Abstract  We report that a subtoxic dose of the succinate dehydrogenase (SDH) inhibitor malonate greatly enhances the neurotoxicity of three different excitatory amino acid agonists: N-methyl-D-aspartate (NMDA), S-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (S-AMPA), and L-glutamate. In male Sprague-Dawley rats, intrastriatal stereotaxic injection of malonate alone (0.6 mumol), NMDA alone (15 nmol), S-AMPA alone (1 nmol), or glutamate alone (0.6 mumol) produced negligible toxicity as assessed by measurement of lesion volume. Coinjection of subtoxic malonate with NMDA produced a large lesion (15.2 +/- 1.4 mm3), as did coinjection of malonate with S-AMPA (11.0 +/- 1.0 mm3) or glutamate (12.8 +/- 0.7 mm3). Administration of the noncompetitive NMDA antagonist MK-801 (5 mg/kg i.p.) completely blocked the toxicity of malonate plus NMDA (0.5 +/- 0.3 mm3). This dose of MK-801 had little effect on the lesion produced by malonate plus S-AMPA (9.0 +/- 0.7 mm3), but it attenuated the toxicity of malonate plus glutamate by approximately 40% (7.5 +/- 0.9 mm3). Coinjection of the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline (NBQX; 2 nmol) had no effect on malonate plus NMDA or malonate plus glutamate toxicity (12.3 +/- 1.8 and 14.0 +/- 0.9 mm3, respectively) but greatly attenuated malonate plus S-AMPA toxicity (1.5 +/- 0.9 mm3). Combination of the two antagonists conferred no additional neuroprotection in any paradigm. These results indicate that metabolic inhibition exacerbates both NMDA receptor- and non-NMDA receptor-mediated excitotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract  The measurement of matrix metalloproteinase (MMP) activity in diseases like inflammation, oncogenesis, or atherosclerosis in vivo is highly desirable. Fine-tuned pyrimidine-2,4,6-triones (barbiturates) offer nonpeptidyl lead structures for developing imaging agents for specifically visualization of activated MMPs in vivo. The aim of this study was to modify a C-5-disubstituted barbiturate and thus design a highly affine, nonpeptidic, optical MMP inhibitor (MMPI)-ligand for imaging of activated MMPs in vivo. A convergent 10 step synthesis was developed, starting with a malonic ester and (4-bromophenoxy)benzene to generate 5-bromo-pyrimidine-2,4,6-trione as the key intermediate. To minimize the interactions between activated MMPs and the dye of the conjugate 6, a PEGylated piperazine derivative was used as a spacer and an azide as a protected amino function. After linking both building blocks, reducing the azide ( Staudinger reaction) and labeling with Cy 5.5, we obtained the nonhydroxamate MMP inhibitor 6 with high affinity (IC 50-value: 48 nM for MMP-2) measured in a fluorogenic assay using commercially available MMP-substrates and the purified enzyme. Zymography revealed an efficient blocking of enzyme activity of purified MMP-2 and MMP-9 and of MMP-containing cell supernatants (HT-1080), (A-673) using the PEGylated barbiturate 5. Fluorescence microscopy studies using a highly (A-673) and a moderate (HT-1080) MMP-2 secreting cell line showed efficient binding of the Cy 5.5 labeled tracer 6 to the MMP-2 positive cells while MMP-2 negative cells (MCF-7) did not bind. Therefore, this new barbiturate-based MMP-probe has a high affinity and specificity toward MMP-2 and -9 and is thus a promising candidate for sensitive MMP detection in vivo.

Abstract  Nine alpha-dibutylaminomethylbenzo[h]quinoline-4-methanols were synthesized from the corresponding 1-amino-naphthalenes by the following sequence: 1-aminonaphthalene leads to 1H-benz[g]indole-2,3-dione leads to benzo[h]quinoline-4-carboxylic acid leads to acid chloride leads to bromomethyl ketone leads to epoxide leads to benzo[h]quinoline-4-methanol. Several acid chlorides substituted in the 3 position reacted incompletely with ethereal diazomethane but were efficiently converted, without isolation of the intermediates, to the bromomethyl ketones by reaction with ethoxymagnesium diethylmalonate, bromination, hydrolysis, and decarboxylation. Several compounds prepared, especially alpha-dibutylaminomethyl-2-(2',4'-dimethylphenyl)-3-methyl-6-chlorobenzo[h]quinoline-4-methanol, showed significant antimalarial activity against Plasmodium berghei in infected mice but were moderately phototoxic.

