Effects of Bis(imino)acenaphthene (Bian)-Derived Ligands on the Cytotoxicity, DNA Interactions, and Redox Activity of Palladium(II) Bipyridine Complexes.

A series of heteroleptic bipyridine Pd(II) complexes based on 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene (dpp-Bian) or 1,2-bis[(2,4,6-trimethylphenyl)imino]acenaphthene (tmp-Bian) were prepared. All complexes were fully characterized by spectrochemical methods, and their crystal structures were confirmed by X-ray diffraction analysis. The 72 h stability of heteroleptic bipyridine Pd(II) complexes with Bian ligands under physiological conditions was investigated using 1H NMR spectroscopy. The anticancer activity of all complexes was assessed in a panel of cancer cell lines in comparison with uncoordinated ligands and clinically used drugs cisplatin and doxorubicin. The ability of the complexes to bind DNA was investigated using several methods, including EtBr replacement assay, density functional theory calculations, circular dichroism spectroscopy, DNA gel electrophoresis, and TUNEL assay. The electrochemical activity of all complexes and the uncoordinated ligands was studied using cyclic voltammetry, and reactive oxygen species production in cancer cells was investigated using confocal microscopy. Heteroleptic bipyridine PdII-Bian complexes were cytotoxic in a low micromolar concentration range and showed some selectivity toward cancer cells in comparison with noncancerous MRC-5 lung fibroblasts.

Trapping of Ag+ into a Perfect Six-Coordinated Environment: Structural Analysis, Quantum Chemical Calculations and Electrochemistry.

Self-assembly of (Bu4N)4[ß-Mo8O26], AgNO3, and 2-bis[(2,6-diisopropylphenyl)-imino]acenaphthene (dpp-bian) in DMF solution resulted in the (Bu4N)2[ß-{Ag(dpp-bian)}2Mo8O26] (1) complex. The complex was characterized by single crystal X-ray diffraction (SCXRD), X-ray powder diffraction (XRPD), diffuse reflectance (DR), infrared spectroscopy (IR), and elemental analysis. Comprehensive SCXRD studies of the crystal structure show the presence of Ag+ in an uncommon coordination environment without a clear preference for Ag-N over Ag-O bonding. Quantum chemical calculations were performed to qualify the nature of the Ag-N/Ag-O interactions and to assign the electronic transitions observed in the UV-Vis absorption spectra. The electrochemical behavior of the complex combines POM and redox ligand signatures. Complex 1 demonstrates catalytic activity in the electrochemical reduction of CO2.

A catalyst-free approach to synthesis of spiroacenaphthylene-pyranopyrazole derivatives in water media.

A simple approach for the synthesis of spiroacenaphthylene-pyranopyrazole derivatives was achieved via the reaction between acenaphthoquinone, pyrazolones, and activated methylene compounds (malononitrile derivatives) in water as a green solvent without using any catalyst in order to avoid the use of transition metal. This method has the advantages of mild reaction condition, short reaction time, easy workup, excellent yields, and avoidance of environmentally hazardous solvents.

Complexes of Cobalt(II) Iodide with Pyridine and Redox Active 1,2-Bis(arylimino)acenaphthene: Synthesis, Structure, Electrochemical, and Single Ion Magnet Properties.

Complexes [(dpp-BIAN)0CoIII2]·MeCN (I) and [(Py)2CoI2] (II) were synthesized by the reaction between cobalt(II) iodide and 1,2-bis(2,6-diisopropylphenylimino)acenaphthene (dpp-BIAN) or pyridine (Py), respectively. The molecular structures of the complexes were determined by X-ray diffraction. The Co(II) ions in both compounds are in a distorted tetrahedral environment (CoN2I2). The electrochemical behavior of complex I was studied by cyclic voltammetry. Magnetochemical measurements revealed that when an external magnetic field is applied, both compounds exhibit the properties of field-induced single ion magnets.

Investigation of geospatial distribution of PAH compounds in soil phase and determination of soil-air exchange direction in a megacity.

In this study, determination of possible sources, soil-air exchange direction, and spatial distribution of PAH concentrations was aimed. In this scope, soil samples were collected from 35 different points, which have the urban and rural characteristics, from European and Asian Sides in Istanbul. The average ∑16PAH concentrations were found as 22.11 ng/g dw for urban site and 19.53 ng/g dw for rural site, respectively. The highest concentration was 279.5 ng/g dw. PAH concentrations were higher in urban site than rural site. Acenaphthene and benzo[k]fluoranthene were observed as the dominant species. PAH concentrations are observed higher mostly in north and west parts of European Side and south and east parts of Asian Side. There was net evaporation from soil to air for lower molecular weight PAHs with 2, 3 rings, while high molecular weight PAHs with 4, 5, 6 rings accumulated in the soil at both urban and rural sites. PAHs were mostly originated from coal burning and the use of diesel engine vehicles.

