Amine Position Research Articles

Iridium α-Carboxyimine Complexes Hyperpolarized with para-Hydrogen Exist in Nuclear Singlet States before Conversion into Iridium Carbonates.

The formation and hyperpolarization of an [Ir(H)2 (amine)(IMes)(η2 -imine)]Cl complex that can be created in a hyperpolarized nuclear singlet state is reported. These complexes are formed when an equilibrium mixture of pyruvate, amine (benzylamine or phenylethylamine), and the corresponding imine condensation product, react with preformed [Ir(H)2 (amine)3 (IMes)]Cl. These iridium α-carboxyimine complexes exist as two regioisomers differentiated by the position of amine. When examined with para-hydrogen the hydride resonances of the isomer with amine trans to hydride become strongly hyperpolarized. The initial hydride singlet states readily transfer to the corresponding 13 C2 state in the labelled imine and exhibit magnetic state lifetimes of up to 11 seconds. Their 13 C signals have been detected with up to 420 fold signal gains at 9.4 T. On a longer timescale, and in the absence of H2 , further reaction leads to the formation of neutral carbonate containing [Ir(amine)(η2 -CO3 )(IMes)(η2 -imine)]. Complexes are characterized by, IR, MS, NMR and X-ray diffraction.

Photothermal conversion performance of perylene diimide radical anion salts modified with tunable moieties

Among photothermal materials, perylene diimide radical anions were promising organic candidates with intense and characteristic near-infrared (NIR) absorption bands and non-fluorescence. Herein, two isolable and ambient stable bay-substituted perylene diimide radical anion salts, namely DBrPDI radical anion salt and TPPDI radical anion salt, were facilely prepared and confirmed by using a very thorough analysis based on the data from UV–Vis/NIR, FL, FTIR, EPR and NMR spectra. Subsequently, two radical anion salts were applied as photothermal conversion agents. DBrPDI radical anion salt exhibited high-performance photothermal conversion in DMF solutions, however a decline in aqueous solution. TPPDI radical anion salt with bulky moieties onto the PDI cores and amine position gave substantial evidence that the photothermal properties could be optimized and enhanced in aqueous solution by modulating the chemical structure of the photothermal conversion agent.

Substructure Reactivity Affecting the Manganese Dioxide Oxidation of Cephalosporins.

Cefotaxime (CTX), cephalexin (CFX), cephradine (CFD), cephapirin (CFP), and cefazolin (CFZ) were selected as target cephalosporin antibiotics to study their oxidative transformation by δ-MnO2. Although they all have the same core structure (7-aminodesacetoxycephalosporanic acid), very different MnO2 oxidation rates were observed at pH 4 (the initial reaction rate constant kinit ranged from 0.014 to 2.6 h-1). An extensive investigation of the substructure compounds and byproduct analysis revealed that the oxidation mainly occurred at the following two sites on the core structure: (1) the sulfur atom in the cephem ring and (2) the carbon-carbon double bond (C═C) and its proximal carboxylic acid group. In the case of (2), when there is an acetyloxymethyl group at the C-3 position of the core structure, the formation of the keto-sulfone byproducts was inhibited. The overall results indicated that a substituent at the C-3 position could stabilize the core structure, which would result in a decrease in the oxidation rate; however, a substituent at the amine position of the core structure might affect the overall degradation rate of the cephalosporin, depending on its reactivity with MnO2. Thus, the apparent reaction rates varied widely in the trend of CTX > CFP > CFD > core structure ≈ CFX > CFZ. The mechanistic elucidation can also help explain the degradation rates of cephalosporin antibiotics in other oxidation processes.

Reactions of Amine–Boranes with Oxalic Acid: Substitution on the N or B Atom Leads to Different Spiroborate Compounds

A mild and convenient reaction of amine–boranes and oxalic acid to bi‐ or tricyclic spiroborate compounds is presented. The substitution position (on the N or B atom) of amine–boranes plays an important role on the divergence of reaction pathways: ammonia–borane (NH3·BH3, AB) or N‐substituted amine–boranes NHnMe3–n·BH3 (n = 0, 1, 2) give bicyclic spiroborate compounds 1a–d, whereas B‐substituted amine–borane NH3·BH2Me leads to tricyclic spiroborate compound 3. Fortunately, acyloxyboranes were detected as important intermediates by NMR spectroscopy in the reaction of ammonia–borane and oxalic acid, uncovering a stepwise dehydrogenation pathway.

