Malonic Acid Derivatives Research Articles

The inhibition of death receptor mediated apoptosis through lysosome stabilization following internalization of carboxyfullerene nanoparticles

Cells undergo apoptosis through two major pathways, the extrinsic pathway (death receptor pathway) and the intrinsic pathway (the mitochondrial pathway). It is well known that nanomaterials of water- soluble fullerene derivatives are potent antioxidants and help to prevent the overproduction of mitochondrial reactive oxygen species (ROS). However, whether their interaction with cells via the death receptor pathway is direct or indirect remains poorly understood. Here, we show that a bis-adduct malonic acid derivative of fullerene, C 60(C(COOH) 2) 2, inhibits tumor necrosis factor alpha-initiated cellular apoptosis via stabilizing lysosomes. Data presented here demonstrate that nano-sized aggregates of this water-soluble fullerene derivative are endocytosed into cells and enriched in the lysosomes. During the internalization of C 60(C(COOH) 2) 2, the expression of Hsp 70 is significantly upregulated, promoting cell survival by inhibiting the permeabilization of lysosomal membranes. In addition, the acidic environment inside lysosomes has a marked but temporary effect on the size distribution of fullerenic nanoparticles, and may disperse the aggregated C 60(C(COOH) 2) 2 nanoparticles into single molecules or smaller aggregates. These single molecules or smaller aggregates may insert into the lysosomal membranes, further stabilizing them and decreasing the release of cathepsins from lysosomes, leading to the inhibition of tumor necrosis factor-induced apoptosis. C 60(C(COOH) 2) 2 nanoparticles can thus protect cells by stabilizing lysosomal membranes via both upregulated expression of Hsp 70 and by their interactions with lysosomal membranes.

N‐Heterocyclic Carbene‐Catalyzed Michael Additions of 1,3‐Dicarbonyl Compounds

A study of the organocatalytic activity of N-heterocyclic carbenes (NHCs) in the Michael addition of 1,3-dicarbonyl compounds has allowed us to identify 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) as an excellent catalyst for this transformation (up to 99 % yield with a 2.5 mol % catalyst loading), and the reaction was found to be of broad scope. Two early applications of this unprecedented catalytic activity of NHCs are described, that is, the domino carbocyclization reactions of simple cyclic 1,3-dicarbonyl and malonic acid derivatives, which allow stereoselective access to bridged bicyclic compounds, and the stereoselective synthesis of cyclohexanols (or cyclohexene). Early mechanistic investigations are also reported.

Synthesis of ( E)-2-(1-ferrocenylmethylidene)malonic acid derivatives by a cobalt-catalyzed domino reaction of ethyl diazoacetate, carbon monoxide and ferrocenylimines

The domino reaction of ethyl diazoacetate, carbon monoxide and ferrocenylimines was investigated in the presence of Co 2(CO) 8 as catalyst. In most cases the main products are 2-(1-ferrocenylmethylidene) malonates formed by an N(1)–C(4) cleavage of the primarily derived β–lactams. The latter compounds could only be isolated when the reaction was carried out at relatively low CO pressure, using an excess of ethyl diazoacetate. trans- N-( tert-Butyl)-3-ethoxycarbonyl-4-ferrocenyl-β-lactam proved to be the most stable one among these compounds and could be isolated in 55% yield. N-alkyl β-lactams were shown to undergo acidic cleavage leading to the E isomers of 2-(1-ferrocenylmethylidene) malonates as the main products. The structures of the two new compounds, ( E)-2-ethoxycarbonyl-3-ferrocenyl- N-(( R)-1-phenylethyl)-2-propenamide and trans- N-( tert-butyl)-3-ethoxycarbonyl-4-ferrocenyl-β-lactam were confirmed by X-ray crystallography. The relative thermodynamical stability of the products as well as the energetics of the acid-mediated cleavage of the β-lactam ring was elucidated with DFT calculations.

Four hydroxyls are better than two. The use of a chiral lithium salt of 3,3′-bis-methanol-2,2′-binaphthol as a multifunctional catalyst of enantioselective Michael addition reactions

The catalytic performance of the Li salt of ( S)- or ( R)-3,3′-bis[bis-(phenyl)hydroxymethyl]-2,2′-dihydroxy-dinaphthalene-1,1′ (BIMBOL) in asymmetric Michael additions of malonic acid derivatives and toluedine has been studied. Nitrostyrene and cyclohex-2-enone were chosen as Michael acceptors. Efficient asymmetric C–C and C–N bond formations with ee’s of up to 95% at room temperature were observed. A transition state model of the malonic ester addition to cyclohex-2-enone has been proposed based on the molecular structure of the acetone solvate of BIMBOL. The impact of the catalyst self-association on its performance is also discussed.