Abstract  The production and use pattern of Diethylmalonate (DEM) and Dimethylmalonate (DMM) are comparable. The two chemicals have very similar physico-chemical properties and both esters are hydrolyzed via a two step reaction to malonic acid and the corresponding alcohol, methanol or ethanol. It is likely that unspecific esterases in the body catalyze the hydrolysis. The alcohols and malonic acid are physiological substances that are metabolized via physiological pathways. Ethanol (CAS No. 64-17-5) and methanol (CAS No. 67-56-1) were assessed at SIAM 19. For ethanol it was concluded that the chemical is currently of low priority for further work, because the hazardous properties of ethanol are manifest only at doses associated with consumption of alcoholic beverages. As it is impossible to reach these exposure levels as a consequence of the manufacture and use of malonates, it can be expected that malonic acid will be the metabolite that determines the toxicity of DEM. For methanol, SIAM 19 decided that this chemical is a candidate for further work. Methanol exhibits potential hazardous properties for human health (neurological effects, CNS depression, ocular effects, reproductive and developmental effects, and other organ toxicity). The effects of methanol on the CNS and retina in humans only occur at doses at which formate accumulates due to a rate-limiting conversion to carbon dioxide. In primates, formate accumulation was observed at methanol doses greater than 500 mg/kg bw (which would require a DMM dose of more than 1000 mg/kg bw). As there were no indications of a methanol associated toxicity from a well performed repeated dose toxicity study with DMM in rodents (which are, however, known to be less sensitive to methanol toxicity than humans), and because methanol toxicity would not be expected up to doses as high as 1000 mg DMM/kg bw/day, it was concluded that methanol does not make a relevant contribution to the toxicity profile of DMM. A possible mode of action for systemic toxicity of DMM and DEM can only be deduced from the repeated dose study with DMM, indicating a reversible liver hypertrophy at the cellular level at high doses of 1000 mg/kg bw/day. This effect can be an indication of an induction of metabolism in the liver rather than a clear systemic toxicity.

Abstract  BIOSIS COPYRIGHT: BIOL ABS. Regression analysis has been applied to examine the structure-activity relationships regarding the acute fish toxicity (96 h LC50 fathead minnow) of organic chemicals. The log P dependent baseline toxicity model has been confirmed for a data set composed of 618 compounds from 24 chemical classes associated with a putative common mode of action. Covariance analysis of the discrete by class regression functions resulted in the combination of chemicals to subsets associated with their mode of action. Separate models were derived for nonpolar (Class I) and polar (Class II and III) compounds. Chemicals which are more toxic than estimated from the baseline model are identified.

Abstract  For the functional enhancement of chelating resins containing carboxylic acids, copolymer beads were prepared by suspension polymerization of styrene (St), methyl methacrylate (MMA), and divinylbenzene (DVB) in the presence of toluene as diluent. The phenyl rings of the beads were directly chloromethylated, and the carboxylic ester groups of the beads were converted into hydroxymethyl groups by reduction followed by chlorination to give chloromethyl groups, respectively. The chelating resins containing a pair of neighboring carboxylic acid groups (NCAGs) were obtained by the alkylation of chloromethyl groups in copolymer beads with diethyl malonate in the presence of sodium hydride followed by hydrolysis using aqueous alkali solution. Accordingly, the structural effects of the resins on the adsorption of heavy metal ions were investigated. Poly(St- co -DVB)-based chelating resin containing NCAGs showed adsorption abilities toward heavy metal ions like Pb 2+ , Cd 2+ , and Cu 2+ , whereas poly(MMA- co -DVB)-based chelating resin containing NCAGs showed adsorption abilities toward heavy metal ions like Cu 2+ , Cd 2+ , and Co 2+ . On the other hand, poly(St- co -MMA- co -DVB)-based chelating resin containing NCAGs showed adsorption abilities toward heavy metal ions like Pb 2+ , Cd 2+ , Hg 2+ , Co 2+ , and Cu 2+ : a synergistic effect on the adsorption of heavy metal ions like Pb 2+ , Cd 2+ , Hg 2+ , and Co 2+ was observed. The adsorption ability of poly(St- co -MMA- co -DVB)-based chelating resin among three kinds of chelating resins was relatively good.