Rapid Evolution of Reduced Susceptibility against a Balanced Dual-Targeting Antibiotic through Stepping-Stone Mutations.

Multitargeting antibiotics, i.e., single compounds capable of inhibiting two or more bacterial targets, are generally considered to be a promising therapeutic strategy against resistance evolution. The rationale for this theory is that multitargeting antibiotics demand the simultaneous acquisition of multiple mutations at their respective target genes to achieve significant resistance. The theory presumes that individual mutations provide little or no benefit to the bacterial host. Here, we propose that such individual stepping-stone mutations can be prevalent in clinical bacterial isolates, as they provide significant resistance to other antimicrobial agents. To test this possibility, we focused on gepotidacin, an antibiotic candidate that selectively inhibits both bacterial DNA gyrase and topoisomerase IV. In a susceptible organism, Klebsiella pneumoniae, a combination of two specific mutations in these target proteins provide an >2,000-fold reduction in susceptibility, while individually, none of these mutations affect resistance significantly. Alarmingly, strains with decreased susceptibility against gepotidacin are found to be as virulent as the wild-type Klebsiella pneumoniae strain in a murine model. Moreover, numerous pathogenic isolates carry mutations which could promote the evolution of clinically significant reduction of susceptibility against gepotidacin in the future. As might be expected, prolonged exposure to ciprofloxacin, a clinically widely employed gyrase inhibitor, coselected for reduced susceptibility against gepotidacin. We conclude that extensive antibiotic usage could select for mutations that serve as stepping-stones toward resistance against antimicrobial compounds still under development. Our research indicates that even balanced multitargeting antibiotics are prone to resistance evolution.

Functionalized 1,3-Thiazolidin-4-Ones from 2-Oxo-Acenaphthoquinylidene- and [2.2]Paracyclophanylidene-Thiosemicarbazones.

The reactions of dialkyl acetylenedicarboxylates with various 2-oxo-acenaphthoquinylidene- and 4-acetyl[2.2]paracyclophanylidene-thiosemicarbazones were investigated. Using simple experimental procedures, 1,3-Thiazolidin-4-ones derived from acenaphthequinone or [2.2]paracyclophane were obtained as major products in good yields. In the case of allyl derivative of acenaphthoquinylidene-thiosemicarbazones, a complex structure of tetramethyl 5-(2-(((Z,E)-N-allyl-N'-(2-oxoacenaphthylen-1(2H)-ylidene)carbamohydrazonoyl)thio)-1,2,3-tris-(methoxycarbonyl)-cyclopropyl)-4-methoxy-7-oxabicyclo[2.2.1]hepta-2,5-diene-1,2,3,6-tetracarboxylate was formed. Single crystal X-ray analysis was used as an efficient tool to confirm the structure of the synthesized compounds as well as different spectroscopic data (1H-NMR, 13C-NMR, 2D-NMR, mass spectrometry and elemental analysis). The mechanism of the obtained products was discussed.

Design, Synthesis and In Vitro Mechanistic Investigation of Novel Hexacyclic Cage-Like Hybrid Heterocycles.

Novel hexacyclic cage-like hybrid heterocycles have been synthesized in excellent yields employing a relatively less explored non-stabilized azomethine ylides derived from acenaphthenequinone and tyrosine with functionalized dipolarophiles using [3 + 2] cycloaddition strategy. The synthesized hexacyclic cage-like hybrid heterocycles were characterized by spectroscopic analysis. Following the physical characterization, these cage-like hybrid heterocycles were tested for their biological activity by means of different cancer (A549 and Jurkat cells) and non-cancer (BRL-3A and PCS-130) in vitro cell culture systems. The results of the study under tested concentrations (up to 100 µM) indicated that these compounds are not affecting any viability to the cell growth of non-cancer cells, while providing significant anticancer activity against both of the cancer cells. Further analysis of in-depth mechanistic study for the cell death indicated that these compounds are exhibiting late apoptosis or early necrosis pathway to the cells where it is operated by the induction of caspases.

An Efficient Synthesis of Acenaphtho[1,2-b]indole Derivatives via Domino Reaction.

A concise and efficient synthesis of acenaphtho[1,2-b]indole derivatives via the domino reactions of enaminones with acenaphthoquinone catalyzed by l-proline has been developed. This protocol has the advantages of good yields, operational convenience and high regioselectivity.

