Side-chain Reaction Research Articles

Watching right and wrong nucleotide insertion captures hidden polymerase fidelity checkpoints

Efficient and accurate DNA synthesis is enabled by DNA polymerase fidelity checkpoints that promote insertion of the right instead of wrong nucleotide. Erroneous X-family polymerase (pol) λ nucleotide insertion leads to genomic instability in double strand break and base-excision repair. Here, time-lapse crystallography captures intermediate catalytic states of pol λ undergoing right and wrong natural nucleotide insertion. The revealed nucleotide sensing mechanism responds to base pair geometry through active site deformation to regulate global polymerase-substrate complex alignment in support of distinct optimal (right) or suboptimal (wrong) reaction pathways. An induced fit during wrong but not right insertion, and associated metal, substrate, side chain and pyrophosphate reaction dynamics modulated nucleotide insertion. A third active site metal hastened right but not wrong insertion and was not essential for DNA synthesis. The previously hidden fidelity checkpoints uncovered reveal fundamental strategies of polymerase DNA repair synthesis in genomic instability.

The fate of char structure and active groups in petroleum coke gasification in a drop tube furnace

A research on the fate of active groups from three typical petroleum cokes (petcokes) during gasification in a drop tube furnace have been presented. The results showed that the relative reduction (R) index can be used to assess the gasification reactivity of petcoke. The decomposition of side chain reaction of dealkylation is easier to proceed. Petcoke with a relative ordered degree of char structure has an energy barrier resulting in the transformation from the ordered graphitic carbon structure to amorphous carbon structure occurred only after the temperature reaches 1200 °C. It is recommended to control the petcoke gasification temperature above 1200 °C. A high temperature is beneficial for the conversion of oxygen-containing functional groups to hydroxyl groups. Petcoke with high ash content promotes the decomposition of functional groups to form active radicals, which favors the formation of amorphous carbon and, consequently, more active sites resulting in the high gasification reactivity. The high temperature gasification can make the stable active radicals (aromatic hydrocarbons groups) to break up the thermal barrier and convert to active radicals (aliphatic hydrocarbons and side chains on aromatic structure, oxygen functional groups and hydroxyl groups). The active radicals react with oxygen adsorbed on the carbon surface to generate CO, H2, CH4, etc.

The oxidation of 4-bromacetophenone by ozone in acetic acid

The kinetics and mechanism of oxidation of 4-bromoacetophenone by ozone in acetic acid solution have been studied. It was shown that 77% of the starting material is oxidized by the benzene ring; 8% of 4-bromobenzoic acid and small amounts of carbon (IV) oxide were identified among the side chain ozonation products. The main reaction products are aliphatic peroxide compounds, which have in their structure one hydroperoxide group. Manganese (II) acetate was shown to be the most effective catalyst for the side chain reaction of 4-bromoacetophenone in acetic acid. High selectivity for the side chain is achieved only at sufficiently high concentrations of catalyst ([Mn(OAc)2]0:[ArH]0=1:4). The main product of the catalytic oxidation of 4-bromoacetophenone is 4-bromobenzoic acid with a yield of 82.5%. The found dependences of the rate of oxidation of 4-bromoacetophenone by ozone on the concentration of reactants are described by the kinetic equation of the third order, the reaction rate has the first order with respect to each reagent. It was found that the decisive role in the selective oxidation of 4-bromoacetophenone is played by two-stage oxidation, in which ozone predominantly reacts with the reduced form of manganese, and the introduction of the substrate into side chain oxidation is carried out by the reaction with the oxidized form of metal. According to the research results, the mechanism of catalytic ozonation of 4-bromoacetophenone in acetic acid has been proposed, which involves ion-radical non-chain oxidation of the substrate.

