Amino Substitution Research Articles

Phosphorylated amino derivatives of thiacalix[4]arene as membrane carriers: synthesis and host–guest molecular recognition of amino, hydroxy and dicarboxylic acids

Promising membrane transport and separation systems for selected dicarboxylic, α‐hydroxy‐ and α‐amino acids based on thiacalixarene platform have been developed. For the first time, p‐tert‐butyl thiacalix[4]arenes functionalized at the lower rim with aminophosphonate fragments have been obtained and characterized. As was established by UV–vis spectroscopy, membrane extraction and HPLC, the substitution of amino groups by α‐aminophosphonate units significantly enhances the selectivity of host molecules that bind to aspartic and glycolic acids. The aminophosphonate compounds synthesized can be used in the development of sensors and systems employed in the purification and separation of organic acids. Copyright © 2013 John Wiley & Sons, Ltd.

Discovery of a potent respiratory syncytial virus RNA polymerase inhibitor

Targeting viral polymerases has been a proven and attractive strategy for antiviral drug discovery. Herein we describe our effort in improving the antiviral activity and physical properties of a series of benzothienoazepine compounds as respiratory syncytial virus (RSV) RNA polymerase inhibitors. The antiviral activity and spectrum of this class was significantly improved by exploring the amino substitution of the pyridine ring, resulting in the discovery of the most potent RSV A polymerase inhibitors reported to date.

ChemInform Abstract: Pathways Leading to 3‐Amino‐ and 3‐Nitro‐2,3‐dideoxy Sugars: Strategies and Synthesis

AbstractReview: 249 refs.

An ST405 NDM-4-producing Escherichia coli isolated from a Danish patient previously hospitalized in Vietnam

This variant, designatedNDM-4, differs from NDM-1 by a single amino substitution and anincreased carbapenemase activity. NDM-4 was first detected inan Escherichia coli isolated from a urinary sample from a patientpreviously hospitalized in India. A second finding of the NDM-4variantwasreportedinanE.colirectalisolatefromapatienttrans-ferredfromCameroontoFrance.

NMR Characterization of Carbon Dioxide Chemical Absorption with Monoethanolamine, Diethanolamine, and Triethanolamine

The present work analyzes and compares the carbon dioxide absorption process in aqueous solutions of different amines (MEA, monoethanolamine; DEA, diethanolamine; TEA, triethanolamine). This study evaluates the influence of the reagents nature upon absorption using a semicontinuous regime in a bubble contactor. 13C and 1H nuclear magnetic resonance (NMR) spectroscopy has been used to analyze species (reagents and/or products) in the reaction medium. In this way, the influence of the amino group substitution degree and carbon dioxide loading upon the chemical absorption mechanism were analyzed.

Preparation and pH-Switching of Fluorescent Borylated Arylisoquinolines for Multilevel Molecular Logic

The preparation of pH-switchable fluorescent borylated arylisoquinoline dyes via a flexible iridium-catalyzed route is reported. The obtained dyes feature aromatic amino substitution and lateral aliphatic amino groups as electron donors. The photophysical properties of the internal charge transfer dyes were studied, which was complemented by density functional theory calculations. Appreciable fluorescence quantum yields (Φf up to ca. 0.4) and characteristic spectral fingerprints in the green to red emission range were observed. The fluorescence modulation upon multiple and orthogonal protonation with triflic acid was studied and led to the interpretation of multilevel switching including off-on-off, ternary, and quaternary responses.

Specifics of photoinduced excited-state intramolecular proton transfer in o-tosylaminobenzoic and o-acetylaminobenzoic acids

In the ground state, o-tosylaminobenzoic and o-acetylaminobenzoic acids exist in the form of two rotamers with intramolecular hydrogen bonds N-H...O=C (cis) and N-H...O(OH)-C (trans). In nonpolar solvents, the formation of dimers with hydrogen bonding between carboxyl groups takes place. Efficient barrierless excited state intramolecular proton transfer (ESIPT) occurs along the N-H...O=C hydrogen bond upon excitation of o-tosylaminobenzoic acid. The efficiency of ESIPT in o-acetylaminobenzoic acid is lower because of the low acidity of the substituted amino group.