Chloroperoxidase-catalyzed amino alcohol oxidation: Substrate specificity and novel strategy for the synthesis of N-Cbz-3-aminopropanal

The ability of chloroperoxidase (CPO) to catalyze amino alcohol oxidations was investigated. The oxidations of compounds with different configurations with respect to the amine position towards hydroxyl – using H2O2 and tert-butyl hydroperoxide (t-BuOOH) – were analyzed in terms of the initial reaction rate, substrate conversion, and CPO operational stability. It was observed that the further the amino group from the hydroxyl, the lower the initial reaction rate. The effect of the amino-protecting group and other substituents (i.e., methyl and hydroxyl) was also examined, revealing an increase in steric hindrance due to the effect of bulky substituents. The observed reaction rates were higher with t-BuOOH, whereas CPO was more stable with H2O2. Moreover, CPO stability had to be determined case by case as the enzyme activity was modulated by the substrate. The oxidation of N-Cbz-3-aminopropanol (Cbz, carboxybenzyl) to N-Cbz-3-aminopropanal was investigated. Main operational conditions such as the reaction medium, initial amino alcohol concentration, and peroxide nature were studied. The reaction kinetics was determined, and no substrate inhibition was observed. By-products from a chemical reaction between the formed amino aldehyde and the peroxide were identified, and a novel reaction mechanism was proposed. Finally, the biotransformation was achieved by reducing side reactions and identifying the key factors to be addressed to further optimize the product yield.

An antioxidant mechanism of morphine and related derivatives

A structural and computational study of the morphine mechanism as an antioxidant or oxidant compound is performed by density functional theory (DFT) calculations. The geometry was obtained using the B3LYP/6-31G(d,p) method. The antioxidant property of morphine is related to the highest occupied molecular orbital (HOMO) energy, ionization potential (IP), stabilization energy (ΔEiso), bond dissociation energy (BDE), and spin density distribution for the electron abstraction at the amine position, which is more favored than other positions for morphine. The decrease in the HOMO and IP values, together with the increase in the ΔEiso values, is related to amine groups, ether and alkyl moieties, benzene rings, hydroxyls, and double bonds. The hydrogen abstraction in the phenol position is more favored than the other positions in morphine. The prevalent spin contribution for these groups is important for the highest stability free radical and other resonance structures. Morphine is more powerful antioxidant than its de-methylated or hydroxylated derivatives.

Phospholipophilicity of CxHyN(+) amines: chromatographic descriptors and molecular simulations for understanding partitioning into membranes.

Using immobilized artificial membrane high-performance liquid chromatography (IAM-HPLC) the sorption affinity of 70 charged amine structures to phospholipids was determined. The amines contained only 1 charged moiety and no other polar groups, the rest of the molecule being aliphatic and/or aromatic hydrocarbon groups. We systematically evaluated the influence of the amine type (1°, 2°, 3° amines and quaternary ammonium), alkyl chain branching, phenyl ring positioning, charge positioning (terminal vs. central in the molecule) on the phospholipid-water partitioning coefficient (KPLIPW). These experimental results were compared with quantum-chemistry based three-dimensional (3D) molecular simulations of the partitioning of charged amines, including the most likely solute conformers, using a hydrated phospholipid bilayer in the COSMOmic module of COSMOtherm software. Both IAM-HPLC retention data and the simulations suggest that the molecular orientation of charged amines at the location in the bilayer with the lowest calculated Gibbs free energy exerts a strong influence over the partitioning within the membrane. The most favourable position of charged amines coincides with the region where the phosphate anions in the phospholipid bilayer are most abundant. Hydrocarbon units oriented in this layer are located more towards the aqueous phase and contribute less to the overall membrane affinity than hydrocarbon units extending into the more hydrophobic core of the bilayer. COSMOmic simulations explain most of the trends between the structural differences observed in IAM-HPLC based KPLIPW. For this set of cationic structures, the mean absolute difference between COSMOmic simulations and IAM-HPLC data, accounting only for amine type corrective increments, is 0.31 log units.

ω-Transaminases for the amination of functionalised cyclic ketones.