Abstract B143: Pharmacogenomic of refractory response to R-CHOP therapy in diffuse large B-cell lymphoma (DLBCL) patients

Abstract Background: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy is standard of care for patients with newly diagnosed DLBCL. A majority of patients respond to R-CHOP, however ∼9% will have primary refractory disease and outcomes in these patients are extremely poor. While there is some knowledge of the pharmacogenomic (PGx) determinants of individual agents within R-CHOP, little is known about the PGx determinants of combination therapy. Our study aims to elucidate germline PGx determinants of drug bioavailability and undesirable side chain reactions in DLBCL patients treated with R-CHOP having potential to influence refractory disease. Methods: Newly diagnosed, DLBCL patients treated with R-CHOP between 2002 and 2012 with germline DNA and genotyping data were selected from the Molecular Epidemiology Resource within the Iowa/Mayo Lymphoma SPORE. Refractory disease was defined as either i) a best response of stable or progressive disease or ii) progressive disease by the end of the planned number of cycles of R-CHOP. PGx candidates within known pharmacokinetics and pharmacodynamics (PD) pathways for 11 genes (1,040 single nucleotide polymorphisms (SNPs)) were selected for study (CPT 2012;92(4):414-7). Odds ratios (ORs) and 95% confidence intervals (CI) were used to estimate the association of SNPs with refractory disease, controlling for age, gender, and age-adjusted International Prognostic Index. Results: The median age at diagnosis of 424 of DLBCL patients treated with R-CHOP was 62 years (range 18-92); 45.7% were female; and 58.4% had Ann Arbor Stage III-IV. By the end of initial therapy 40 patients had primary refractory disease. Of the 1,040 SNPs evaluated, 120 (12%) were significantly associated with refractory disease at the 5% significance threshold suggesting novel associations with drug metabolism. The top SNP from each PGx candidate gene are shown in Table, with ALDH5A1 and CYP2B6 showing the most significant associations. Conclusions: While needing replication, we identified associations within two PGx candidate genes that are potentially functionally related to cyclophosphamide PD: alleles within CYP2B6 may have relevance in R-CHOP outcomes due to potential competition with other drug metabolizing enzymes shared with prednisone and vincristine biotransformation in the liver, and alleles withinALDH5A1 may impact a deactivating side chain reaction in B lymphocytes. Table: R-CHOP PGx candidates with known side chain reactionsPGx candidaten SNPsTop SNPChrOR* (95% CI)P-valueMAFABCB1365rs3480093571.86 (1.14 – 3.04)1.32E-020.29ADH1A32rs122996841.66 (0.60 - 4.53)3.27E-010.038ALDH3A116rs2228100171.26 (0.71 - 2.22)4.28E-010.24ALDH5A1192rs946103466.30 (2.43 - 16.4)1.55E-040.030CBR110rs2835266212.10 (0.90 - 4.89)8.76E-020.052CBR356rs45527331212.12 (0.91 - 4.98)8.29E-020.050CYP2B6107rs1038376192.38 (1.44 - 3.94)7.74E-040.27CYP3A421rs2898858372.32 (0.80 - 6.78)1.23E-010.028CYP3A531rs778032871.69 (0.68 - 4.16)2.57E-010.054SLC22A16193rs11217403561.80 (1.06 - 3.03)2.78E-020.21SOD116rs1041740211.35 (0.83 - 2.19)2.26E-010.32Chr=chromosome, MAF=minor allele frequency, *Adjusted for age, sex, and age-adjusted International Prognostic Index Citation Format: Matthew K. Breitenstein, Susan L. Slager, Anne J. Novak, Matthew J. Maurer, Carrie A. Thompson, Umar Farooq, Brian K. Link, Thomas M. Habermann, Curtis L. Olswold, Andrew L. Feldman, Grzegorz S. Nowakowski, Stephen M. Ansell, Thomas E. Witzig, Richard M. Weinshilboum, Liewei Wang, James R. Cerhan. Pharmacogenomic of refractory response to R-CHOP therapy in diffuse large B-cell lymphoma (DLBCL) patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B143.

