Studies on the biological action of malononitriles. III. Effect of malononitrile administration on excretion of thiocyanate in normal and Walker carcinoma 256-bearing rats.
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Animals↗
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Studies on the biological action of malononitriles. I. The effect of substituted malononitriles on the growth of transplanted tumors in mice.
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Animals↗
Studies on the biological action of malononitriles. II. Distribution of rhodanese (transulfurase) in the tissues of normal and tumor-bearing animals and the effect of malononitriles thereon.
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Animals↗
Effect of the labeling group in structural analyses of malononitrile-labeled oligosaccharides by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and electrospray ionization mass spectrometry
Structural analyses of oligosaccharide-malononitrile derivatives were conducted by matrix-assisted laser desorption/ionization post-source decay (MALDI-PSD) analysis in positive ion mode, and by electrospray ionization collision-induced dissociation (ESI-CID) analysis in negative ion mode. The malononitrile derivatives of oligosaccharides, which were developed for separation and detection of multi-component oligosaccharides by negative ion electrospray ionization mass spectrometry (ESI-MS), were detected by positive ion MALDI with a detection limit at a 400 fmol level even without any purification procedure for the derivatized oligosaccharide mixture. The results of structural analyses of oligosaccharide-malononitrile derivatives by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) were affected drastically by the choice of matrix used, and gave much more structural information than the free oligosaccharide. The effects of the malononitrile labeling group on the structural analyses of oligosaccharide-malononitrile derivatives by positive-ion MALDI-PSD analysis in reflectron mode, and by MALDI time-of-flight mass spectrometry (MALDI-TOFMS) in linear mode, are compared with those of in-source ESI-CID analysis in negative ion mode. The malononitrile derivatization method could be a powerful tool for structural analyses of oligosaccharides. Copyright 1999 John Wiley & Sons, Ltd.
Journal Article↗
4-Nitrobenzylidene malononitrile reduces apoptosis-mediated liver injury in mice.
BACKGROUND: Apoptosis plays a role in experimental and clinically related liver damage. Inhibitors of tyrosine kinases were shown to modulate apoptosis induced by different agents in various cell types. AIMS: Investigation of the effect of 4-nitrobenzylidene malononitrile (belonging to the tyrphostins family which are selective inhibitors of protein tyrosine kinases) on apoptosis-mediated acute liver injury. METHODS: Two murine experimental models exhibiting apoptosis-mediated liver injury were used: (1) mice treated with tumor necrosis factor-alpha and D-galactosamine; and (2) mice treated with anti-Fas antibody. Liver injury was assessed by serum levels of transaminases and by microscopic analysis. Apoptosis was assessed by labeling of apoptotic cells in the liver by the TUNEL assay and by determination of caspase-3 activity. RESULTS: Pretreatment of mice with 4-nitrobenzylidene malononitrile reduced tumor necrosis factor-alpha/D-galactosamine-induced hepatotoxicity. TUNEL positive cells in sections from livers treated with vehicle (control), 4-nitrobenzylidene malononitrile, tumor necrosis factor-/d-galactosamine and tumor necrosis factor-alpha/D-galactosamine and 4-nitrobenzylidene malononitrile, were >0.2, >0.2, 49+/-2.3 and 4+/-0.2 per mm(2), respectively. 4-Nitrobenzylidene malononitrile also reduced hepatotoxicity induced by anti-Fas antibody. Caspase-3 activation induced by either tumor necrosis factor-alpha/D-glactosamine or by anti-Fas treatment, was reduced by pretreatment with N-nitrobenzylidene malononitrile. CONCLUSIONS: The findings may provide a base for development of a new therapeutic modality to reduce apoptosis-mediated liver damage.
Animals↗
Radioautographic study of the effect of malononitrile dimer on RNA synthesis in mice.