The potential of a number of enantiocomplementary ω-transaminases (ω-TAms) in the amination of cyclic ketones has been investigated. After a preliminary screening of several compounds with increasing complexity, different approaches to shift the equilibrium of the reaction to the amine products were studied, and reaction conditions (temperature and pH) optimised. Interestingly, 2-propylamine as an amine donor was tolerated by all five selected ω-TAms, and therefore used in further experiments. Due to the higher conversions observed and interest in chiral amines studies then focused on the amination of α-tetralone and 2-methylcyclohexanone. Both ketones were aminated to give the corresponding amine with at least one of the employed enzymes. Moreover, the amination of 2-methylcyclohexanone was investigated in more detail due to the different stereoselectivities observed with TAms used. The highest yields and stereoselectivities were obtained using the ω-TAm from Chromobacterium violaceum (CV-TAm), producing 2-methylcyclohexylamine with complete stereoselectivity at the (1S)-amine position and up to 24 : 1 selectivity for the cis : trans [(1S,2R) : (1S,2S)] isomer.

Synthesis and α‐Glucosidase and α‐Amylase Inhibitory Activity Evaluation of Azido‐ and Aminocyclitols

AbstractFor the synthesis of some azido‐ and aminocyclitols, (3aRS,7aSR)‐1,3,3a,7a‐tetrahydroisobenzofuran was used as the starting material. For further functionalization of the diene unit, the diene was subjected to epoxidation reactions to give mono‐ and bisepoxides depending on the amount of m‐chloroperbenzoic acid used. The ring‐opening of the epoxide functionality with NaN3 resulted in the formation of mono‐ and bisazido cyclitols. The tetrahydrofuran ring was opened in an acid‐catalysed reaction with sulfamic acid. The reduction of azide groups to give amines provided various amino‐ and bisaminocyclitol derivatives. The inhibitory effects of 20 compounds against α‐glucosidase and α‐amylase were tested. The results indicated that some of these compounds seem to have good inhibitory activity against α‐glucosidase, and low inhibitory activity against α‐amylase. Furthermore, it was demonstrated that the number and position of azides, amines, and hydroxy groups appeared to play an important role in determining the inhibitory potency of these compounds.

Insights from quantum chemistry into piperazine-based ionic liquids and their behavior with regard to CO2

The short-range properties of alkylpiperazine ionic liquids paired with propionate and lactate anions were analyzed and their affinity for CO₂ molecules studied using density functional theory. Anion-cation interactions led to the development of strong intermolecular hydrogen bonding through the cation amine position, as confirmed through variations in structural and vibrational properties upon pair formation. Topological analysis via the atoms-in-molecules approach revealed the development of intense bond and ring critical points in the intermolecular regions, which is in agreement with charge transfer from lone pairs in anion oxygen atoms of carboxylate groups through antibonding orbitals in cation amine groups. Such anion-cation interactions are weakly dependent on cation alkyl chain length but are remarkably affected by the presence of an anion hydroxyl group. Interactions with CO₂ molecules are stronger for anions than for cations, especially for propionate anions, and are also affected strongly by the anion hydroxyl group.

Rhenium‐Catalyzed Oxidative Cyanation of Tertiary Amines with TMSCN

AbstractOxidative cyanation of sp3 C–H bonds at the α position of tertiary amines by using TMSCN as the cyanide donor and a novel high‐valent rhenium(V) complex was developed. The reaction offers the corresponding α‐aminonitriles in good yields with tert‐butyl hydroperoxide as the oxidant under mild and acid‐free reaction conditions.

Improved Protocol for the Synthesis of Flexibly Protected Morpholino Monomers from Unprotected Ribonucleosides

An inexpensive and much improved protocol has been developed for the synthesis of protected morpholino monomers from unprotected ribonucleosides in high overall yield, using oxidative glycol cleavage and reductive amination strategy. Unlike the previous methods, the present strategy allows installing the exocyclic amine protections at a later stage, and thus avoids the use of expensive, or commercially unavailable, exocyclic amine-protected ribonucleosides as starting materials. To demonstrate the flexibility of the present method in choosing protecting groups, the monomers have been protected with several such groups of different deblocking properties at the exocyclic amine position.