Design, synthesis and characterization of a pH-sensitive DS/GM hydrogel

Dextran sulfate/glycidyl methacrylate (DS/GM) hydrogels were synthesized by intermolecular side-chain reaction of DS hydroxyl groups with monomeric crosslinking agent, GM in aqueous solutions at 75 °C in the basic medium in this study. The optimum conditions of effective crosslinking for DS/GM system were determined with changing amounts of crosslinker and initiator (benzoyl peroxide, BPO). The swelling abilities of the hydrogels were explained with determining of certain structural parameters for the hydrogel such as equilibrium water content, percentages of gellation, and swelling ratio. pH dependent swelling behaviors of hydrogels were investigated and swelling ability at basic medium was higher than that at acidic medium. Surface morphologies of DS and its hydrogels were examined by scanning electron microscope (SEM) and they compared. Structures and thermal stabilities of DS/GM hydrogels were characterized by infrared (FTIR), thermal gravimetric analysis (TGA), differential thermal analysis (DTA), and Differential Scanning Calorimeter (DSC); effect of GM on crosslinking was investigated. The viscosities of DS/GM reaction products were recorded continuously as a function of time with rotary viscometer and gellation points of binary system reaction between DS and GM were determined via observed viscosity numbers, changes during reaction.

Fructose and uric acid in diabetic nephropathy.

Clinical studies have reported associations between serum uric acid levels and the development of diabetic nephropathy, but the underlying mechanisms remain elusive. There is evidence from animal studies that blocking uric acid production protects the kidney from tubulointerstitial injury, which may suggest a causal role for uric acid in the development of diabetic tubular injury. In turn, when fructose, which is endogenously produced in diabetes via the polyol pathway, is metabolised, uric acid is generated from a side-chain reaction driven by ATP depletion and purine nucleotide turnover. For this reason, uric acid derived from endogenous fructose could cause tubulointerstitial injury in diabetes. Accordingly, our research group recently demonstrated that blocking fructose metabolism in a diabetic mouse model mitigated the development of tubulointerstitial injury by lowering tubular uric acid production. In this review we discuss the relationship between uric acid and fructose as a novel mechanism for the development of diabetic tubular injury.

Tunable synthesis of self-assembled cyclic peptide nanotubes and nanoparticles.

While tremendous efforts have been made in investigating scalable approaches for fabricating nanoparticles, less progress has been made in scalable synthesis of cyclic peptide nanoparticles and nanotubes, despite their great potential for broader biomedical applications. In this paper, tunable synthesis of self-assembled cyclic peptide nanotubes and nanoparticles using three different methods, phase equilibrium, pH-driven, and pH-sensitive methods, were proposed and investigated. The goal is scalable nanomanufacturing of cyclic peptide nanoparticles and nanotubes with different sizes in large quality by controlling multiple process parameters. Cyclo-(L-Gln-D-Ala-L-Glu-D-Ala-)2 was applied to illustrate the proposed ideas. In the study, mass spectrometry and high performance liquid chromatography were employed to verify the chemical structures and purity of the cyclic peptides. Morphology and size of the synthesized nanomaterials were characterized using atomic force microscopy and dynamic light scattering. The dimensions of the self-assembled nanostructures were found to be strongly influenced by the cyclic peptide concentration, side chain modification, pH values, reaction time, stirring intensity, and sonication time. This paper proposed an overall strategy to integrate all the parameters to achieve optimal synthesis outputs. Mechanisms of the self-assembly of the cyclic peptide nanotubes and nanoparticles under variable conditions and tunable parameters were discussed. This study contributes to scalable nanomanufacturing of cyclic peptide based self-assembled nanoparticles and nanotubes for broader biomedical applications.

Synthesis and application of novel solid acid-base catalysts for side chain alkylation of toluene with methanol

Novel solid acid-base catalysts with aluminum and nitrogen were prepared from phenolic compounds and formaldehyde by using triblock copolymer Pluronic F127 as a template via evaporation induced organic-organic assembly method. The catalysts were characterized by Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectra (XPS). The acid-base properties of the catalyst were determined by temperature programmed desorption (TPD) using CO2 and NH3 as probe molecules. The side chain alkylation of toluene with methanol over the catalyst was studied, the results demonstrated that the catalyst Cat-TDMMP was of the higher activity [(ethylbenzene + styrene) yield was 41.0%] than the conventional alkali exchanged zeolites [(ethylbenzene + styrene) yield was about 20%]. This fact may due to the strength and distance of the specific surface acid-base pairs of the catalyst, which are favored to bimolecular side-chain alkylation reaction.

