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PubMed1996

Nephrotoxicity of N-(3-bromophenyl)-2-hydroxysuccinimide: role of halogen groups in the nephrotoxic potential of N-(halophenyl) succinimides.

Among N-(halophenyl)succinimides. N-(3,5-dichlorophenyl)succinimide (NDPS) is a potent nephrotoxicant as well as an agricultural fungicide. Although two chloride groups on the phenyl ring are essential to induce optimal nephrotoxicity, the role of halogen groups in NDPS nephrotoxicity is not clear. In this study, N-(3-bromophenyl)-2-hydroxysuccinimide (NBPHS) was prepared as a monohalophenyl derivative of N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS), an oxidative and nephrotoxicant metabolite of NDPS. The nephrotoxic potential of NBPHS was evaluated in vivo and in vitro to determine the role of halogen groups in N-(halophenyl)succinimide nephrotoxicity. Male Fischer 344 rats (four/group) were administered a single intraperitoneal (i.p.) injection of NBPHS (0.1, 0.4 or 0.8 mmol/kg) or vehicle (25% dimethyl sulfoxide in sesame oil) and renal function monitored for 48 h. Administration of NBPHS (0.8 mmol/kg) induced nephrotoxicity, while very mild changes or no changes in renal function were observed following administration of 0.4 mmol/kg or 0.1 mmol/kg of NBPHS, respectively. Nephrotoxicity induced by NBPHS (0.8 mmol/kg) was characterized by diuresis, transiently increased proteinuria, glucosuria and hematuria elevated kidney weight and reduced tetraethylammonium (TEA) uptake by renal cortical slices, and was not as marked as nephrotoxicity induced by NDHS (0.1 mmol/kg) or NDPS (0.4 mmol/kg). In the in vitro studies the effects of NBPHS on organic ion accumulation, pyruvate-stimulated gluconeogenesis, and lactate dehydrogenase (LDH) release were measured using renal cortical slices. NBPHS decreased p-aminohippurate (PAH) and TEA accumulation at NBPHS bath concentrations of 0.05 mM and 0.5 mM and 0.5 mM or greater, respectively. Renal gluconeogenesis was inhibited by NBPHS at 1 mM bath concentration, while LDH leakage was not increased at NBPHS bath concentrations up to 1 mM. The results demonstrate that NBPHS is a mild nephrotoxicant in vivo and in vitro, but does not have cytotoxic effects to renal tissues at the concentrations tested. From these results, it appears that halogen groups are essential to the nephrotoxic potential of N-(halophenyl)-2-hydroxysuccinimides or N-(halophenyl)succinimides and play an important role in the mechanism of NDPS nephrotoxicity following NDHS formation.

Analysis of Variance↗

PubMed2003

Nephrotoxic and hepatotoxic potential of imidazolidinedione-, oxazolidinedione- and thiazolidinedione-containing analogues of N-(3,5-dichlorophenyl)succinimide (NDPS) in Fischer 344 rats.

Nephrotoxicity of the agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) in rats is believed to involve metabolism on the succinimide ring. To further investigate this hypothesis, we synthesized and tested the following NDPS analogues, which contain other cyclic imide rings and may therefore be metabolized differently than NDPS: 3-(3,5-dichlorophenyl)-2,4-oxazolidinedione (DCPO), 3-(3,5-dichlorophenyl)-2,4-imidazolidinedione (DCPI), 3-(3,5-dichlorophenyl)-1-methyl-2,4-imidazolidinedione (DCPM) and 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT). Male Fischer 344 rats were administered DCPO, DCPI, DCPM, DCPT (0.6 or 1.0 mmol/kg, i.p. in corn oil), NDPS (0.6 mmol/kg, i.p. in corn oil) or corn oil (4 ml/kg). As evidenced by diuresis, proteinuria, elevated blood urea nitrogen levels, increased kidney weights and proximal tubular damage, NDPS produced severe nephrotoxicity in the rats. In contrast, DCPO, DCPI, DCPM and DCPT were mild nephrotoxicants. None of the compounds elevated serum alanine transferase activity or liver weights in the rats, however DCPT produced centrilobular necrosis. These experiments confirm that NDPS-induced nephrotoxicity is critically dependent on the presence of the succinimide ring. Furthermore, replacement of the succinimide ring with a thiazolidinedione ring produced a more pronounced effect on the liver than on the kidney. Liver damage has been reported in type II diabetic patients taking troglitazone, rosiglitazone and pioglitazone. Since these compounds also contain a thiazolidinedione ring, DCPT may be useful for investigating the role of this structural feature in hepatotoxicity.

