Aminophenyl Moiety Research Articles

Novel pyrrolidine-aminophenyl-1,4-naphthoquinones: structure-related mechanisms of leukemia cell death.

Novel derivatives of aminophenyl-1,4-naphthoquinones, in which a pyrrolidine group was added to the naphthoquinone ring, were synthesized and investigated for the mechanisms of leukemic cell killing. The novel compounds, TW-85 and TW-96, differ in the functional (methyl or hydroxyl) group at the para-position of the aminophenyl moiety. TW-85 and TW-96 were found to induce concentration- and time-dependent apoptotic and/or necrotic cell death in human U937 promonocytic leukemia cells but only TW-96 could also kill K562 chronic myeloid leukemia cells and CCRF-CEM lymphoblastic leukemia cells. Normal peripheral blood mononuclear cells were noticeably less responsive to both compounds than leukemia cells. At low micromolar concentrations used, TW-85 killed U937 cells mainly by inducing apoptosis. TW-96 was a weaker apoptotic agent in U937 cells but proved to be cytotoxic and a stronger inducer of necrosis in all three leukemic cell lines tested. Both compounds induced mitochondrial permeability transition pore opening, cytochrome c release, and caspase activation in U937 cells. Cytotoxicity induced by TW-96, but not by TW-85, was associated with the elevation of the cytosolic levels of reactive oxygen species (ROS). The latter was attenuated by diphenyleneiodonium, indicating that NADPH oxidase was likely to be the source of ROS generation. Activation of p38 MAPK by the two agents appeared to prevent necrosis but differentially affected apoptotic cell death in U937 cells. These results further expand our understanding of the structure-activity relationship of aminophenyl-1,4-naphthoquinones as potential anti-leukemic agents with distinct modes of action.

Active Quinolinequinones against Methicillin-Resistant Staphylococcus spp.

Serious bacterial infections could be caused by Gram-positive microorganisms, in particular methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis. Aiming to address this challenging issue by developing the potent and selective antimicrobial lead structures against methicillin-resistant Staphylococcus spp., herein, we report in vitro evaluation of quinolinequinones (QQ1-QQ10) against the Gram-negative and Gram-positive strains using the broth microdilution technique. The design principle of the quinolinequinones was based on the variation of the structures attached to the 1,4-quinone moiety and substituent(s) within amino phenyl moiety. A series of ten quinolinequinones displayed activity mainly against the Gram-positive strains with a minimal inhibitory concentration (MIC=1.22-1250 mg/L) within the Clinical and Laboratory Standards Institute (CLSI) levels. Interestingly, QQ3, QQ5, and QQ6 displayed equal antibacterial inhibitory activity against S. aureus (MIC=1.22 mg/L), respectively, to the standard positive control Cefuroxime-Na. QQ2, QQ3, and QQ5 had the best inhibitory activity with the MIC value of 1.22 mg/L (4-fold more potent compared reference standard Cefuroxime) against S. epidermidis. On the other hand, QQ3 was the most effective quinolinequinone against fungi, in particular C. albicans. The identified lead quinolinequinones (QQ3 and QQ5) with a comprehensive analysis of structure-activity relationships and further studies showed high activity against methicillin-resistant Staphylococcus spp. It is worth noting that the isopropyl group has importance for excellent bioactivity. Remarkably, the in vitro antibiofilm and bactericidal activities (each of 32 clinically obtained strains of Gram-positive bacteria) of the selected two quinolinequinones (QQ3 and QQ5) have been evaluated for the mode of action in addition to the time-kill curve study.

Computational study of IR, Raman, and NMR spectra of 4-methylmethcathinone drug.

Molecular electronic structure, IR, UV, and NMR spectra of the most popular cathinone, known as mephedrone or 4-methylmethcathinone (4-MMC), is studied thoroughly by quantum chemical calculation in terms of the density functional theory (DFT). Geometry optimization of 4-MMC and its hydrochloride complex is performed with the B3LYP functional, and all vibrational frequencies are analyzed in all details. On this background, the IR and Raman spectra are interpreted. The importance of low-frequency terahertz and Raman spectra is stressed for distinguishing of various MMC isomers. The UV spectrum is calculated by time-dependent DFT method which allows complete interpretation of intense absorption bands at 270 and 210nm as combinations of various ππ*, nπ*, and charge transfer excitations in amino-phenyl moieties. Very informative analysis of UV absorption and NMR spectra provides useful details on the structure-activity relationship for mephedrone molecule.