The drug malononitrile dimer (1,1,3-tricyano-2-amino-1-propene) was administered intraperitoneally to groups of mice at 20 mg/kg body weight, either as a single injection or as chronic 2-month injections. To study the effect of malononitrile dimer on RNA synthesis in the brain, it was necessary to choose a precursor that would pass the blood-brain barrier. Animals were injected with 14C-formate, then sacrificed 1 h later. RNA synthesis in the brain, liver and kidney of the drug-injected and control animals was determined by the amount of 14C-formate incorporated into newly synthesized RNA. A new method involving the comparison of RNase-extracted with non-extracted slides is described for determining the proportion of 14C-formate incorporated into RNA radioautographically. The results show that RNA synthesis was significantly increased as a result of both single and chronic malononitrile dimer injections in all tissues studied. In most cases, malononitrile dimer nearly doubled the percentage of 14C-formate incorporated into newly synthesized RNA. The effect of the chronic injections was most pronounced in the brain. The mechanism of malononitrile action on RNA synthesis are mediated by thyroxine is discussed.
Animals↗
Malononitrile as a new derivatizing reagent for high-sensitivity analysis of oligosaccharides by electrospray ionization mass spectrometry.
A new method for the high-sensitivity analysis of oligosaccharides by negative ion electrospray ionization mass spectrometry was developed through a chemical derivatization of oligosaccharides. Oligosaccharides were derivatized to dinitrile compounds from the reaction with malononitrile under mildly basic conditions. The derivative of maltoheptaose was detected mainly as the [M-2H]2- ion in negative ion mode with 20 fmol sensitivity, even in unpurified samples. In this malononitrile derivatization method, no inorganic reagent, other than sodium hydroxide as a base catalyst, is used. Also, because excess ligand (malononitrile) is volatile, high sensitivity detection is realized without any solvent extraction or chromatographic purification. The detection limit can also be decreased by simple on-line cartridge filtration to 200 attomol which is 10(5) times better than that of free maltoheptaose. Structural information for oligosaccharide derivatives was obtained by collision induced dissociation. This malononitrile derivatization method is convenient and efficient for the sensitive analysis of oligosaccharides.
Carbohydrate Sequence↗
Molecular basis of the protonophoric and uncoupling activities of the potent uncoupler SF-6847 [3,5-di-tert-butyl-4-hydroxybenzylidene)malononitrile) and derivatives. Regulation of their electronic structures by restricted intramolecular rotation.
We reported recently (Yoshikawa, K. and Terada, H. (1982) J. Am. Chem. Soc. 104, 7644-7646) that the potent uncoupler of oxidative phosphorylation SF-6847 [3,5-di-tert-butyl-4-hydroxybenzylidene)malononitrile) shows unique intramolecular restricted rotation of the malononitrile moiety. In this study, values for the activation energy Ea of the restricted rotation of SF-6847 derivatives with the same alkyl chain R in both ortho positions of the phenolic hydroxyl group were determined from the temperature-dependent change in the 1H-NMR signals of their aromatic protons. The Ea values of the neutral forms of these derivatives were found to be the same irrespective of R, but those of the anionic forms increased with increase in the alkyl chain length of R. It was found that the restricted rotation of the malononitrile moiety regulates its electron-withdrawing ability in such a way as to keep the acid dissociability of these derivatives similar, overcoming the effect of steric hindrance by R. The protonophoric activity of these derivatives, in a phospholipid bilayer membrane and their uncoupling activity in rat-liver mitochondria were both found to depend on Ea of their anionic forms. The stability of the uncoupler anions regulated by the restricted rotation of the malononitrile group in a nonpolar membrane environment was found to be important for exhibition of these activities. The hydrophobicity of the anionic forms of these derivatives was suggested also to be affected by the intramolecular rotation.
Animals↗
The fate of 2-chlorobenzylidene malononitrile (CS) in rats.
