues of the partial GABA_AR agonists 4‐PIOL and 4‐PHP have been designed, synthesized, and characterized pharmacologically. The unsubstituted 3‐hydroxypyrazole analogue of 4‐PIOL ( 2 a ; IC₅₀～300 μM ) is a weak antagonist at the α₁β₂γ₂ GABA_AR, whereas substituting the N₁‐ or N₂‐position with alkyl or aryl substituents resulted in antagonists with binding affinities in the high nanomolar to low micromolar range at native rat GABA_ARs. Docking studies using a α₁β₂γ₂ GABA_AR homology model along with the obtained SAR indicate that the N₁‐substituted analogues of 4‐PIOL and 4‐PHP, 2 a – k , and previously reported 3‐substituted 4‐PHP analogues share a common binding mode to the orthosteric binding site in the receptor. Interestingly, the core scaffold of the N₂‐substituted analogues of 4‐PIOL and 4‐PHP, 3 b – k , are suggested to flip 180° thereby adapting to the binding pocket and addressing a cavity situated above the core scaffold.     

tert‐Butyl Hydroperoxide and Tetrabutylammonium Iodide‐Promoted Free Radical Cyclization of α‐Imino‐N‐arylamides and α‐Azido‐N‐arylamides

The oxidizing system of tert‐butyl hydroperoxide (TBHP) and tetrabutylammonium iodide (TBAI) is capable of generating α‐(arylaminocarbonyl)iminyl radicals from ethyl 2‐(N‐arylcarbamoyl)‐2‐iminoacetates. These iminyl radicals preferably undergo intramolecular ipso attack on the benzene ring to give azaspirocyclohexadienyl radicals, which are readily captured by molecular oxygen under an oxygen atmosphere to yield azaspirocyclohexadienones. In the absence of oxygen, the reaction affords quinoxalin‐2‐one products. This oxidizing system is also effective to convert α‐aryl‐α‐azido‐N‐arylamides to the corresponding iminyl radicals under basic conditions (sodium tert‐butoxide, t‐BuONa), and the subsequent cyclization of these iminyl radicals results in the formation of azaspirocyclohexadienone products in high yields under an oxygen atmosphere. Plausible mechanisms are proposed to rationalize the experimental results, and factors influencing the reactions are discussed.

     

An Organocatalytic Synthesis of cis‐N‐Alkyl‐ and N‐Arylaziridine Carboxylates

An extremely mild protocol that employs readily available starting materials, i.e., aldehyde, amine and alkyl diazoacetate, returns structurally diverse N‐substituted‐C‐2/3‐difunctionalised aziridines in excellent yields and stereoselectivities when pyridinium triflate is incorporated as an organocatalyst. The reaction process is environmentally benign affording water and nitrogen as the only by‐products. This racemic protocol paves the way for the development of novel asymmetric organocatalysts capable of generating optically active aziridines.     

Gold(I)‐Catalyzed Intramolecular Hydroamination of N‐Allylic N′‐Arylureas to form Imidazolidin‐2‐ones

Treatment of N‐allylic N′‐arylureas with a catalytic 1:1 mixture of di‐tert‐butyl‐o‐biphenylphoshphine gold(I) chloride and silver hexafluorophosphate (1 mol%) in chloroform at room temperature led to 5‐exo‐hydroamination to form the corresponding imidazolidin‐2‐ones in excellent yield. In the case of N‐allylic ureas that possessed an allylic alkyl, benzyloxymethyl, or acetoxymethyl substituent, gold(I)‐catalyzed 5‐exo‐hydroamination leads to formation of the corresponding trans‐3,4‐disubstituted imidazolidin‐2‐ones in excellent yield with ≥50:1 diastereoselectivity.     