A Simple and Efficient Synthesis of Highly Substituted Indeno[1,2-b]pyrrole and Acenaphtho[1,2-b]pyrrole Derivatives by Tandem Three-Component Reactions.

A green, convenient and tandem procedure for the efficient synthesis of highly substituted indeno[1,2-b]pyrrole and acenaphtho[1,2-b]pyrrole derivatives by domino three-component reaction of tryptamine/benzylamine, 1,3-dicarbonyl compounds and ninhydrin/ acenaphthenequinone is described. The significant features of this procedure were characterized by mild reaction conditions, high yields, operational simplicity and it being environmentally benign.

Tridecacyclene: A Cyclic Tetramer of Acenaphthylene.

In this manuscript, we describe the single-step preparation of a cyclic tetramer of acenaphthylene through a Lewis acid-catalyzed aldol cyclization of 1-acenaphthenone. The previously unexplored cyclic tetramer material differs from the better-known cyclic trimer, decacyclene, due to the presence of a central eight-membered ring. This ring not only forces the molecule to distort significantly from planarity, but is also responsible for its unique electronic properties, including a decrease in the reduction potential (by about 0.4 eV) and optical gap (by about 0.73 eV), compared to the more planar decacyclene. The synthesized compound crystallizes into a unique packing structure with significant π-stacking observed between adjacent molecules. Furthermore, due to its saddle-like shape, the cyclic tetramer is able to form shape-complementary interactions between its concave surface and the convex outer surface of buckminsterfullerene to generate cocrystalline supramolecular assemblies.

A Sustainable Approach to the Stereoselective Synthesis of Diazaheptacyclic Cage Systems Based on a Multicomponent Strategy in an Ionic Liquid.

The microwave-assisted three-component reactions of 3,5-bis(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones, acenaphthenequinone and cyclic α-amino acids in an ionic liquid, 1-butyl-3-methylimidazolium bromide, occurred through a domino sequence affording structurally intriguing diazaheptacyclic cage-like compounds in excellent yields.

Oxidation of Acenaphthene and Acenaphthylene by Human Cytochrome P450 Enzymes.

Acenaphthene and acenaphthylene, two known environmental polycyclic aromatic hydrocarbon (PAH)pollutants, were incubated at 50 µM concentrations in a standard reaction mixture with human P450s 2A6, 2A13, 1B1,1A2, 2C9, and 3A4, and the oxidation products were determined using HPLC and LC-MS. HPLC analysis showed that P450 2A6 converted acenaphthene and acenaphthylene to several mono- and dioxygenated products. LC-MS analysis of acenaphthene oxidation by P450s indicated the formation of1-acenaphthenol as a major product, with turnover rates of 6.7,4.5, and 3.6 nmol product formed/min/nmol P450 for P4502A6, 2A13, and 1B1, respectively. Acenaphthylene oxidation by P450 2A6 showed the formation of 1,2-epoxyacenaphthene as a major product (4.4 nmol epoxide formed/min/nmol P450) and also several mono- and dioxygenated products.P450 2A13, 1B1, 1A2, 2C9, and 3A4 formed 1,2-epoxyacenaphthene at rates of 0.18, 5.3 2.4, 0.16, and 3.8 nmol/min/nmol P450, respectively. 1-Acenaphthenol, which induced Type I binding spectra with P450 2A13, was further oxidized by P450 2A13 but not P450 2A6. 1,2-Epoxyacenaphthene induced Type I binding spectra with P450 2A6 and 2A13 (K(s) 1.8 and 0.16 µM,respectively) and was also oxidized to several oxidation products by these P450s. Molecular docking analysis suggested different orientations of acenaphthene, acenaphthylene, 1-acenaphthenol, and 1,2-epoxyacenaphthene in their interactions with P450 2A6a nd 2A13. Neither of these four PAHs induced umu gene expression in a Salmonella typhimurium NM tester strain. These results suggest, for the first time, that acenaphthene and acenaphthylene are oxidized by human P450s 2A6 and 2A13 and other P450s to form several mono- and dioxygenated products. The results are of use in considering the biological and toxicological significance of these environmental PAHs in humans.

Tunable Electrochemical and Catalytic Features of BIAN- and BIAO-Derived Ruthenium Complexes.