Separation and Solubility of Cis and Trans Isomers in Nanostructured Double-Decker Silsequioxanes

A fractional crystallization method was used to separate the cis and trans isomers of three double-decker silsesquioxanes (DDSQs) with an aminophenyl moiety in a THF + hexanes solvent mixture. The experimental solubilities were fitted to the Schroder–van Laar equation with activity coefficients determined using the NRTL model by adjusting the binary interaction parameters. The ability to separate these cis and trans isomers was affected by the regioisomer (m- or p-aminophenyl) and the R moiety (cyclohexyl or methyl) coupled via silicon. For a given DDSQ compound, the variances between the solubilities of the cis and trans isomers depend on differences in thermal properties (Schroder–van Laar). Cis isomers were 33 times more soluble than trans isomers for p-aminophenyl (R = methyl) and 22 times more soluble for the analogous m-aminophenyl in a solution of THF and hexanes. For a more sterically hindered m-aminophenyl (R = cyclohexyl), the cis isomers were only 3.5 times more soluble, and the overall solubil...

Tricarbonylrhenium complexes from 2-pyridyl-1,2,3-triazole ligands bearing a 4-substituted phenyl arm: a combined experimental and theoretical study

Three new pyridyltriazole ligands (named pyta) bearing a 4-substituted phenyl arm (nitro- (2a), chloro- (2b) or aminophenyl (2c) moiety) have been synthesized using a convenient click chemistry strategy. The corresponding tricarbonylrhenium complexes 3a, 3b and 3c were prepared and fully characterized by means of NMR, IR and mass spectrometry, as well as X-ray crystallography for two of them (3a and 3b). The direct connection of a 4-substituted phenyl arm at the N1 position of the triazolyl ring has a significant influence on the geometry of both, the ligands and their corresponding Re-complexes. The dominant structural feature of these complexes concerns the crystal cohesion. Slip-stacked π-π interactions between two molecules of the complex were observed for 3a and 3b probably resulting from the co-planarity of the organic framework. Furthermore, a combined experimental study and DFT calculations showed that the nature of the pendant arm (X = NO2, NH2 or Cl) could affect the electronic properties of the Re-complexes. If the chloro- or aminophenyl moieties unmodified the photo-physical properties of the complexes 3b and 3c, the presence of a nitrophenyl arm for the complex 3a quenched the luminescence, due to a high probability of non-radiative deactivation.

Aniline-1,4-benzoquinone as a model system for the characterization of products from aniline oligomerization in low acidic media

Increase in the pH medium of aniline polymerization is used for giving products of different morphologies, which are often wrongly attributed to PANI chains. Infrared and Raman spectroscopic data, supported by quantum chemical calculations, show that aniline-1,4-benzoquinone (AnBzq) is a model system for the characterization of the products of aniline oligomerization in low acidic media. The Raman spectra excited at different laser lines reveal the bichromophoric nature of AnBzq, whose absorption bands at 550nm and 440nm can be attributed to π–π∗ transitions of the delocalized benzoquinone and amino-phenyl moieties, respectively.

Electron Transfer from Organic Aminophenyl Acid Sensitizers to Titanium Dioxide Nanoparticle Films

Electron transfer from three conjugated amino-phenyl acid dyes to titanium and aluminum oxide nanocrystalline films was studied by using transient absorption spectroscopy with sub 20 fs time-resolution over the visible spectral region. All the dyes attached to TiO2 showed long-lived ground state bleach signals indicative of formation of new species. Global analysis of the transient kinetics of the dyes on TiO2 revealed stimulated emission decays of about 40 fs and less than 300 fs assigned to electron injection. The same dyes on Al2O3 substrates displayed long stimulated emission decays (ns) suggesting that electron transfer is blocked in this high band gap semiconductor. For two of the dyes (NK1 and NK2) with amino methyl terminal groups cation formation was seen at 670 nm probe wavelength, in the onset region of cation absorption predicted by time-dependent density functional theory calculations, with dynamics matching that of stimulated emission decay. Early excited-state dynamics observed in the NK7 dye bound to both TiO2 and Al2O3, with pulse limited rise and 30−40 fs decay times, was assigned to rearrangement of charge in the amino phenyl moiety and/or possibly isomerization, which competes with electron injection in NK7 sensitized TiO2 films. This additional relaxation channel could be the reason for the low efficiency reported for the NK7 sensitized solar cell.