Hydrogen-bonded dimers in 3-amino-4-anilino-1H-isochromen-1-one and a hydrogen-bonded sheet in 3-amino-4-[methyl(phenyl)amino]-1H-isochromen-1-one

The molecules of 3-amino-4-anilino-1H-isochromen-1-one, C15H12N2O2, (I), and 3-amino-4-[methyl(phenyl)amino]-1H-isochromen-1-one, C16H14N2O2, (II), adopt very similar conformations, with the substituted amino group PhNR, where R = H in (I) and R = Me in (II), almost orthogonal to the adjacent heterocyclic ring. The molecules of (I) are linked into cyclic centrosymmetric dimers by pairs of N-H···O hydrogen bonds, while those of (II) are linked into complex sheets by a combination of one three-centre N-H···(O)2 hydrogen bond, one two-centre C-H···O hydrogen bond and two C-H···π(arene) hydrogen bonds.

A comparative study of the structure and vibrational spectra of diphenylmethane, the carcinogen 4,4′-methylenedianiline and 4,4′-methylenebis(N,N-dimethylaniline)

The structural stability of 4,4′-methylenedianiline (MDA), 4,4′-methylenebis(N,N-dimethylaniline) (MBDMA) and their parent diphenylmethane (DPM) was investigated by the DFT-B3LYP and ab initio MP2 calculations with the 6-311G** basis set. From the calculations the three diphenylmethanes were predicted to exist predominantly in a non-planar structure with a near C2 molecular symmetry in agreement with X-ray studies. The CCCC angles in DPM and the two dianilines were calculated to be nearly equal of about 60° as compared to X-ray angles of 17° and 67° for MDA. The NH2 inversion barriers in MDA was estimated to be about 1–5kcal/mol. On comparison of the Raman spectra of the three compounds, the line intensity and position of the characteristic ring breathing mode were shown to be sensitive to the amino substitution. The vibrational wavenumbers of the optimized structures of the two dianilines were computed at the DFT-B3LYP level of theory. Tentative vibrational assignments were made on the basis of combined DFT and experimental FT-IR and FT-Raman data of MDA and MBDMA.

Quantum chemical investigation on the influence of amino substitution on proton affinity of oxazolidin-2-one

The scenarios of preferred protonation sites and the absolute gas-phase proton affinities of C5- and N4-amino derivatives of oxazolidinone (OXA) molecules possessing two oxygen and two nitrogen atoms, are studied to investigate the effect of substitution of amino group on geometry, electronic structure, and proton affinities of these molecules. The natural bond orbital analysis is invoked to obtain the second-order delocalization energies, occupations of lone pairs, charge distribution, and bond orders to rationalize the obtained results. Our findings reveal a strong nucleophilicity of O1 site in C5-amino and N4-amino-substituted OXA isomers just as in un-substituted OXA. The substituent nitrogen in N4-amino-substituted OXA has comparable electrophilicity to O1 site while lesser than acyl oxygen and higher than nitrogen of OXA ring in C5-amino-substituted OXA. The PA values of C5- and N4-amino-substituted OXA isomers span in the range 172.06–205.77 kcal mol−1 (at CBS-Q). The PA values for the potential sites increase in the range 1.96–27.08 kcal mol−1 as a result of the amino substitution at C5 and N4 in orientation (b) while exceptionally they decrease by 0.57–2.95 kcal mol−1 as a result of the amino substitution at N4 in orientation (a). The results for the order of PA values of potential sites have been supported by molecular electrostatic potential maps. Our findings indicate that the factors such as geometrical rearrangements, variations in atomic charge densities and electron delocalization, effect of substituent, intramolecular hydrogen bonding, and electronic changes direct the relative stabilities and proton affinities of N, C5-substituted amino OXA isomers.