Total synthesis of (−)-jaspine B and its 4-epi-analogue from d-xylose

The total synthesis of the HCl salts of (−)-jaspine B ent-1 and its 4-epi-congener ent-4 was accomplished starting from the common template 13 derived from d-xylose. The cornerstone of our synthesis was [3,3]-heterosigmatropic rearrangements, which effectively provided scaffolds with a chiral amino group. A subsequent Wittig olefination installed a C14 alkyl side chain and acid-mediated ring-closing reaction established the tetrahydrofuran core.

Synthesis and characterization of biodegradable pH and reduction dual-sensitive polymeric micelles for doxorubicin delivery

Novel pH and reduction dual-sensitive biodegradable polymeric micelles for efficient intracellular delivery of anticancer drugs were prepared based on a block copolymer of methyloxy-poly(ethylene glycol)-b-poly[(benzyl-l-aspartate)-co-(N-(3-aminopropyl) imidazole-l-aspartamide)] [mPEG-SS-P(BLA-co-APILA), MPBA] synthesized by a combination of ring-opening polymerization and side-chain reaction. The pH/reduction-responsive behavior of MPBA was observed by both dynamic light scattering and UV–vis experiments. The polymeric micelles and DOX-loaded micelles could be prepared simply by adjusting the pH of the polymer solution without the use of any organic solvents. The drug release study indicated that the DOX-loaded micelles showed retarded drug release in phosphate-buffered saline at pH 7.4 and a rapid release after exposure to weakly acidic or reductive environment. The empty micelles were nontoxic and the DOX-loaded micelles displayed obvious anticancer activity similar to free DOX against HeLa cells. Confocal microscopy observation demonstrated that the DOX-loaded MPBA micelles can be quickly internalized into the cells, and effectively deliver the drugs into nuclei. Thus, the pH and reduction dual-responsive MPBA polymeric micelles are an attractive platform to achieve the fast intracellular release of anticancer drugs. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 1771–1780

Study on Low Temperature Co-Carbonization of Coal and Algae

Co-carbonization characteristics of long flame coal mixed with algae in different proportions were studied in a dry distillation equipment, and focusing on the coal tar of the product with GC-MS and FT-IR in order to investigate the changes in coal tar, The results show that the tar yield increases with the increasing of algae added, the light oil components of co-carbonized coal tar (with the optimal proportion 20:10 ) compared with conventional coal tar increased 29.55% while naphthalene content increased 9.15% and phenol content increased 23.93%. The algae sample played a role in hydrogen donating and the reactions involved opening-ring reaction, alkyl aromatic side chain reaction and condensation reaction, etc.

Synthesis of diethylaminoethyl dextran hydrogel and its heavy metal ion adsorption characteristics

Epichlorohydrin-crosslinked diethylaminoethyl dextran (DEAE-D/ECH) hydrogel was synthesized by intermolecular side-chain reaction of DEAE-D hydroxyl groups with monomeric crosslinking agent, ECH. Swelling ability, adsorption capacity and metal removal of the hydrogel were profoundly determined and some structural parameters for the hydrogel such as volume of non-swollen gel, percentages of gellation, swelling ratio and equilibrium water content were evaluated in this study.The ability of removing heavy metal ions from Orontes River by the synthesized hydrogel, thoroughly characterized by photometric spectrometer and the adsorption characteristics of metal ions, was investigated as well as surface morphologies of the hydrogel before and after metal adsorption were examined by SEM.Structure of DEAE-D/ECH gel was analyzed by FTIR, TGA, and DSC. Gellation point of binary system reaction between DEAE-D and ECH was determined via monitoring viscosity changes during reaction. The order of affinity based on amount of metal ion uptake was found as follows: Zn2+>Mn2+>Pb2+>Cd2+.