Molecular Characterization of Clinical Isolates of Human Immunodeficiency Virus Resistant to the Protease Inhibitor Darunavir

Darunavir is the most recently approved human immunodeficiency virus (HIV) protease (PR) inhibitor (PI) and is active against many HIV type 1 PR variants resistant to earlier-generation PIs. Darunavir shows a high genetic barrier to resistance development, and virus strains with lower sensitivity to darunavir have a higher number of PI resistance-associated mutations than viruses resistant to other PIs. In this work, we have enzymologically and structurally characterized a number of highly mutated clinically derived PRs with high levels of phenotypic resistance to darunavir. With 18 to 21 amino acid residue changes, the PR variants studied in this work are the most highly mutated HIV PR species ever studied by means of enzyme kinetics and X-ray crystallography. The recombinant proteins showed major defects in substrate binding, while the substrate turnover was less affected. Remarkably, the overall catalytic efficiency of the recombinant PRs (5% that of the wild-type enzyme) is still sufficient to support polyprotein processing and particle maturation in the corresponding viruses. The X-ray structures of drug-resistant PRs complexed with darunavir suggest that the impaired inhibitor binding could be explained by change in the PR-inhibitor hydrogen bond pattern in the P2' binding pocket due to a substantial shift of the aminophenyl moiety of the inhibitor. Recombinant virus phenotypic characterization, enzyme kinetics, and X-ray structural analysis thus help to explain darunavir resistance development in HIV-positive patients.

Synthesis and characterization of novel conducting homopolymers based on amino β-styryl terthiophene

Novel ECPs (electronic conducting polymers) based on amino β-styryl-substituted terthiophene (AST) were synthetized by direct electropolymerization. The ECPs were characterized by cyclic voltammetry, square-wave voltammetry, Fourier transform infrared (FTIR) spectroscopy, and X-ray photoelectron spectroscopy (XPS). The poly(amino β-styryl terthiophene) displayed cyclic and square-wave voltammograms with redox peaks that can be assigned to the aminophenyl moiety and the polyterthiophene backbone. The presence of free primary amine groups on the ECP film permitted further biological functionalization (i.e., covalent bonding of various bioreceptors on its surface). The electrochemical performance of Biotin grafted at the AST modified glassy carbon electrode was investigated to detect the Avidin protein in solution by cyclic voltammetry and square-wave voltammetry.Key words: electronic conducting polymer, electrode surface modification, biosensor, β-styryl-substitued terthiophene, functionalization, cyclic, square-wave voltammetry.

C-7 analogues of progesterone as potent inhibitors of the P-glycoprotein efflux pump.

The P-glycoprotein product (Pgp) of the MDR1 gene has been implicated in the multiple drug resistance phenotype expressed by many cancers. Functioning as an efflux pump, P-glycoprotein prevents the accumulation of high intracellular concentrations of substrates. We have taken a rational approach to designing inhibitors of P-glycoprotein function, selecting a natural substrate (progesterone) as our lead compound. We hypothesized that progesterone, substituted at C-7 with an aromatic moiety(s), would exhibit reduced Pgp affinity, significantly increased antiPgp activity, and reduced affinity for progesterone receptors (PGR). We synthesized 7 alpha-[4'-(aminophenyl)thio]pregna-4-ene-3,20-dione (2), which comprises a C-7 alpha thiol bridge linking an aminophenyl moiety to progesterone, from pregna-4,6-diene-3,20-dione (1). The subsequent addition reaction of 2 with the appropriate isocyanate produced an initial series of compounds (3-6). Compounds 3-5 (respectively, -CH(2)CH(2)Cl; -CH(2)CH(3); and -CH(CH(3))C(6)H(5)) exhibit a significantly increased ability to inhibit P-glycoprotein. Potency for restoring doxorubicin accumulation in MDR1-transduced human breast cancer cells is increased up to 60-fold as compared with progesterone. Compound 5 has greater potency than verapamil and is equipotent with cyclosporin A, for inhibiting P-glycoprotein function. Furthermore, 5 does not bind to PGR, implying a potential reduction in in vivo toxicity. These data identify C-7-substituted progesterone analogues and 5, in particular, as rationally designed antiPgp compounds worthy of further evaluation/development.