Pathways leading to 3-amino- and 3-nitro-2,3-dideoxy sugars: strategies and synthesis

3-Amino- and 3-nitro-2,3-dideoxy sugars, which are structurally diverse and uncommon sugars bearing an amino substitution on a sugar scaffold, have been shown to play crucial roles in the biological activities of aminoglycoside antibiotics and aminoglycoside containing natural products. Over the past few decades, there have been continuing efforts on the convenient synthesis of monosaccharides and oligosaccharides containing 3-amino- and 3-nitro-2,3-dideoxysugar motifs, beginning from either carbohydrate or non-carbohydrate precursors. This review article is intended to provide an updated overview of the most striking contributions in this field, based on the various strategies to construct the 3-amino sugar ring.

Vibronic and cation spectroscopy of structural isomers p- and m-diaminobenzene and the amino substitution effect

► We report the R2PI and MATI spectra of p -diaminobenzene and m -diaminobenzene. ► The first electronic transition and ionization energies are precisely measured. ► The data help us to learn the amino substitution effects on molecular properties. We applied the resonant two-photon ionization and mass-analyzed threshold ionization techniques to record the vibronic and cation spectra of p -diaminobenzene (PDAB) and m -diaminobenzene (MDAB). The band origins of the S 1 ← S 0 electronic transition of PDAB and MDAB were found to be 29 805 ± 2 and 33 395 ± 2 cm −1 , whereas the adiabatic ionization energies were determined to be 54 624 ± 5 and 58 321 ± 5 cm −1 , respectively. Most of the observed active vibrations of these two structural isomers in the electronically excited S 1 and cationic ground D 0 states result from in-plane ring deformation and bending vibrations. Comparing the present data with those of aniline suggests that the interaction of the amino substituent and aromatic ring in the upper (S 1 or D 0 ) state is stronger than that in the S 0 state. In addition, the frequency of observed active vibrations may depend on the nature, relative location, vibrational pattern, and the extent of the amino group participated in the normal vibration.

Aminonitrocyclopropanes as Possible High-Energy Materials. Quantum Chemical Calculations

The structures, vibrational spectra, and thermodynamic properties of three cyclopropane derivatives with amino and nitro substitutions were evaluated using standard density functional calculations. Calculations of thermodynamic properties show that the energy content per unit mass of these compounds is higher than current high energy materials. The actual density of these substances may be higher than that calculated because of expected intermolecular interactions between adjacent NH2 and NO2 groups.

On the Accessibility to Conical Intersections in Purines: Hypoxanthine and its Singly Protonated and Deprotonated Forms

The dynamics following electronic excitation of hypoxanthine and its nucleoside inosine were studied by femtosecond fluorescence up-conversion. Our objective was to explore variants of the purinic DNA bases in order to determine the molecular parameters that increase or reduce the accessibility to ground state conical intersections. From experiments in water and methanol solution we conclude that both dominant neutral tautomers of hypoxanthine exhibit ultrashort excited state lifetimes (τ < 0.2 ps), which are significantly shorter than in the related nucleobase guanine. This points to a more accessible conical intersection for the fluorescent state upon removal of the amino group, present in guanine but absent in hypoxanthine. The excited state dynamics of singly protonated hypoxanthine were also studied, showing biexponential decays with a 1.1 ps component (5%) besides a sub-0.2 ps ultrafast component. On the other hand, the S(1) lifetimes of the singly deprotonated forms of hypoxanthine and inosine show drastic differences, where the latter remains ultrafast but the singly deprotonated hypoxanthine shows a much longer lifetime of 19 ps. This significant variation is related to the different deprotonation sites in hypoxanthine versus inosine, which gives rise to significantly different resonance structures. In our study we also include multireference perturbation theory (MRMP2) excited state calculations in order to determine the nature of the initial electronic excitation in our experiments and clarify the ordering of the states in the singlet manifold at the ground state geometry. In addition, we performed multireference configuration interaction calculations (MR-CIS) that identify the presence of low-lying conical intersections for both prominent neutral tautomers of hypoxanthine. In both cases, the surface crossings occur at geometries reached by out of plane opposite motions of C2 and N3. The study of this simpler purine gives several insights into how small structural modifications, including amino substitution and protonation site and state, determine the accessibility to conical intersections in this kind of heterocycles.