Synthesis and antioxidant activity of long chain alkyl hydroxycinnamates

Long chain alkyl hydroxycinnamates ( 8– 21) were synthesized from the corresponding half esters of malonic acid ( 5– 7) and benzaldehyde derivatives by Knoevenagel condensation. The total antioxidant capacity of these hydroxycinnamyl esters was evaluated using DPPH and ABTS assays. The observed antioxidant activity was highest for esters of caffeic acid followed by sinapic esters and ferulic esters. The parameters for drug-likeness of these hydroxycinnamyl esters were also evaluated according to the Lipinski’s ‘rule-of-five’. All the ester derivatives were found to violate one of the Lipinski’s parameters (cLogP >5), even though they have been found to be soluble in protic solvents. The predictive topological polar surface area (TPSA) data allow concluding that they could have a good capacity for penetrating cell membranes. Therefore, one can propose these novel lipophilic compounds as potential antioxidants for tackling oxidative processes.

Centrosymmetric Structures of Three Substituted Malonic Acids

Crystal structures of 2-methylmalonic acid, 2-ethylmalonic acid and 2-phenylmalonic acid, which are derivatives of malonic acid and have found usefulness in diagnostics and biochemical evaluations as markers and organic synthesis, are reported. 2-Methylmalonic acid and 2-ethylmalonic acid both crystallize in triclinic P-1 space group with cell parameters of a = 5.1033(7), b = 5.4231(7), c = 10.0887(14) A, α = 88.074(4), β = 89.999(5) and γ = 67.955(4)° for 2-methylmalonic acid, and a = 5.2073(4), b = 7.2258(6), c = 8.5655(6) A, α = 88.086(2), β = 75.307(2) and γ = 85.904(3)° for 2-ethylmalonic acid, 2-phenylmalonic acid on the other hand crystallizes in monoclinic P21/c with cell parameters a = 8.6494(4), b = 5.48733(19), c = 17.1706(6) A and β = 90.1068(17)°. The observed topology of the hydrogen bonding network is to a large extent dictated by the symmetrical substitution pattern with an open arrangement of hydrogen bonds. Each of the C=O double bonds in both 2-methylmalonic acid and 2-ethylmalonic acid is translationally offset, forming planar centrosymmetric carboxy-dimers. Molecules related by centre of inversion in spite of the constraints imposed by substituents are linked by O–H···O hydrogen bonds. This results in the formation of parallel zig-zag chains running along the [101] direction. In 2-phenylmalonic acid, the zig-zag molecular residue is parallely stacked with successive catemers. These laterally displaced catemers are also coiled in a twofold twist on the screw axis (x, ½ + y, ½ − z) along the b-glide (x, ½ − y, ½ + z) when viewed along the (101) plane. Crystal structures of 2-methylmalonic acid (I), 2-ethylmalonic acid (II) and 2-phenylmalonic acid (III), which are derivatives of malonic acid and have found usefulness in diagnostics and biochemical evaluations as markers and organic synthesis, are reported showing topology of hydrogen bonding network dictated by symmetric substitution pattern with an open arrangement of hydrogen bonds.

ChemInform Abstract: Reactions of Titanium Derivatives of Some CH-Acids with Carbonyl Compounds. Part 4. Synthesis and Some Transformations of (2- Alkenylidene)malonic Acid Derivatives.

ChemInform Abstract: Reactions of Titanium Derivatives of Some CH-Acids with Carbonyl Compounds. Part 4. Synthesis and Some Transformations of (2- Alkenylidene)malonic Acid Derivatives.

ChemInform Abstract: Conjugate Addition of 2-(Bromozincmethyl)-3-phenoxy-1-propene to Derivatives of Methylene Malonic Acid. Further Conversion to Methylenecyclopentanes.

ChemInform Abstract: Conjugate Addition of 2-(Bromozincmethyl)-3-phenoxy-1-propene to Derivatives of Methylene Malonic Acid. Further Conversion to Methylenecyclopentanes.