1. The fate of 3H-ring labelled, 14C-cyanide labelled and (14C = C) side chain labelled 2-chlorobenzylidene malononitrile (CS), 2-chlorobenzyl alcohol and 2-chlorobenzyl malononitrile (dihydro CS) in rats and isolated rat liver cells has been examined. 2. CS was administered both i.v. and i.g. to rats at doses from 0.08 to 159 mumol/kg and in most cases the greatest proportion of the dose was eliminated in the urine (44-100%). The principal urinary metabolites were 2-chlorohippuric acid, 1-O-(2-chlorobenzyl) glucuronic acid, 2-chlorobenzyl cysteine and 2-chlorobenzoic acid. Lesser amounts of 2-chlorophenyl acetyl glycine, 2-chlorobenzyl alcohol and 2-chlorophenyl 2-cyano propionate were identified. 3. The major urinary metabolite from 2-chlorobenzyl alcohol was 2-chlorohippuric acid (43%), 2-chlorobenzyl cysteine, 2-chlorobenzoic acid and 2-chlorobenzyl glucuronic acid were identified. 4. The products of dihydro-CS metabolism were 2-chlorophenyl acetyl glycine, 2-chlorophenyl 2-cyanopropionate and 2-chlorophenyl proprionamide. 5. Urinary thiocyanate levels increased with the dose of CS up to 159 mumol/kg. At 212 mumol/kg there was a large increase in the amount of thiocyanate produced (molar conversion: 21.5-29.9%). Similarly malononitrile, the hydrolysis product of CS, gave a dose related increase in urinary thiocyanate levels. However at a higher dose (212 mumol/kg) the molar conversion was greater than 60%. 6. The metabolism of CS by isolated rat liver cells confirmed the results in vivo but demonstrated a marked limitation of this preparation to form conjugates. 7. It is concluded that CS in vivo is hydrolysed mainly to 2-chlorobenzaldehyde which is then either oxidized to 2-chlorobenzoic acid for subsequent glycine conjugation, or reduced to 2-chlorobenzyl alcohol for ultimate excretion as 2-chlorobenzyl acetyl cysteine or 1-O-(2-chlorobenzyl) glucuronic acid. Malononitrile is converted to thiocyanate via the formation of cyanide.
Animals↗
Efficient synthesis of 3H-imidazo[4,5-b]pyridines from malononitrile and 5-amino-4-(cyanoformimidoyl)imidazoles.
1-Aryl-5-amino-4-(cyanoformimidoyl)imidazoles 2 were reacted with malononitrile under mild experimental conditions and led to 3-aryl-5,7-diamino-6-cyano-3H-imidazo[4,5-b]pyridines 5, when the reaction was carried out in the presence of DBU, or to 3-aryl-5-amino-6,7-dicyano-3H-imidazo[4,5-b]pyridines 3, in its absence. Both reactions evolved from the adduct formed by nucleophilic attack of the malononitrile anion to the carbon of the cyanoformimidoyl substituent. A 5-amino-1-aryl-4-(1-amino-2,2-dicyanovinyl)imidazole 4 was isolated when this reaction was carried out in the presence of DBU. The structure of compound 4 was confirmed by spectroscopic methods and by reaction with triethyl orthoformate and with acetic anhydride, leading respectively to 9-aryl-6-(cyanomethylidene)purines 11 and 12. Imidazole 2b was also reacted with ethyl acetoacetate, a carbon acid with a pK(a) comparable to that of malononitrile. Similar reaction conditions were used and the product isolated was a 6-carbamoyl-1,2-dihydropurine 10, showing that a different mechanism was operating in this case.
Journal Article↗
An evaluation of the relative potential public health concern for the self-defense spray active ingredients oleoresin capsicum, o-chlorobenzylidene malononitrile, and 2-chloroacetophenone.
In 1996, the New York State Department of Health was charged by the State Legislature to develop regulations regarding the types of self-defense spray devices which could lawfully be purchased, possessed, and used in New York State. Prior to this legislation, sale or possession of self-defense spray devices in New York State was illegal. The Department of Health used existing data to evaluate three commonly used self-defense spray active ingredients (oleoresin capsicum, o-chlorobenzylidene malononitrile, and 2-chloroacetophenone) with respect to their relative toxicity and their involvement in accidental poisonings. Based on the balance of the available information, the Department of Health determined that oleoresin capsicum posed a lower public health concern than o-chlorobenzylidene malononitrile or 2-chloroacetophenone, and developed a rule that specifies oleoresin capsicum as the only active ingredient to be used in self-defense sprays for sale and use in New York State.