Glycopolymer modification on physicochemical and biological properties of poly(l-lysine) for gene delivery

Poly(l-lysine) (PLL) has excellent plasmid DNA (pDNA) condensation capacity. However, the relatively high cytotoxicity and low transfection efficiency limit its application as gene delivery vectors. Here, well-defined glycopolymers are synthesized by reversible addition fragmentation transfer polymerization and grafted onto PLL to improve the gene delivery performance. After glycopolymer modification, PLL shows reduced cytotoxicity. By regulating the glycopolymer length and amino group substitution degree, the glycopolymer modified PLL can condense pDNA with proper strength, protect the condensed pDNA from degradation and release them in time. Transfection with NIH3T3 and HepG2 cells shows that the glycopolymer modified PLL has improved transfection efficiencies. The low cytotoxicity, effective pDNA protection and enhanced transfection efficiencies indicate that glycopolymer modification would be an effective strategy to improve the polycation properties for gene delivery.

Mechanisms of Drug Resistance Against JAK2 Inhibitors

Abstract 1426 The discovery of activating somatic mutations of JAK2 kinase as a contributing factor in the pathogenesis of myeloproliferative neoplasms (MPNs) —polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (MF)—prompted the development of JAK2-targeted therapies for these diseases1–3. Therapy with JAK2 inhibitors (INCB018424 and TG101348) induces rapid and marked reductions in spleen size and can lead to remarkable improvements in constitutional symptoms and overall quality of life suggesting that therapeutic targeting of JAK2 holds great promise for the treatment of JAK2 mediated disorders. It is likely that these two clinical agents will soon be approved by the FDA for the treatment of these diseases. Given our experience in development of resistance in tyrosine kinase inhibitor therapy (TKI) especially in the context of BCR/ABL targeting by Gleevec, we anticipate that resistance to JAK2 inhibitors will develop as well. To understand the mechanism of resistance against JAK2 targeted therapies, we performed mutagenesis studies and in vitro screening for resistance as previously reported for selection of resistance mutation in BCR/ABL (Azam et. al. (2003), Cell and Azam et. al. (2006), PNAS.). We sequenced the resistant clones isolated from INCB018424 resistant screening and identified 125 different amino substitutions spanning across FERM, SH2, pseudokinase and kinase domains. Frequency of resistant mutations demonstrated several major hot-spots clustered in the FERM, pseudokinase and kinase domain. We observed sixty different mutations in the kinase domain that clustered into eight major hot-spots with several minor-spots in regulatory regions including the hinge region, catalytic-loop, activation-loop and in the helical region of c-lobe. Structural modeling of these mutations suggests that the JAK2 kinase, like ABL kinase, is subject to auto-inhibited regulatory mechanisms and selects for drug resistant mutations from allosteric domains (FERM, SH2 and Pseudokinase domain). We anticipate that these results will be valuable in diagnosis of clinical resistance and in the identification and design of next generation small molecule JAK2 inhibitors Disclosures: No relevant conflicts of interest to declare.