A Room-Temperature, Copper-Catalyzed Cascade Process for Diethyl 2-Aryl-3,4-dihydro-4-oxo-1,1(2H)-naphthalenedicarboxylate

A room-temperature cascade process for the formation of diethyl 2-aryl-3,4-dihydro-4-oxo-1,1(2H)-naphthalenedicarboxylate is described by using a combination of Michael addition and copper-catalyzed α-arylation of malonic acid derivatives. The protocol worked well for a variety of 1-(2-iodoaryl)enones and displayed great functional group compatibility.

ChemInform Abstract: Molecular Rotors: Synthesis and Evaluation as Viscosity Sensors.

AbstractA variety of molecular rotors, mainly p‐N,N‐dialkylaminobenzylidene compounds, are prepared from the aromatic aldehydes and malonic acid derivatives.

Synthesis of Chalcone and Flavanone Derivatives from Condensation of 2’-Hydroxyacetophenones and Benzaldehyde over Basic <i>β</i>-Zeolites

The basic strength of alkali metal ion-exchanged β-zeolites was assessed based on the extent of Knoevenagel reaction using malonic acid derivatives and benzaldehyde. Preparation of chalcone and flavanone derivatives from the condensation of 2’-hydroxyacetophenones and benzaldehyde were carried out over the zeolites. The conversions of chalcone and flavanone derivatives and the selectivity of flavanone derivatives increased with the basic strength of the catalyst. A cyclization from chalcone to flavanone was controlled with intermolecular hydrogen bond strength of chalcone derivatives.

ChemInform Abstract: Co2(CO)8‐Induced Domino Reactions of Ethyl Diazoacetate, Carbon Monoxide and Ferrocenylimines Leading to 2‐(1‐Ferrocenyl‐methylidene)‐malonic Acid Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Studies of Azulen-1-ylmethylene Malonic Acid Derivatives by Electrochemistry

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Co 2(CO) 8-induced domino reactions of ethyl diazoacetate, carbon monoxide and ferrocenylimines leading to 2-(1-ferrocenyl-methylidene)-malonic acid derivatives

Novel 2-(1-ferrocenyl-methylidene)-malonic acid derivatives are obtained upon reacting ethyl diazoacetate, carbon monoxide and ferrocenylimines in the presence of Co 2(CO) 8 as catalyst under mild conditions. Presumably, the reaction involves three steps taking place in a domino fashion, (i) carbonylation of ethyl diazoacetate leading to a ketene derivative, (ii) [2+2] cycloaddition of the ketene with the ferrocenylimine present in the reaction mixture resulting in the formation of a β-lactam and (iii) N(1)-C(4) cleavage of the β-lactam ring. In most cases, 2-(1-ferrocenyl-methylidene)-malonic acid derivatives are obtained as a separable mixture of E- and Z-isomers in ratios depending on the structure of the imine component.

Biological activity of bis-benzimidazole derivatives on DNA topoisomerase I and HeLa, MCF7 and A431 cells

Benzimidazoles of both natural and synthetic sources are the key components of many bio-active compounds. Several reports have shown antifungal, antiviral, H2 receptor blocker and antitumor activities for benzimidazoles and their derivatives. In this study, we synthesized twelve bis-benzimidazole derivatives by selecting di(1H-benzo[d]imidazol-2-yl)methane as the main compound. The numbers of carbons at 2 positions of bis-benzimidazole derivatives were changed from 1 to 4, and derivatives were synthesized with methyl substitutions at 5- and/or 6- positions. The compounds were screened via in vitro plasmid superciol relaxation assays using mammalian DNA topoisomerase I and cytostatic assays were carried out against HeLa (cervix adenocarcinoma), MCF7 (breast adenocarcinoma) and A431 (skin epidermoid carcinoma) cells for selected derivatives. Our results suggest that the malonic acid derivatives of bis-benzimidazoles, namely, bis(5-methyl-1H-benzo[d]imidazol-2-yl)methane and bis(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)methane, were remarkably active compounds in interfering with DNA topoisomerase I and the former compound was also found to be cytotoxic against MCF7 and A431 cells. The inhibitory effects obtained with these derivatives are significant as these compounds can be potential sources of anticancer agents.