Accidents↗
Glutathione conjugation of chlorobenzylidene malononitriles in vitro and the biotransformation to mercapturic acids in rats.
The glutathione conjugation of 2-chloro-, 3-chloro-, 4-chloro- and 2,6-dichlorobenzylidene malononitrile (chloroBMNs) was investigated in vitro. In incubation mixtures containing rat liver cytosol (9000 g), the decrease in the initial amount of glutathione due to the various chloroBMNs ranged from 40 to 60% and occurred both enzymatically and spontaneously at physiological conditions (37 degrees C, pH 7.4). 2,6-DichloroBMN, however, depleted glutathione largely spontaneously (38 +/- 3%). The steric hindrance of the two chlorosubstituents probably plays an important role during the glutathione-S-transferase catalyzed reaction. The hydrolysis of the chloroBMNs to the corresponding chlorobenzaldehydes and malononitrile was studied in a mixture of buffer pH 7.4 and ethanol. The rate of hydrolysis of 2,6-dichloroBMN was slower than those of the related chloroBMNs. This means that 2,6-dichloroBMN will be the most stable compound in the presence of water. Only IP administration of 2-chloroBMN (CS) to adult male Wistar rats gave enhancement of urinary thioether excretion. A thioether could be isolated and was identified as the N-acetyl-S-[2-chlorobenzyl]-L-cysteine. The quantity of this benzylmercapturic acid in the urine of rats amounted to 4.4% dose (0.07 mmol/kg, n = 12). After IP administration of 2-chloro- and 3-chlorobenzaldehyde to rats benzylmercapturic acid excretion in the urine was found to be 7.6 and 1.1% of the dose, respectively. Administration of the related 4-chloro- and 2,6-dichlorobenzaldehyde, however, resulted in no urinary mercapturic acid excretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcysteine↗
The application of malononitriles as microviscosity probes in pharmaceutical systems.
Three molecules were investigated for their ability to distinguish variations in the microviscosity of the surrounding medium. Julolidinemalononitrile (JMN), p-(N-dimethylaminobenzylidene) malononitrile (BMN), and p-(N-dimethylaminocinnamylidene) malononitrile (CMN) were dissolved in media of various micro- and bulk viscosities. The fluorescence intensity of each dissolved probe and the bulk viscosity of each medium were measured. In solutions of low molecular weight substances, where the micro- and bulk viscosities are expected to correspond, the fluorescence behavior of each probe was a function of bulk viscosity and was independent of solution composition. In contrast, in aqueous solutions of methylcellulose, the fluorescence behavior of the probes corresponds to microviscosities significantly lower than the measured bulk viscosities. Thus, the probes are useful in resolving the microviscosity from bulk viscosity of neat liquid and solution systems. The sensitivity of the probes to viscosity is in the order JMN > BMN > CMN. Due to its limited water solubility, JMN is not particularly useful for pharmaceutical systems. CMN is the preferred probe for these applications due to its high fluorescence intensity over a large viscosity range.
Chemistry, Pharmaceutical↗
Electron microscopic observations on spinal ganglion cells of Rana pipiens after injection of malononitrile.
Spinal ganglionic cells of Rana pipiens were studied with light and electron microscopes in normal animals and in animals which had received graded dosages of malononitrile intraperitoneally. After treatment no increase in the intensity of staining was noted in the Nissl substance when spinal ganglion cells were examined with the light microscope. The electron micrographs demonstrated the following in malononitrile-treated animals: 1. The cisternae of the endoplasmic reticulum composing the Nissl bodies appeared to fragment and lose their parallel orientation. 2. The microvesicular components of the Golgi complex appeared to increase in number, and the increase was apparently due to fragmentation of the membrane system of the Golgi complex. 3. The mitochondria enlarged and became pleomorphic, but displayed no alterations of internal structure. The morphological changes may be interpreted as reflections of biochemical alterations.