A Comparative Study of Organic Cobalt Complex Catalysts for Oxygen Reduction in Polymer Electrolyte Fuel Cells

Reduction of platinum catalysts loading is a central issue in polymer electrolyte fuel cells. As alternatives for platinum, some organic metal chelate compounds are tested as cathode catalysts, such as cobalt aza-complexes or cobalt complexes possessing aminophenyl moieties featured as Co-N4 or Co-N2O2 chelate structures. The way of immobilization of catalysts on the graphite surface influences their stability as well as the performance of oxygen reduction. Heat-treated catalysts supported on graphite at 600°C show much better oxygen reduction abilities than as-received metal complexes. The original chemical structure of metal complexes affects crucially the catalytic ability, though initial structures of molecules are no more intact after the heat treatment. The catalytic activity of these complexes may originate from the central chelate unit CoN4 on the carbon substrate, and this unit is assumed to constitute the basic coordination site for an oxygen molecule. Electropolymerized catalysts impart a high level of oxygen reduction ability, probably due to the improved molecular orientation for oxygen coordination and formation of good chelate sites on the graphite surface.

Electrochemical modification of a carbon electrode using aromatic diazonium salts. 2. Electrochemistry of 4-nitrophenyl modified glassy carbon electrodes in aqueous media

The electrochemical behavior of a 4-nitrophenyl modified glassy carbon electrode has been investigated in the absence and presence of electroactive species such as ferricyanide, ruthenium hexaamine and hydroquinone following its electrochemical reduction in aqueous acidic media. The blocking properties of the grafted film are significantly altered following the reduction of the 4-nitrophenyl film. The reduction yields nitrosophenyl, hydroxyaminophenyl and aminophenyl moieties. A set of redox waves, attributed to the products of the reduction of the 4-nitrophenyl, is observed at about 0.42 V versus Ag|AgCl and is related to the nitrosophenyl/hydroxyaminophenyl interconversion. XPS measurements at the N1s core level have confirmed a loss of nitro groups upon electrochemical reduction of the grafted film. The decrease of the 406 eV peak associated with nitro groups is larger than the increase of the peak at about 400 eV that would correspond to the nitro group reduction products. This can be attributed to the cleavage of a fraction of the substituted phenyl group from the glassy carbon electrode surface. The XPS data also suggest that only a fraction of the grafted 4-nitrophenyl groups are electrochemically reduced under our experimental conditions. Nonetheless, the barrier properties of the resulting layer are maintained as shown by the suppression of the Ru(NH3)63+electrochemistry.

Cytotoxic and antitumor activity of MEN 10710, a novel alkylating derivative of distamycin

MEN 10710 is a new synthetic distamycin derivative possessing four pyrrole rings and a bis-(2-chloroethyl)aminophenyl moiety linked to the oligopyrrole backbone by a flexible butanamido chain. Its biological properties have been investigated in comparison with the structurally related compound, tallimustine (FCE24517), and the classical alkylating agent, melphalan (L-PAM). Cytotoxic potency of MEN 10710 was increased from 10- to 100-fold, as compared to tallimustine or L-PAM in murine L1210, human LoVo and MCF7 tumor cell lines. MEN 10710 was still active against L1210/L-PAM leukemic cells, while a partial cross-resistance was observed in LoVo/DX and in MCF7/DX cells selected for resistance to doxorubicin and expressing a MDR phenotype. Treatment with verapamil (VRP) reduced the resistance to tallimustine, but not to MEN 10710, in MCF7/DX cells. The cytotoxic effects reflect in vivo antitumor potency and toxicity in the treatment of human tumor xenografts. MEN 10710 was more effective in A2780/DDP, an ovarian carcinoma selected for resistance to cisplatin. On the other hand, the IC30 for inhibiting murine granulocyte/macrophage colony formation was 50 times higher for MEN 10710 than for tallimustine, suggesting a lower myelotoxic potential. In conclusion, the particular biological profile of MEN 10710 characterized by a marked cytotoxic potency, an interesting antitumor efficacy and a reduced in vitro myelosuppressive action may represent a further improvement in the rational design of a novel distamycin-related alkylating compound.

Preparation of SERS-active silver colloids by photosensitizing cyanine dyes

Silver colloids have been prepared by sensitized photochemical reduction of silver nitrate solutions. Substituted aminophenylethenyl-alkylpyridinium dyes, with strongly hydrophobic character, were used as sensitizers. Surface-enhanced resonance Raman (SERR) spectra of the adsorbed dye have been observed during colloid formation. With prolonged irradiation, the spectrum disappears as the dye is consumed in the photochemical reduction. For dye solutions without silver nitrate, only fluorescence is observed. The influence of the attachment of a crown ether ring onto the aminophenyl moiety of the dye and that of the counter ion (Br−,NO3−) on photochemical colloid formation are investigated. For comparison, dye solutions have been added to chemically prepared silver colloids, where EDTA or BH4− were used as reducing agents. Similar SERR spectra are obtained on the photochemically and chemically prepared colloids.