Solid‐Phase Synthesis of 3,4‐Dihydroquinoxalin‐2(1H)‐ones via the Cyclative Cleavage of N‐Arylated Carboxamides

We describe a practical (time‐efficient, with commercially available building blocks, user friendly reaction conditions, high purity of products) synthesis of pharmacologically relevant quinoxalinones with three points of diversification that takes advantage of solid‐phase synthesis and cyclative cleavage. Resin‐bound (S)‐2‐(N‐alkyl‐2‐nitrophenyl)sulfonamide‐3‐alkyl‐N‐(2‐hydroxyethyl)propanamides, which are accessible from Fmoc‐protected α‐amino acids, 2‐nitrobenzenesulfonyl chloride and alcohols, underwent base‐mediated N‐arylation. The reduction of the nitro group produced acyclic intermediates that were subjected to acid‐mediated cyclative cleavage to yield 3,4‐dihydroquinoxalin‐2(1H)‐ones.

     

1‐Arylsulfonyl‐5‐(N‐hydroxyacrylamide)indolines Histone Deacetylase Inhibitors Are Potent Cytokine Release Suppressors

A series of 1‐arylsulfonyl‐5‐(N‐hydroxyacrylamide)indolines ( 7 – 15 ) has been developed; the compounds exhibited potent histone deacetylase (HDAC) inhibitory activities. Notably, almost all of this series exhibited better HDAC‐inhibitory and antiproliferative activities than 3‐(1‐benzenesulfonyl‐1H‐indol‐5‐yl)‐N‐hydroxyacrylamide ( 6 ), as reported in a previous study. Among these compounds, 3‐[1‐(4‐methoxybenzenesulfonyl)‐2,3‐dihydro‐1H‐indol‐5‐yl]‐N‐hydroxyacrylamide ( 9 ) showed a two‐ to tenfold increase in activity compared to SAHA ( 1 ) in the suppression of lipopolysaccharide‐induced cytokine production. Compound 9 also caused a marked reduction in carrageenan‐induced acute inflammation in a rat model. Taken together, these data indicated that 1‐arylsulfonyl‐5‐(N‐hydroxyacrylamide)indolines HDAC inhibitors exhibit potent anti‐inflammatory activity.     

A Simple Copper‐Catalyzed Cascade Synthesis of 2‐Amino‐1H‐indole‐3‐carboxylate Derivatives

We have developed a simple and efficient copper‐catalyzed method for the synthesis of 2‐amino‐1H‐indole‐3‐carboxylate derivatives via cascade reactions of substituted N‐(2‐halophenyl)‐2,2,2‐trifluoroacetamide with alkyl 2‐cyanoacetate or malononitrile under mild conditions, and the method is of wide practical application.     

Synthesis and properties of novel polyimides from 3‐(4‐aminophenylthio)‐N‐aminophthalimide

A novel, asymmetric diamine, 3‐(4‐aminophenylthio)‐N‐aminophthalimide, was prepared from 3‐chloro‐N‐aminophthalimide and 4‐aminobenzenethiol. The structure of the diamine was determined via IR and ¹H‐NMR spectroscopy and elemental analysis. A series of polyimides were synthesized from 3‐(4‐aminophenylthio)‐N‐aminophthalimide and aromatic dianhydrides by a conventional two‐step method in N,N‐dimethylacetamide and by a one‐step method in phenols. These polyimides showed good solubility in 1‐methyl‐2‐pyrrolidinone, m‐cresol, and p‐chlorophenol, except polyimide from pyromellitic dianhydride, which was only soluble in p‐chlorophenol. The 5% weight loss temperatures of these polyimides ranged from 460 to 498°C in air. Dynamic mechanical thermal analysis indicated that the glass‐transition temperatures of the polyimides were in the range 278–395°C. The tensile strengths at break, moduli, and elongations of these polyimides were 146–178 MPa, 1.95–2.58 GPa, and 9.1–13.3%, respectively. Compared with corresponding polyimides from 4,4′‐diamiodiphenyl ether, these polymers showed enhanced solubility and higher glass‐transition temperatures. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Determination of Alkyl‐Donor Promiscuity of Tyrosine‐O‐Prenyltransferase SirD from Leptosphaeria maculans

Natural product prenyltransferases are known to display relaxed acceptor substrate specificity. Although recent studies with a small set of unnatural alkyl donors have revealed that prenyltransferases are flexible with regard to their alkyl donors, the scope of their alkyl donor specificity remains poorly understood. Towards this goal, we report the synthesis of 20 unnatural alkyl pyrophosphate donors and an assessment of the reactions of these synthetic unnatural alkyl pyrophosphate analogues catalyzed by tyrosine O‐prenyltransferase SirD. This study demonstrates that SirD can utilize 16 out of 21 alkyl pyrophosphate analogues (including the natural donor) in catalyzing mostly O‐alkylation of l ‐tyrosine. This study reveals the broad alkyl donor specificity of SirD and opens the door for the interrogation of the alkyl donor specificity of other prenyltransferases for potential utility as biocatalysts for differential alkylation applications.     