Azoles and azines: CXXVIII. Reaction of 2-aryl-4-hydroxy-6H-1,3-thiazin-6-ones with 6-bromo-4-oxo-4H-chromene-3-carbaldehyde

We previously studied reactions of 2-aryl-4-hydroxy-6H-1,3-thiazin-6-ones with aliphatic and aromatic aldehydes [2]; in these studies, specific attention was given to reactions of such 1,3-thiazines with salicylaldehyde derivatives [3], taking into account possible closure of coumarin ring in the reactions with malonic acid derivatives, including cyclic ones (e.g., barbituric acid or 2-aryl-4-hydroxy-6H-1,3-thiazin-6-ones). Derivatives of 3-formylchromone also attract strong theoretical and practical interest due to the presence of double carbon–carbon bond (C 2 =C 3 ) activated by two carbonyl groups, which is capable of taking up nucleophilic reagents, including compounds with an activated methylene group [4]. Reactions of such chromones with polyhydroxypyrimidines (which can be regarded as cyclic analogs of malonic acid) give rise only to the corresponding ylidene derivatives as a result of condensation at the aldehyde group [5]. Reactions of 4-hydroxy-6H-1,3-thiazin-6-ones with substituted 3-formylchromones were not studied. We have found that 2-aryl-4-hydroxy-6H-1,3-thiazin6-ones Ia and Ib react with 6-bromo-4-oxo-4Hchromene-3-carbaldehyde (II) in polar aprotic solvents (such as DMSO or pyridine) to give 3,10-dioxo-Nthioaroyl-4,4a-dihydro-3H,10H-pyrano[4,3-b]chromene4-carboxamides VIIa and VIIb in 60–70% yield. It should be noted that the formation of such products is quite surprising, taking into account that the reaction of 3-formylchromone with barbituric acid leads to the formation of 5-(4-oxochromene-3-ylmethylidene)bar

Formylnitroenamines: useful building blocks for nitrated pyridones and aminopyridines with functional groups

beta-formyl-beta-nitroenamines possess both an electrophilic formyl group and a nucleophilic amino group and, therefore, serve as C3N1 building blocks having a nitro group to afford nitropyridones and aminonitropyridines with a functional group at the 3-position. Upon treatment with malonic acid derivatives or beta-keto esters, nitropyridones were obtained, whereas reactions with functionalized acetonitriles afford aminonitropyridines, via a formal transfer of an alkyl group from the ring nitrogen to the imino group. These procedures provide practical and useful methods for preparation of heterocycles with a nitro group.

Functionalization of the unsaturated organophosphorus compounds. Study of reaction of dialkylaminoethynephosphonates with malonic acid derivatives and benzenesulfonylacetonitrile

Reactions of some CH-acids with dimethyl dialkylaminoethynephosphonates were studied aiming to develop methods of syntheses of the functionalized organophosphorus compounds. Reactions with malonodinitrile, ethyl cyanoacetate, and benzenesulfonylacetonitrile were shown to proceed effectively in anhydrous acetonitrile in the presence of catalytic amounts of potassium carbonate to form products of CHacids addition at the triple bond followed by prototropic isomerization to give the corresponding β-dialkylamino-β-phosphonomethyl-α-substituted acrylonitriles. In reaction with malonic acid aminoethynephosphonates are hydrolyzed to form phosphonoacetic acid dialkylamides as main products.

Asymmetric Malonic and Acetoacetic Acid Syntheses – A Century of Enantioselective Decarboxylative Protonations

AbstractThe enantioselective decarboxylative protonation (EDP) of malonic or acetoacetic acid derivatives is a synthetic methodology by which the chirality of the product is generated during the enol/enolate protonation step. Although EDP is a century‐old reaction, it has not received much attention until recently. This review focuses on the EDP as an alternative to the strong‐base‐mediated deprotonation/asymmetric reprotonation for the stereocontrol of C–H bond formation. The diverse synthetic approaches are classified according to the type of catalysis used, which are organic, metallic or enzymatic.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Design and Synthesis of Bis-amide and Hydrazide-containing Derivatives of Malonic Acid as Potential HIV-1 Integrase Inhibitors

HIV-1 integrase (IN) is an attractive and validated target for the development of novel therapeutics against AIDS. In the search for new IN inhibitors, we designed and synthesized three series of bis-amide and hydrazide-containing derivatives of malonic acid. We performed a docking study to investigate the potential interactions of the title compounds with essential amino acids on the IN active site.