This article deals with a class of ruthenium-BIAN-derived complexes, [Ru(II)(tpm)(R-BIAN)Cl]ClO4 (tpm = tris(1-pyrazolyl)methane, R-BIAN = bis(arylimino)acenaphthene, R = 4-OMe ([1a]ClO4), 4-F ([1b]ClO4), 4-Cl ([1c]ClO4), 4-NO2 ([1d]ClO4)) and [Ru(II)(tpm)(OMe-BIAN)H2O](2+) ([3a](ClO4)2). The R-BIAN framework with R = H, however, leads to the selective formation of partially hydrolyzed BIAO ([N-(phenyl)imino]acenapthenone)-derived complex [Ru(II)(tpm)(BIAO)Cl]ClO4 ([2]ClO4). The redox-sensitive bond parameters involving -N═C-C═N- or -N═C-C═O of BIAN or BIAO in the crystals of representative [1a]ClO4, [3a](PF6)2, or [2]ClO4 establish its unreduced form. The chloro derivatives 1a(+)-1d(+) and 2(+) exhibit one oxidation and successive reduction processes in CH3CN within the potential limit of ±2.0 V versus SCE, and the redox potentials follow the order 1a(+) < 1b(+) < 1c(+) < 1d(+) ≈ 2(+). The electronic structural aspects of 1a(n)-1d(n) and 2(n) (n = +2, +1, 0, -1, -2, -3) have been assessed by UV-vis and EPR spectroelectrochemistry, DFT-calculated MO compositions, and Mulliken spin density distributions in paramagnetic intermediate states which reveal metal-based (Ru(II) → Ru(III)) oxidation and primarily BIAN- or BIAO-based successive reduction processes. The aqua complex 3a(2+) undergoes two proton-coupled redox processes at 0.56 and 0.85 V versus SCE in phosphate buffer (pH 7) corresponding to {Ru(II)-H2O}/{Ru(III)-OH} and {Ru(III)-OH}/{Ru(IV)═O}, respectively. The chloro (1a(+)-1d(+)) and aqua (3a(2+)) derivatives are found to be equally active in functioning as efficient precatalysts toward the epoxidation of a wide variety of alkenes in the presence of PhI(OAc)2 as oxidant in CH2Cl2 at 298 K, though the analogous 2(+) remains virtually inactive. The detailed experimental analysis with the representative precatalyst 1a(+) suggests the involvement of the active {Ru(IV)═O} species in the catalytic cycle, and the reaction proceeds through the radical mechanism, as also supported by the DFT calculations.

A new approach to the 8b-azaacenaphthylene ring system.

A stereoselective approach to the 8b-azaacenaphthylene ring system is described. This new route features a dichloroketene-enol ether [2 + 2] cycloaddition, a vinylogous Mannich reaction, and an aza-Prins cyclization as key stereoselective transformations.

Synthesis, Fluorescence Spectra, Redox Property and the DNA Binding Studies of 7-phenylacenaphtho[1,2-b]quinoxalin-7-ium chloride: Evidences of the Formation of Neutral Radical Analogue.

Reaction of acenaphthoquinone with N-phenyl-o-phenylenediamine in methanol in presence of HCl yielded 7-phenylacenaphtho[1,2-b]quinoxalin-7-ium chloride, [1][Cl]. [1][Cl] is brightly fluorescencent in dichloromethane (λex = 403 nm and λem = 442, 464, 488 nm) and water (λex = 408 nm and λem = 545 nm). Density functional theory (DFT) and time dependent (TD) DFT calculations on [1](+) at the B3LYP level of the theory elucidated that the origin of the lower energy excitation at around 400 nm is due to π → π(*) transition. [1](+) is redox active and exhibits a reversible cathodic wave at -0.66 V referenced to Fc(+)/Fc couple due to [1](+)/[1](•) redox couple. Electrogenerated neutral radical analogue [1](•) was characterized by electron paramagnetic resonance (EPR), UV-vis spectra and DFT calculations. DNA binding studies using the techniques of UV-vis absorption, fluorescence, circular dichroism (CD) spectra, viscosity, gel electrophoresis, hydrodynamic, isothermal titration calorimetry (ITC) and UV optical melting studies of [1][Cl] revealed that [1](+) is a strong DNA intercalator obeying neighbor exclusion principle. ITC experiment authenticated that the binding of [1](+) to DNA is entropy driven.

High Temperature Chemistry of Chlorinated Acenaphthylene. 3C Bay Acetylene Additions and Annealing by Five-Membered Ring Shifts.