Studies on recyclability of polyhydroxybutyrate‐co‐valerate bioplastic: Multiple melt processing and performance evaluations

AbstractRecyclability of the bioplastic polyhydroxybutyrate‐co‐valerate (PHBV) was studied with multiple melt processing (five cycles), with their performances evaluated. A batch of PHBV was processed with a twin screw extrusion followed by injection molding. This operation was repeated five times and samples were collected from each cycle for characterization. For each cycle, the mechanical properties were characterized with tensile, flexural, and impact testing, along with dynamic mechanical analysis. The results showed that the mechanical properties are maintained for four cycles; but in the fifth cycle, there was slight decrease in the properties. Gel permeation chromatography studies revealed that the molecular weight of the polymer does not decrease drastically; however, a drop was observed after third, fourth, and fifth cycle (8.7% decrease after third cycle, 13.5% decrease after fourth cycle, and 16.6% decrease after fifth cycle). The differential scanning calorimeter showed that the glass transition and melting temperatures did not change upon reprocessing, but the degree of crystallinity was reduced as a consequence of melt processing. The thermal gravimetric analysis showed that the onset value of thermal decomposition decreased very slightly. It was observed by Fourier transform infrared spectroscopy that the chemical structure of PHBV was maintained without any side chain reaction during processing. Scanning electron microscopy studies from the fractured surfaces of Cycles 1 and 5 confirmed that the uniformity of PHBV surfaces was maintained after five cycles, coinciding with the mechanical tests. The density measurements revealed that there was no change in the density of PHBV. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012

Side-chain Alkylation of Toluene With Methanol over a Novel Solid Acid-base Catalyst

A novel solid acid-base catalyst Cat-NH(CH3)2 with aluminum and nitrogen was prepared from phenol and formaldehyde by using the triblock copolymer Pluronic F127 as a template and resol as a catalyst precursor via evaporation induced by the organic–organic assembly method. The catalyst was characterized by Fourier transform infrared spectroscopy and X-ray diffraction. The base properties of the catalyst were determined by temperature programmed desorption using CO2 as a probe molecule. The side chain alkylation of toluene with methanol over the catalyst had been studied, the results showed that Cat-NH(CH3)2 has demonstrated a higher activity and selectivity than the alkali exchanged zeolites. This may be because the strength of the specific surface base sites of this catalyst is favored to bimolecular side-chain alkylation reaction.

Nitrogen-Incorporated NaY Zeolite as Promising Basic Microporous Catalytic Material

A promising basic microporous catalytic material is prepared by nitridation of dehydrated NaY zeolite. The base strength of zeolite framework is enhanced due to the replacement of oxygen by nitrogen with lower electronegativity. Various characterization methods, including XRD, CHN elemental analysis, SEM and FTIR spectra of CO adsorption, are employed to analyze the physico-chemical properties of the nitrogen-incorporated NaY zeolite. High crystallinity and high specific surface areas of NaY are well preserved in nitrogen-incorporated NaY. Compared to parent NaY zeolite, the nitridized materials exhibit improved basic catalytic performances in Knoevenagel condensation reaction and side-chain monomethylation reaction of phenylacetonitrile.

Purification of PEGylated Protein Using Membrane Chromatography

N-terminus-specific PEGylation was used to produce mono-PEGylated lysozyme. However, some di- and tri-PEGylated proteins were also produced due to side chain reaction. The reaction products were characterized by chromatographic and electrophoretic methods. Commercial cation exchange membrane Sartobind S was used for chromatographic purification of PEGylated lysozyme, the basis of separation being the shielding of protein charge by PEG. Using the membrane chromatographic method, lysozyme and mono-, di-, and tri-PEGylated lysozyme could be resolved into separate peaks. Increasing the superficial velocity during chromatographic separation from 24 cm/h to 240 cm/h increased both protein binding capacity and resolution due to enhancement of protein mass transfer coefficient.

ChemInform Abstract: Practical Synthesis of 1β-Methylcarbapenem Antibiotics: Side-Chain Substitution Reaction of 2-Arylsulfinyl and 2-Arylsulfonyl Carbapenems.

The C-2 side-chain substitution reaction of a sulfoxide and a sulfone derived from a p-nitrobenzyl (1R, 5S, 6S)-6-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-2-[2-(diethylcarbamoyl)phenylthio]-1-methylcarbapen-2-em-3-carboxylate with various mercaptans progressed smoothly in the presence of magnesium bromide. Bromomagnesium thiolate prepared from mercaptans proved to be especially effective for the substitution reaction and gave precursors of 1β-methylcarbapenem antibiotics in high yield.