PH-dependent spectral properties of para-aminobenzoic acid and its derivatives

The local environment dictates the structural and functional properties of many important chemical and biological systems. The impact of pH on the photophysical properties of a series of para-aminobenzoic acids is examined using a combination of experimental spectroscopy and quantum chemical calculations. Following photoexcitation, PABA derivatives may undergo an intramolecular charge transfer (ICT) resulting in the formation of a zwitterionic species. The thermodynamics of the excited state reaction and temperature-dependence of the radiative emission processes are evaluated through variable temperature fluorescence spectroscopy carried out in a range of aqueous buffers. Quantum chemical calculations are used to analyze structural changes with modifications at the amine position and different protonation states. The ICT is only observed in the tertiary amine, which calculations show has more sp 2 character than the primary or secondary amines. Thermodynamic analysis indicates the ICT reaction is driven by entropy.

Metal-Interrupted Perylene Diimide: Toward a New Class of Tunable n-Type Inorganic−Organic Hybrid Semiconductors

In organic thin-film transistors (OTFTs), organic electron-transport materials (n-type semiconductors) are well behind the advances in development of hole-transport materials (p-type semiconductors). Currently, one class of organic n-type semiconductor materials that is widely utilized is N,N'-dialkyl-3,4,9,10-perylenetetracarboxylic diimide (PTCDI-R) derivatives with high electron affinities (EAs), such as N,N'-dioctyl-3,4,9,10-perylenetetracarboxylic diimide with a reported EA as high as 4.4 eV. The PTCDI-R derivatives have been manipulated by adding substituents on the perylene moiety or at the amine position to afford more stable compounds and higher EAs. On the basis of these materials, we have developed metal-containing perylenediimide analogues, placing a salpen ligand for metal ion chelation between two n-isobutylnaphthalimides. We demonstrate here that the electronic properties of this class of materials can be systematically tuned in a divergent manner by simply changing the metal center. The synthesis, characterization, electrochemistry, and band-gap analysis are discussed herein.

One-pot derivatization of medicinally important 9-aminoacridines by reductive amination and SNAr reaction

A new highly efficient one-pot derivatization of medicinally important 9-aminoacridines (9-AA) at the amine position is described. Simple reductive amination and S N Ar reaction using easily accessible starting materials give a fast entry to novel 9-AA derivatives for biological screening.

Nitric oxide reduction of copper(II) complex with tetradentate amine ligand followed by ligand transformation

Abstract Copper(II) complex 1 with a tetradentate ligand L [ L = tris(2-aminoethyl)amine, tren] has been prepared as its perchlorate salt. Single crystal X-ray structure of 1 indicates its trigonal bipyramidal shape in the solid state. The complex, in dry and degassed acetonitrile solvent, was made to react with nitric oxide gas and the copper(II) center has been observed to reduce to Cu(I) with simultaneous nitrosation followed by diazotization at the terminal primary amine positions of the ligand to result into cyclization product, 1-(2-aminoethyl)piperzine, L ′ along with tris(2-aminoethyl)ammonium perchlorate, L ′′-perchlorate. However, when an acetonitrile:water (10:1, v/v) mixture has been used as the solvent, the reduction of Cu(II) to Cu(I) is observed and the ligand is found to be precipitated out only as L ′′-perchlorate. The reduction of Cu(II) to Cu(I) has been studied by UV–visible, 1 H NMR and EPR spectroscopic techniques and by X-ray single crystal structure determination. Both the L ′ and L ′′-perchlorate have been isolated from the reaction mixture and characterized by using microanalytical studies, various spectroscopic techniques and X-ray single crystal structure determination.

Dual potency anti-HER2/neu and anti-EGFR anthracycline immunoconjugates in chemotherapeutic-resistant mammary carcinoma combined with cyclosporin A and verapamil P-glycoprotein inhibition

Immunoconjugates of epirubicin were synthesized with monoclonal antibodies against the epidermal growth factor receptors, HER2/neu and EGFR, by creating a sulfhydryl-reactive epirubicin intermediate applying heterobifunctional succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), which was introduced at α-monoamide groups of the epirubicin carbohydrate moiety. In parallel, N-succinimidyl-S-acetylthioacetate (SATA) was used to incorporate a sulfhydryl group into immunoglobulin at the terminal amine position of ϵ-lysine amino acid residues. Eprirubicin–SMCC–SATA–IgG immunoconjugates were produced by reacting epirubicin–SMCC and SATA–IgG at appropriate molar ratios. Epirubicin–(anti-HER2/neu) and epirubicin–(anti-EGFR) had greater potency against chemotherapeutic-resistant SKBr-3 mammary carcinoma than did epirubicin at epirubicin-equivalent concentrations. Epirubicin–(anti-HER2/neu) was more potent than epirubicin–(anti-EGFR), and a synergistic level of antineoplastic activity was detected with an epirubicin immunoconjugate 50/50 combination. Competitive P-glycoprotein inhibition with cyclosporin A or verapamil enhanced the potency of the epirubicin immunoconjugate 50/50 combination. Minor levels of antineoplastic activity were detected only with an immunoglobulin 50/50 combination of anti-HER2/neu and anti-EGFR. The investigations represent a potential strategy for enhancing the selective internalization, intracellular deposition, and antineoplastic potency of chemotherapeutics in multidrug-resistant neoplasias.