Haplotypic variation and characteristics across the toll‐like receptor 3 locus in chickens

Toll-like receptor 3 (TLR3) has an important protective function against viral infection. The ability of an individual to respond properly to TLR ligands may be impaired by variants located in the TLR genes. By directly PCR sequencing four exons and their flanking sequence of chicken TLR3, a total of 50 nucleotide variants were identified from five breeds. Tibetan chickens and Silkies exhibited more abundant variation sites and rare alleles. Thirty haplotypes were reconstructed, with 31 variants whose minor allelic frequency was above 5% in five breeds, which revealed four divergent clades. Chicken TLR3 was partitioned into three haplotype blocks by the htSNPer program, and six tag SNPs could be used to distinguish these 30 haplotypes. Thirty variants were located in the coding sequence of chicken TLR3, and 16 of them were non-synonymous substitutions. It is predicted that p.Ser180Gly amino substitution could form an N-myristoylation site; the p.Lys240Thr amino substitution in chicken TLR3 could result in the loss of one protein kinase C phosphorylation site. These data provide a basic understanding of chicken TLR3 sequence variation and provide haplotypic markers for disease association studies.

Dicyanostilbene-derived two-photon fluorescence dyes with large two-photon absorption cross sections

Four dicyanostilbene-derived two-photon fluorescence (TPF) dyes were synthesized as the model compounds to systematically study the effect of the dicyano and the terminal substituent on the two-photon absorption (TPA). These four compounds ( DSO , DCY , DTO and DPH ) exhibit very large two-photon absorption cross sections ( δ ). DCY (A– π –A) with the terminal cyano group has especially high fluorescence quantum yield (0.71) and relatively large δ (1480 GM), while DPH (D– π –A) with the substitutedamino group at its terminus possesses the largest δ (2800 GM) and the longest emission wavelength (620 nm). The idealest terminal substituent should not be the alkoxy group but the substitutedamino group. This class of dicyanostilbene dyes possess small molecule size, large δ (830–2800 GM), long-wavelength emission (459−620 nm) and large Stokes shift (80−206 nm), and are ideal chromophores for TPF labels and probes.

Staining diatoms with rhodamine dyes: control of emission colour in photonic biocomposites

The incorporation of rhodamine dyes in the cell wall of diatoms Coscinodiscus granii and Coscinodiscus wailesii for the production of luminescent hybrid nanostructures is investigated. By systematic variation of the substitution pattern of the rhodamine core, we found that carbonic acids are considerably better suited than esters because of their physiological compatibility. The amino substitution pattern that controls the optical properties of the chromophore has no critical influence on dye uptake and incorporation, thus a variety of biocomposites with different emission maxima can be prepared. Applications in biomineralization studies as well as in materials science are envisioned.

Genetic Variants of Human Granzyme B Predict Transplant Outcomes after HLA Matched Unrelated Bone Marrow Transplantation for Myeloid Malignancies

Serine protease granzyme B plays important roles in infections, autoimmunity, transplant rejection, and antitumor immunity. A triple-mutated granzyme B variant that encodes three amino substitutions (Q48R, P88A, and Y245H) has been reported to have altered biological functions. In the polymorphism rs8192917 (2364A>G), the A and G alleles represent wild type QPY and RAH mutant variants, respectively. In this study, we analyzed the impact of granzyme B polymorphisms on transplant outcomes in recipients undergoing unrelated HLA-fully matched T-cell-replete bone marrow transplantation (BMT) through the Japan Donor Marrow Program. The granzyme B genotypes were retrospectively analyzed in a cohort of 613 pairs of recipients with hematological malignancies and their unrelated donors. In patients with myeloid malignancies consisting of acute myeloid leukemia and myelodysplastic syndrome, the donor G/G or A/G genotype was associated with improved overall survival (OS; adjusted hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.41–0.89; P = 0.01) as well as transplant related mortality (TRM; adjusted HR, 0.48; 95% CI, 0.27–0.86, P = 0.01). The recipient G/G or A/G genotype was associated with a better OS (adjusted HR, 0.68; 95% CI, 0.47–0.99; P = 0.05) and a trend toward a reduced TRM (adjusted HR, 0.61; 95% CI, 0.35–1.06; P = 0.08). Granzyme B polymorphism did not have any effect on the transplant outcomes in patients with lymphoid malignancies consisting of acute lymphoid leukemia and malignant lymphoma. These data suggest that there is an association between the granzyme B genotype and better clinical outcomes in patients with myeloid malignancies after unrelated BMT.