Immediate Hypersensitivity to Moxifloxacin with Tolerance to Ciprofloxacin: Report of Three Cases and Review of the Literature

To report 3 cases of immediate hypersensitivity reactions to moxifloxacin in patients who tolerated ciprofloxacin. A 71-year-old man, a 44-year-old woman, and a 70-year-old woman with a history of a moxifloxacin reaction developed an immediate hypersensitivity reaction upon oral challenge with moxifloxacin in our Drug Safety Clinic. The reaction was mainly characterized by pruritus and urticaria, although dyspnea and hypotension were noted in the first and second patient, respectively. Two of the patients had negative oral challenge tests with ciprofloxacin and all 3 patients tolerated full treatment courses of oral ciprofloxacin. In all 3 cases, use of the Naranjo probability scale indicated a highly probable adverse drug reaction. Moxifloxacin, similar to other fluoroquinolones, can cause immediate hypersensitivity reactions. Previous publications have reported both cross-reactivity and a lack of cross-reactivity among various fluoroquinolones. The 3 patients discussed demonstrated a lack of cross-reactivity between moxifloxacin and ciprofloxacin since they tolerated oral challenge tests and full treatment courses of ciprofloxacin. Moxifloxacin has unique side chains at positions 7 and 8 on its bicyclic ring structure. Antigenic specificity to particular side chains at positions 7 and 8 on the bicyclic ring structure of moxifloxacin may explain this lack of cross-reactivity. Higher reporting rates of anaphylaxis to moxifloxacin compared to other fluoroquinolones may also be related to side chain specificity, although definitive evidence for this is lacking. Based on our experience, patients who develop immediate hypersensitivity reactions to moxifloxacin may receive ciprofloxacin therapy in an appropriately monitored setting if they have previously tolerated full treatment courses of ciprofloxacin. Research into whether there is a specific side chain reaction unique to moxifloxacin is warranted.

Kinetic models for mechanoenzymes: Structural aspects under large loads

A broad class of chemical kinetic model for mechanoenzymes is analyzed theoretically in order to uncover structural aspects of the underlying free-energy landscape that determine the behavior under large resisting and assisting loads, specifically the turnover rate or, for a translocatory motor protein, the mean velocity, say, V. A systematic graphical reduction algorithm is presented that provides explicit analytical expressions for mean occupation times in individual biomechanochemical states, for the splitting or backward/forward fractions, for the overall mean dwell time, and for the turnover rate. Application to the previously studied N-state sequential and (N alpha,N beta)-parallel-chain models provides explicit structural criteria (independent of the zero-load transition rates) that determine whether mid /V/ diverges to large values or, conversely, exhibits extrema and converges to a vanishing value as the externally imposed load grows. Closed-form analytical extensions accommodate side-chain and looped side-chain reaction sequences in the enzymatic cycle. A general divided-pathway model is analyzed in detail.

New insights on toluene biodegradation by Pseudomonas putida F1: influence of pollutant concentration and excreted metabolites

The influence of toluene concentration on the specific growth rate, cellular yield, specific CO(2), and metabolite production by Pseudomonas putida F1 (PpF1) was investigated. Both cellular yield and specific CO(2) production remained constant at 1.0 +/- 0.1 g biomass dry weight (DW) g(-1) toluene and 1.91 +/- 0.31 g CO(2) g(-1) biomass, respectively, under the tested range of concentrations (2-250 mg toluene l(-1)). The specific growth rate increased up to 70 mg toluene l(-1). Further increases in toluene concentration inhibited PpF1 growth, although inhibitory concentrations were far from the application range of biological treatment processes. The specific ATP content increased with toluene concentration up to toluene concentrations of 170 mg l(-1). 3-Methyl catechol (3-MC) was never detected in the cultivation medium despite being an intermediary in the TOD pathway. This suggested that the transformation from toluene to 3-MC was the limiting step in the biodegradation process. On the other hand, benzyl alcohol (BA) was produced from toluene in a side chain reaction. This is, to the best of our knowledge, the first reported case of methyl monoxygenation of toluene by PpF1 not harboring the pWW0 TOL plasmid. In addition, the influence of 3-MC, BA, and o-cresol on toluene degradation was investigated respirometrically, showing that toluene-associated respiration was not significantly inhibited in the presence of 10-100 mg l(-1) of the above-mentioned compounds.