Further Insight into the Mechanism of Stereoselective Proton Abstraction by Bacterial Copper Amine Oxidase

During the catalytic reaction of copper amine oxidase, one of the two prochiral hydrogen atoms at the C1 position of substrate amine is stereoselectively abstracted by a conserved Asp residue serving as a general base. Using stereospecifically deuterium-labeled enantiomers of 2-phenylethylamine, we previously showed that the pro-S alpha-proton is abstracted by the enzyme from Arthrobacter globiformis (AGAO) [Uchida, M., et al. (2003) Biosci. Biotechnol. Biochem. 67, 2664-2667]. More recently, we have also demonstrated that the pro-S selectivity of alpha-proton abstraction is fully retained even in the reaction of a mutant AGAO lacking the catalytic base [Chiu, Y.-C., et al. (2006) Biochemistry 45, 4105-4120]. On the basis of these findings, we have proposed that the stereoselectivity of alpha-proton abstraction is primarily determined by the conformation of the Schiff base intermediate formed between the substrate and the topa quinone cofactor (TPQ), stabilized by the binding of the distal part of the substrate to a hydrophobic pocket of the enzyme. In this conformation, the pro-S hydrogen atom to be abstracted is nearly perpendicular to the plane of the Schiff base-TPQ conjugate system, achieving the maximum overlap of sigma- and pi-orbitals. To further elucidate the stereochemical details, we have synthesized stereospecifically deuterium-labeled enantiomers of ethylamine, a very poor substrate for AGAO, in addition to those structurally related to the preferred substrate, 2-phenylethylamine. In marked contrast to the nearly complete pro-S selectivity of alpha-proton abstraction for most substrates that have been examined, the stereoselectivity for ethylamine decreased significantly to as little as 88%. The crystal structure of AGAO soaked with ethylamine showed very poor electron densities for the substrate Schiff base intermediate, showing that its conformation is not defined uniquely. Thus, the stereoselectivity of alpha-proton abstraction during the copper amine oxidase reaction is closely associated with the conformational flexibility of the substrate Schiff base intermediate.

Potent Nonpeptide Antagonists of the Bradykinin B1 Receptor: Structure−Activity Relationship Studies with Novel Diaminochroman Carboxamides

The bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this receptor have been studied as promising candidates for treatment of chronic pain. We have identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists of the human B1 receptor. Our previously communicated lead, compound 2, served as a proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance from metabolic profiling, we performed structure-activity relationship studies and have identified potent analogs of 2. Variation of the sulfonamide moiety revealed a preference for 3- and 3,4-disubstituted aryl sulfonamides, while bulky secondary and tertiary amines were preferred at the benzylic amine position for potency at the B1 receptor. Modifying the beta-amino acid core of the molecule lead to the discovery of highly potent compounds with improved in vitro pharmacokinetic properties. The most potent analog at the human receptor, compound 38, was also active in a rabbit B1 receptor cellular assay. Furthermore, compound 38 displayed in vivo activity in two rabbit models, a pharmacodynamic model with a blood pressure readout and an efficacy model of inflammatory pain.

Amide-nitrophenyl based colorimetric receptors for selective sensing of fluoride ions

New chromogenic receptors containing 2-nitrophenyl or 3,5-dinitrophenyl groups appended to the amide or in secondary amine positions have been synthesized and characterized. Upon addition of fluoride to two of the receptors in acetonitrile, the solution acquired a yellow colour. The third receptor showed an intense purple colour with fluoride in acetonitrile and the appearance of the purple colour can be detected by the naked eye at parts per million level. The addition of chloride, bromide and iodide to the receptors did not induce any colour. Thus the receptors can act as fluoride ion sensors even in the presence of other halide ions.