Abstract  We report an efficient process for the synthesis of diethyl malonate (DEM) and other malonates through the palladium-catalyzed carbonylation of chloroacetates. Excellent selectivity (96?%) and yield (94?%) were obtained without the formation of Pd black. For the first time, a weakly alkaline buffer was used to control the selectivity for DEM in the reaction and we discuss the relationship between the buffer medium and selectivity in the reaction. The combination of anisole as the solvent and a Na2HPO4/NaH2PO4 buffer was beneficial for completely restraining the phase-transfer-catalyzed substitution of DEM with ethyl chloroacetate, as well as accommodating the proposed [(PPh3)2PdI]-[Bu4N]+ intermediate, by providing a suitable environment for its stable existence. We achieved the highest efficiency in the catalytic cycle by fine-tuning the balance between the rates of oxidative addition and reductive elimination; moreover, we synthesized a recoverable heterogeneous polymer-bound Pd catalyst in 85?% yield that could be reused without an appreciable loss in activity over four cycles.

Abstract  The synthesis and structure of Rh(I) and Pd(II) complexes of chiral P,C-chelating phosphino-(alpha-sulfinylalkyl)phosphonium ylide ligands with a trisubstituted asymmetric ylidic center P(+)-C*(S*(O)p-Tol)-M (R = alkyl group) have been investigated, and compared to those of the analogous disubstituted ylide complexes (R = H). Reaction of the ethyl onium ylide of o-bis(diphenylphosphino)benzene with (-)-menthyl-(S)-p-tolylsulfinate afforded the corresponding racemic erythro phosphino-(alpha-sulfinylethyl)phosphonium in 90% de (R = Me). The racemization process is interpreted by a Berry-like pseudorotation mechanism driven by the steric repulsion between the alpha-methyl substituent and the bulky menthyloxy S-substituent or sulfur lone pair in the intermediate ylide-sulfinyl adduct. The ylide of phosphino-(alpha-sulfinylethyl)phosphonium reacts with [Rh(cod)(2)][PF(6)] and PdCl(2)(MeCN)(2) to afford the corresponding PC-chelated threo-Rh(I) and erythro-Pd(II) mononuclear complexes in 70% yield and total diastereoselectivity. These respective complexes act as efficient catalytic precursors for the hydrogenation of (Z)-alpha-acetamidocinnamic acid and allylic substitution of 3-acetoxy-1,3-diphenyl-1-propene with sodium dimethyl malonate. The bonding features of the erythro-Pd(11) complex exhibiting a sulfinyl O center dot center dot center dot Pd interaction are studied theoretically at the DFT level using ELF and MESP analyses. The eta(2)-P,C haptomeric form of the ylide ligand is estimated to compete at 19% with the eta(1)-C haptomeric form dominating at 81%. (C) 2010 Elsevier Ltd. All rights reserved.

Abstract  Copper(II)-directed condensation of 1,9-diamino-3,7-dithianonan-5-ol with nitroethane or diethyl malonate yields (6-methyl-6-nitro-1,11-dithia-4,8-diazacyclotetradecan-13-ol)copper(II) and (diethyl 13-hydroxy-1,11-dithia-4,8-diazacyclotetradecane-6-6-dicarboxylate)copper(II) respectively in good yields, with the latter readily converted by decarboxylation into the complex of ethyl 13-hydroxy-1,11-dithia-4,8-diazacyclotetradecane-6-carboxylate. Analogues without the alcohol group based on 3,7-dithianonane-1,9-diamine are also described. The pendant alcohol group fused directly to a macrocyclic ring carbon can act as an axial donor group, as illustrated in the X-ray crystal structure analysis of (diethyl 13-hydroxy-1,11-dithia-4,8-diazacyclotetradecane-6,6-dicarboxylate) copper(II)) perchlorate. This complex crystallizes in the P 2(1)/c space group, a 12 . 650(3), b 8 . 620(1), c 24 . 382(4) Angstrom, beta 96 . 10(2)degrees. The copper ion lies in a distorted square-based pyramidal environment of two sulfur donors (average Cu-S 2 . 338 Angstrom), two nitrogen donors (average Cu-N 2 . 035 Angstrom) and the pendant alcohol donor [Cu-O 2 . 319(6) Angstrom], with the copper ion displaced slightly (0 . 043 Angstrom) out of the macrocycle donor plane towards the pendant alcohol donor.