Experimental and theoretical results concerning the growth and isomerization of chlorinated acenaphthylene, C12H8, during the pyrolysis of chlorohydrocarbons are presented here. A fullerene subunit, C12H8, is a useful system to investigate regarding C60 formation. However, direct experimental observation of isomerization and annealing processes in particular are difficult to confirm due to the high symmetry of the parent molecule. Chlorination lowers the symmetry, essentially labeling carbon atoms, allowing growth and isomerization to be followed directly. Pyrolysis of dichloro- and trichloroethylene, and their copyrolyses with trichlorobenzenes, provides an efficient and general source of chlorinated acenaphthylenes in a range of degrees of chlorination and over a number of unique congeners. Analysis of congener yields as a function of reagents employed, guided by DFT/B3LYP/6-311G(d,p) level calculations, strongly suggests that C2 addition across three-carbon bays in naphthalene is a major driver of growth. Additionally, extremely facile five-membered ring shifts are operative, with chlorine promoting isomerization. Theoretical study of C16H10- and C18H10-based congeners indicate that this is a general phenomenon, and with chlorine also favoring internal cyclopentafused rings in addition to increased isomerization rates, this suggests halogen moieties may be an important feature for efficient fullerene growth.

Elimination of positive and negative sampling artifacts in particulate organic carbon and PAHs using multi-sorbent coated and uncoated denuders.

Within the scope of this study, two equivalent PM2.5 samplers were designed and developed to eliminate sampling artifacts in the results of atmospheric particulate organic carbon (OC) and particulate polycyclic aromatic hydrocarbons (PAH) caused by volatile organic compounds (VOCs) and gas phase PAH compounds, respectively. A mass loss of less than 10% due to the denuders was observed. Study results showed that if an impregnated denuder is not used, the results of atmospheric particle OC concentrations will be reported with higher values due to positive errors of 53.2 ± 7.23% (median: 52.00%) on average. It was observed that the total error (net error) was still positive, but decreased to an average of 35.1 ± 16.8% (median: 31.0%) after including the negative errors quantified from the backup filter into the calculation. In cases where denuders were not used in the sampling, it was observed that the results with positive errors of 41.0 ± 14.6% (median: 33.8%) on average would be obtained for the total PAHs. Ozone-induced negative interference was the highest in Acenapthylene (28%), followed by Fluoranthane (20%), Phenanthrene (18%), and 15% for Np and Benzo[g,h,i]perylene compounds, relative to their medians. Negative errors of 10% or less were found in all other individual PAH compounds.

Structure of the oncoprotein Rcl bound to three nucleotide analogues.

Rcl is a novel N-glycoside hydrolase found in mammals that shows specificity for the hydrolysis of 5'-monophosphate nucleotides. Its role in nucleotide catabolism and the resulting production of 2-deoxyribose 5-phosphate has suggested that it might fuel cancer growth. Its expression is regulated by c-Myc, but its role as an oncoprotein remains to be clarified. In parallel, various nucleosides have been shown to acquire pro-apoptotic properties upon 5'-monophosphorylation in cells. These include triciribine, a tricyclic nucleoside analogue that is currently in clinical trials in combination with a farnesyltransferase inhibitor. Similarly, an N(6)-alkyl-AMP has been shown to be cytotoxic. Interestingly, Rcl has been shown to be inhibited by such compounds in vitro. In order to gain better insight into the precise ligand-recognition determinants, the crystallization of Rcl with these nucleotide analogues was attempted. The first crystal structure of Rcl was solved by molecular replacement using its NMR structure in combination with distantly related crystal structures. The structures of Rcl bound to two other nucleotides were then solved by molecular replacement using the previous crystal structure as a template. The resulting structures, solved at high resolution, led to a clear characterization of the protein-ligand interactions that will guide further rational drug design.

An off-on COX-2-specific fluorescent probe: targeting the Golgi apparatus of cancer cells.

Identifying cancer cells and quantifying cancer-related events in particular organelles in a rapid and sensitive fashion are important for early diagnosis and for studies on pathology and therapeutics of cancers. Herein a smart "off-on" cyclooxygenase-2-specific fluorescence probe (ANQ-IMC-6), able to report the presence of cancer cells and to image Golgi-related events, has been designed and evaluated. Cyclooxygenase-2 (COX-2) has been used as imaging target in the probe design, since this enzyme is a biomarker of virtually all cancer cell lines. In the free state in aqueous solution, ANQ-IMC-6 mainly exists in a folded conformation where probe fluorescence is quenched through photoinduced electron transfer between the fluorophore acenaphtho[1,2-b]quinoxaline (ANQ) and the recognition group, indomethacin (IMC). Fluorescence is turned on, by restraining the photoinduced electron transfer, when ANQ-IMC-6 is forced to adopt the unfolded state following binding to COX-2 in the Golgi apparatus of cancer cells. ANQ-IMC-6 provides high signal-to-background staining and has been successfully used to rapidly differentiate cancer cells from normal cells when using flow cytometry and one- and two-photon fluorescence microscopic imaging. Furthermore, ANQ-IMC-6 may be able to visualize dynamic changes of the Golgi apparatus during cancer cell apoptosis, with possible application to early diagnosis.