Animals↗
Stability and absorption spectrum of malononitrile.
1) Spectra in the ultraviolet and visible regions have been obtained on samples of malononitrile under different conditions. The samples were manufactured by several companies in America and Sweden. 2) The spectral analysis has demonstrated that the compound used by Hydén and Hartelius is not the same as that employed by American investigators. If, however, an aqueous solution of the American product is allowed to stand at room temperature for a long enough time, it develops the same spectral characteristics as the Swedish solution. 3) Future studies will concern themselves with attempts to identify, the active substance and to examine its effect on neuronal nucleoproteins.
Nitriles↗
Mutagenicity evaluation of riot control agent o-chlorobenzylidene malononitrile (CS) in the Ames Salmonella/microsome test.
o-Chlorobenzylidene malononitrile (CS), a riot control agent, was evaluated for its possible mutagenic activity in the Ames Salmonella/mammalian microsome mutagenicity test. Five histidine-deficient (His-) mutant tester strains of Salmonella typhimurium--TA97a, TA98, TA100, TA102 and TA104--were used. The liquid preincubation procedure was used with metabolic activation (presence of S9 mixture) and without metabolic activation (absence of S9 mixture). For the experiments with metabolic activation, three different concentrations of S9 fraction (supernatant of Aroclor 1254-induced rat liver homogenate at 9000 g)--5%, 15% and 30% in S9 mixture--were used. Along with mutagenic activity, CS was also evaluated for cytotoxic activity in all the five tester strains of Salmonella typhimurium, both in the presence and absence of S9 mixture. The mutagenic and cytotoxic activities of CS were assessed by counting the His+ revertant colonies and by counting the microcolonies (His-, auxotrophs in the background lawn), respectively, and the respective mean values were compared with the relative negative (solvent) control. A dose range of 12.5-800 micrograms plate-1 for CS did not induce a mutagenic response either in the presence or absence of S9 mix. No change in the negative mutagenic response of CS has been observed even in the presence of an elevated level of S9 fraction in the S9 mix. A dose of 200 micrograms plate-1 for CS was found to be cytotoxic by decreasing the surviving cells as well as His+ revertant colonies; however, the effect was reduced in the presence of an elevated level of S9 fraction in the S9 mix.
Animals↗
2-Chlorobenzylmercapturic acid, a metabolite of the riot control agent 2-chlorobenzylidene malononitrile (CS) in the rat.
Adult male Wistar rats administered i.p. with 2-chlorobenzylidene malononitrile (CS) excreted one mercapturic acid in urine. The amount of mercapturic acid determined gaschromatographically was about 4% of the dose (0.07 mmol/kg, n = 12). The structure of the mercapturic acid methylester was identified by t.l.c. and confirmed by synthesis and mass-spectrography. The acid appeared to be 2-chlorobenzylmercapturic acid [N-acetyl-S-(2-chlorobenzyl)-L-cysteine]. CS and some of its metabolites were also tested in the Ames Salmonella/microsome assay. Both mutagenic and toxic effects were measured with strain TA 100 as the indicator organism. No mutagenic effects were found with any of the tested substances. At dosages of CS, higher than 1,000 micrograms/plate a bacteriotoxicity was revealed.
Acetylcysteine↗
The comparative acute mammalian toxicity of 1-chloroacetophenone (CN) and 2-chlorobenzylidene malononitrile (CS).
The comparative acute toxicity of two peripheral sensory irritant materials, 1-chloroacetophenone (CN) and 2-chlorobenzylidene malononitrile (CS), has been investigated in several species of small mammal using solutions in polyethylene glycol 300 for intravenous, intraperitoneal and oral administration, and as pure aerosols for inhalation exposure. Additionally, the comparative potency for inducing primary contact dermatitis was studied. CN and CS were found to be about equitoxic by intravenous and intraperitoneal injection, but CS was significantly less toxic by the oral and inhalation routes and less likely to cause non-lethal tissue damage than CN.
Administration, Oral↗