Abstract  Chiral spiro diphosphines (SDP) are efficient ligands for the Pd-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate and related nucleophiles. The newly synthesized ligand DMM-SDP (1e) with 3,5-dimethyl-4-methoxy groups on the P-phenyl rings of the phosphine shows the highest enantioselectivity (up to 99.1% ee). Diethylzinc as a base is critical for obtaining high enantioselectivity in the allylic alkylation using beta-dicarbonyl nucleophiles. The structure of catalyst [PdCl(2)((S)-SDP)] was determined by single crystal X-ray diffraction. The SDP ligands create an effective asymmetric environment around the palladium, resulting in high enantioselectivities for the asymmetric allylic alkylation reaction.

Abstract  The most difficult and costly step in the industrial manufacturing of antimicrobial quinolones is the synthesis of ethoxymethylene malonate (EMME), which is influenced by three main parameters: ethyl orthoformate/diethyl malonate molar ratio, acetic anhydride/diethyl l malonate molar ratio and time. In order to establish the optimum reaction conditions a planned factorial experiment of second-degree order was accomplished, in which the real values of the parameters and their limits Of variation were chosen arbitrarily. Feedforward neural networks with a single hidden layer were used in direct and inverse modeling of the process, to predict the yield of the reaction for different reaction conditions or the reaction conditions for a pre-established yield. Both mathematical modeling and the neural modeling of EMME obtaining process enabled to settle the optimum values of the parameters for a maximum yield in EMME.

Abstract  [image omitted] The article describes an efficient, economical, and environmentally friendly approach for Michael addition of diethyl malonate to ferrocenyl substituted chalcones in the presence of microwave irradiation under solvent-free conditions, affording the corresponding Michael adducts in moderate to good yields of 53-94%.

Abstract  Octan-1-ol, acetophenone, ethyl butanoate (ethyl butyrate), ethyl pentanoate (ethyl valerate), and 1,3-diethyl propanedioate (diethyl malonate) were used as solvents for determining the ternary liquid phase diagrams of aqueous mixtures consisting butyric acid, with the intention of bringing more effective and environmental friendly solvents into use. The liquid-liquid equilibrium (LLE) data for water + butyric acid + solvent ternary systems were investigated at 298.15 K and atmospheric pressure. The ternary phase diagrams composed of solubility data and tie-lines were presented graphically. The reliability of the experimental tie-lines was tested by Othmer-Tobias correlation. The experimental tie-line data were compared with the results correlated by means of UNIQUAC model, and predicted by the UNIFAC method. It is concluded that the used solvents may be adequate extractants to extract butyric acid from its dilute aqueous solutions

Abstract  Allylation of dimethyl malonate with 1-(4-chlorophenyl)prop-2-enyl methyl carbonate in the presence of [Pd(All)Cl](2), [Rh(COD)Cl](2), [Ir(COD)Cl](2) (COD is cycloocta-1,5-diene), and a chiral ferrocenyl-containing phosphite ligand based on (R)-BINOL (BINOL is 2,2'-dihydroxy-1,1'-binaphthyl) in CH2Cl2 gave a mixture of linear and branched cross-coupling products, the latter having a moderate optical purity (below 51%). The rhodium-and iridium-catalyzed reactions were very highly regioselective (regiospecific in the case of Ir), giving a branched product. In ionic liquids ([bmim][BF4] and [bdmim][BF4]) (bmim is 1-butyl-3-methylimidazolium and bdmim is 1-butyl-2,3-dimethylimidazolium), the Ir-catalyzed reaction regiospecifically afforded a branched product as a racemate. The same result was obtained with [Ir(COD)Cl](2) as a catalyst; this reaction easily occurred in ionic liquids even without a base.