Ligand‐Free Copper‐Catalyzed Amination of Heteroaryl Halides with Alkyl‐ and Arylamines

N‐Heteroarylations of alkyl‐ and arylamines with various heteroaryl halides have been achieved by ligand‐free copper‐catalyzed cross‐couplings affording aminopyridines and aminopyrimidines in moderate to high yields (up to 99% yield).     

Synthesis and characterization of α‐butyl‐omega‐{3‐[2‐hydroxy‐3‐(N‐methyl‐N‐hydroxy‐ ethylamino)propoxy]propyl}polydimethylsiloxane

A novel synthesis path for the monotelechelic polydimethylsiloxane with a diol‐end group, α‐butyl‐omega‐{3‐[2‐hydroxy‐3‐(N‐methyl‐N‐hydroxyethylamino)propoxy]propyl}polydimethylsiloxane, is described in this article. The preparation included three steps, which were anionic ring‐opening polymerization, hydrosilylation, and epoxy addition. The structure and polydispersity index of the products were analyzed and confirmed by FTIR, ¹H NMR, ¹³C NMR, H? H, and C? H. Correlated Spectroscopy and gel permeation chromatography. The results demonstrated that each step was successfully carried out and the targeted products were accessed in all cases. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Forgotten monomers: access to α‐modified N‐vinylpyrrolidone polymers via C‐alkylation

Alkylation of N‐vinylpyrrolidone using lithium diisopropylamide and bis(2‐bromoethyl) ether was carried out to obtain 3‐(2‐(2‐bromoethoxy)ethyl)‐1‐vinyl‐2‐pyrrolidone ( 2 ). The derivative 2 represents a versatile starting molecule for further modification via nucleophilic displacement yielding, for example, the bicyclic 2‐vinyl‐8‐oxa‐2‐azaspiro[4.5]decan‐1‐one ( 4 ) or the ammonium salt 3‐diethoxy‐N,N′‐((dimethylbenzyl)ammonium bromide)‐1‐vinyl‐2‐pyrrolidone ( 10 ). Via free radical polymerization of 4 and 10 , the corresponding homopolymers were obtained. Copolymerization of 4 and 10 with N,N′‐diethylacrylamide yielded water‐soluble materials. The thermosensitive solubility of copolymers poly[(2‐vinyl‐8‐oxa‐2‐azaspiro[4.5]decan‐1‐one)‐co‐(N,N′‐diethylacrylamide)] and poly[(3‐diethoxy‐N,N′‐((dimethylbenzyl)ammonium bromide)‐1‐vinyl‐2‐pyrrolidone)‐co‐(N‐vinylpyrrolidone)] in water was investigated. © 2015 Society of Chemical Industry     

Synthesis of a glycosaminoglycan polymer mimetic using an N‐alkyl‐N,N‐linked urea oligomer containing glucose pendant groups

The synthesis of a glycosaminoglycan polymer mimetic is reported. An isopropylidene protected glucose methacrylate monomer was copolymerized under reversible addition fragmentation chain transfer polymerization control with an azido‐containing comonomer to a molecular weight of 29 000 g mol^?1 with polydispersity of 1.21. The comonomer ratio was determined to be 15:1 based on ¹H NMR spectroscopy. This copolymer was coupled to sugar‐functionalized N‐alkyl‐N,N‐linked urea oligomers using a copper catalyzed alkyne/azide cycloaddition reaction. The reaction efficiency was 100% as monitored by ¹H NMR spectroscopy. The isopropylidene protecting groups on the polymer and N‐alkyl‐N,N‐linked urea oligomers were removed using acid hydrolysis to give the final polysaccharide mimetic. It is expected that these polymers will have applications in a variety of future therapeutic applications. © 2013 Society of Chemical Industry