Abstract  A convenient one-pot synthesis of stable phosphorus ylides by the condensation of triphenylphosphine with dialkyl acetylenedicarboxylate and CH acids, such as penta-2,4-dione or diethyl propane-1,3-dioate, in the presence of beta-cyclodextrin as a catalyst (to increase the solubility of the reactants in water) without using toxic organic solvents was proposed. This methodology is of interest due to the use of water as a solvent, thus minimizing such factors as the cost, operational hazards, and environmental pollution.

Abstract  Complexation of the chiral P,N-bidentate ferrocene- and cymantrene-based iminoarylphosphites with [Rh(CO)(2)O-12, [Rh(COD)(THF)(2)]BF4, [Pd(allyl)Cl](2), [Pt(allyl)Cl](4), [Pd(COD)Cl-2] and [Pt(COD)Cl-2] was found to give chelate complexes [Rh(CO)(eta(2)-PN)Cl], [Rh(COD)(eta(2)-PN)]BF4, [M(allyl)(eta(2)-PN)]BF4 (M = Pd, Pt) and cis-[M(eta(2)-PN)Cl-2)] (M = Pd, Pt), correspondingly. With the new P,N-ligands, up to 97% ee was achieved in the asymmetric Pd-catalysed alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate. In the enantioselective amination of 1,3-diphenyl-2-propenyl acetate with sodium diformylamide, up to 96% enantioselectivity was achieved. (c) 2006 Elsevier B.V. All rights reserved.

Abstract  Dimethyl 4-methoxycarbonylcyclopenta-1,3-diene-1,2-diacetate has been prepared from benzyl methyl malonate by reaction with 2-propynyl bromide, followed by palladium-catalyzed ring-forming oxidative carbonylation and by elimination of the benzyloxycarbonyl group and double bonds isomerization. The anion of the diacetate readily reacts with transition metal complexes, to give the corresponding cyclopentadienyl derivatives. We describe here some complexes, obtained from [{RhCl(L)(2)}(2)] [L = CO, C2H4, or 1,5-cyclooctadiene (COD)], which are efficient catalysts for the alkyne-nitrile co-cyclization to pyridines and for the hydroformylation of styrene and 1-hexene.

Abstract  alpha -Enones 1a,b react additively with hydrazine hydrate, thiourea, diethyl malonate, malononitrile, as well as ethyl cyanoacetate. Simultaneous cyclisation of the resulting 1:1 adducts yields indazole, thiazine, chromene and quinoline derivatives. The structures of all the synthesised compounds were confirmed by micro analytical and spectral data. The antimicrobial activity of some of the synthesised compounds were tested.

Abstract  Skeletal structure of copiamycin (C sub(54)H sub(95)N sub(3)O sub(17)), a potent antifungal antibiotic, was determined from the physicochemical properties of this compound and of its degradation products. This compound consists of 32-membered polyhydroxy lactone ring, an alpha , beta -unsaturated ester group, as well as a side chain with a disubstituted guanidine moiety as its terminal. One of the hydroxyl groups (presumably at C-19) forms a hemiketal ring with the keto group at C-15, and another (at either C-21 or C-23) forms a hemiester with a malonic acid moiety.

Abstract  The s-cis-[Cr(S,S-eddv)L]-complexes (1,2) (S,S-eddv = (S,S)-ethylenediamine-N,Na2-di-2-(3-methyl)butanoato ion; L = oxalate or malonate ion) were prepared. The complexes were purified by ion-exchange chromatography. The geometry of the complexes has been supposed on the basis of the infrared and electronic absorption spectra, and the absolute configurations of the isolated s-cis-[Cr(S,S-eddv)L]-complexes have been predicted on the basis of their circular dichroism (CD) spectra. Also, the results of thermal decomposition have been discussed. Antimicrobial activity of the prepared complexes (1a4) was investigated against 28 species of microorganisms. Testing was performed by microdilution method and minimum inhibitory concentrations (MIC) and minimum microbicidal concentration (MMC) have been determined. Complexes demonstrated in generally low antibacterial and antifungal activity.

Abstract  The new steroidal pyrimidine derivatives (4-6) were synthesized by the reaction of steroidal thiosemicarbazones with (2-methyl) diethyl malonate in absolute ethanol. After characterization by spectral and analytical data, the DNA interaction studies of compounds (4-6) were carried out by UV-vis, fluorescence spectroscopy, hydrodynamic measurements, molecular docking and gel electrophoresis. The compounds bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb; 2.31×103M-1, 1.93×103M-1 and 2.05×103M-1, respectively indicating the higher binding affinity of compound 4 towards DNA. Gel electrophoresis demonstrated that compound 4 showed a strong interaction during the concentration dependent cleavage activity with pBR322 DNA. The molecular docking study suggested the intercalation of steroidal pyrimidine moiety in the minor groove of DNA. During in vitro cytotoxicity, compounds (4-6) revealed potential toxicity against the different human cancer cells (MTT assay). During DAPI staining, the nuclear fragmentations on cells occurred after treatment with compounds 4 and 5. Western blotting analysis clearly indicates that compound 4 causes apoptosis in MCF-7 cancer cells. The results revealed that compound 4 has better prospectus to act as a cancer chemotherapeutic candidate, which warrants further in vivo anticancer investigations.

Abstract  A novel series of N-substituted-benzimidazolyl linked para substituted benzylidene based molecules containing three pharmacologically potent hydrogen bonding parts namely; 2,4-thiazolidinedione (TZD: a 2,4-dicarbonyl), diethyl malonate (DEM: a 1,3-diester and an isooxazolidinedione analog) and methyl acetoacetate (MAA: a β-ketoester) (6a-11b) were synthesized and evaluated for in vitro α-glucosidase inhibition. The structure of the novel synthesized compounds was confirmed through the spectral studies (LC-MS, 1H NMR, 13C NMR, FT-IR). Comparative evaluation of these compounds revealed that the compound 9b showed maximum inhibitory potential against α-amylase and α-glucosidase giving an IC50 value of 0.54 ± 0.01 μM. Furthermore, binding affinities in terms of G score values and hydrogen bond interactions between all the synthesized compounds and the AA residues in the active site of the protein (PDB code: 3TOP) to that of Acarbose (standard drug) were explored with the help of molecular docking studies. Compound 9b was considered as promising candidate of this series.

Abstract  A discrete tetranuclear thiourea-based metal-organic macrocycle (MOM) with a large size was constructed by a well-designed organic ligand and nickel(ii) ions via self-assembly. Incorporating thiourea groups as hydrogen-bond donors into a metal-organic complex system leads to a new approach for synthesizing functionalized heterogeneous catalysts, as this not only introduces coordination sites serving as chelators, but also overcomes the issues of self-association via intermolecular H-bonding, often occurring in homogeneous systems. The packing structure of this material formed a confined environment suitable for the access of substrate molecules dragged by the strong hydrogen-bond interactions from the thiourea groups, thus achieving a high catalytic performance in Michael additions of nitrostyrenes to nitroalkanes, with remarkable yields and size-selectivity in heterogeneous phase. Moreover, a comparison of the IR spectrum of Ni-SPT with the spectra of dimethyl malonate- and β-nitrostyrene-impregnated Ni-SPT indicated that both substrate molecules, β-nitrostyrene and dimethyl malonate, were able to access the cavity of the trimeric subunit.

Abstract  A new malonate possessing two pyrene moieties was synthesized as a fluoroionophore, and its structure and fluorescence spectroscopic properties were investigated. When excited at 344 nm in acetonitrile/chloroform (9:1, v/v), the synthesized bispyrenyl malonate has the fluorescence of intramolecular excimer (λem = 467 nm) emissions and not a pyrene monomer emission (λem = 394 nm). A large absolute fluorescence quantum yield was obtained in the solid state (ΦPL = 0.65) rather than in solution (ΦPL = 0.13). X-ray crystallography analysis clarified the molecular structure and alignment of the bispyrenyl malonate in the crystal phase, elucidating its fluorescence spectroscopic properties. Such analysis also suggests there are intramolecular C-H···π interactions and intermolecular π···π interactions between the pyrenyl rings. Interestingly, the synthesized bispyrenyl malonate exhibits excellent fluorescence sensing for the Cu2+ ion. Remarkable fluorescence intensity enhancement was only observed with the addition of the Cu2+ ion.