Alanine Transaminase↗

PubMed1994

Isolation and characterization of 101-succinimide lysozyme that possesses the cyclic imide at Asp101-Gly102.

Lytic activity of lysozyme solution gradually increased on incubation at pH 4, 40 degrees C. When the solution was analyzed by use of cation-exchange HPLC at pH 5, a new peak appeared with increased incubation time. The derivative in the new peak was identified to be 101-succinimide lysozyme in which cyclic imide formed at Asp101-Gly102. The formation of 101-succinimide lysozyme increased with increases in concentration of acetate buffer. Kinetic analysis of the formation of 101-succinimide lysozyme indicated that the cyclic imide was stable below pH 5 due to suppression of the hydrolysis of cyclic imide. Its lytic activity against M. luteus, which has a negative charge, was 165% at pH 7, whereas its activity against glycol chitin, which has no charge, was 90%. Since the lytic activity of Asn101 lysozyme, where one negative charge is eliminated, reached a maximum of 125%, it was suggested that the increase of lytic activity against bacterial cells in 101-succinimide lysozyme was due not only to the disappearance of the negative charge at Asp101 but also to the removal of steric hindrance at the upper part of the active site cleft.

Acetates↗

PubMed1987

Rapid degradation of D- and L-succinimide-containing peptides by a post-proline endopeptidase from human erythrocytes.

We have been interested in the metabolic fate of proteins containing aspartyl succinimide (Asu) residues. These residues can be derived from the spontaneous rearrangement of Asp and Asn residues and from the spontaneous demethylation of enzymatically methylated L-isoAsp and D-Asp residues. Incubation of the synthetic hexapeptide N-Ac-Val-Tyr-Pro-Asu-Gly-Ala with the cytosolic fraction of human erythrocytes resulted in rapid cleavage of the prolyl-aspartyl succinimide bond producing the tripeptide N-Ac-Val-Tyr-Pro. The rate of this reaction is equal for both L- and D-Asu-containing peptides and is 10-fold greater than the rate of cleavage of a corresponding peptide containing a normal Pro-Asp linkage. When the aspartyl succinimide ring was replaced with an isoaspartyl residue, the cleavage rate was about 5 times that of the normal Pro-Asp peptide. The tripeptide-producing activity copurified on DEAE-cellulose chromatography with an activity that cleaves N-carbobenzoxy-Gly-Pro-4-methylcoumarin-7-amide, a post-proline endopeptidase substrate. These two activities were both inhibited by an antiserum to rat brain post-proline endopeptidase, and it appears that they are catalyzed by the same enzyme. This enzyme has a molecular weight of approximately 80,000 and is covalently labeled and inhibited by [3H]diisopropyl fluorophosphate. The facile cleavage of the succinimide- and isoaspartyl-containing peptides by this post-proline endopeptidase suggests that it may play a role in the metabolism of peptides containing altered aspartyl residues.

Amino Acid Sequence↗

PubMed2003

Antifungal properties of novel N- and alpha,beta-substituted succinimides against dermatophytes.

The synthesis and antifungal properties of a series of new N-aryl alpha,beta-substituted succinimides against a panel of dermatophytes of clinical relevance are reported. Among those compounds possessing a N-phenyl substituent, 7-thia-2-azabicyclo[2,2,1]hept-2-en-3-amine[5,6-c]succinimide was the better inhibitor of Trichophyton rubrum, the major ethiological agent of all infections produced by dermatophytes. In contrast, succinimides containing a N-(p-sulfonylphenyl) substituent, only inhibited Epidermophyton floccosum, all active compounds possessing an oxabicyclo group in positions alpha,beta of the imide. Substituents on the oxabicyclo group were important for the activity. Regarding the mechanism of action, N-(p-N'-4-methoxyphenylsulfamoylphenyl)-8-oxabicyclo[2,2,1]hept-4-en-3- methyl[5,6-c]succinimide produced a mottled inhibition halo in the Neurospora crassa assay, showing that it would act by inhibiting the synthesis or assembly of the fungal cell wall.

Antifungal Agents↗

PubMed1991

Isolation and characterization of a succinimide variant of methionyl human growth hormone.

Deamidation of asparagine and glutamine residues, isomerization of aspartic acid side chains, and racemization of the L- to the D-form of the amino acids are common spontaneous chemical reactions known to occur in proteins. Previous studies have implicated succinimides as intermediates in these reactions; however, the evidence has been indirect. Our results demonstrate, for the first time, the presence of a succinimide intermediate in an intact protein. The succinimide (cyclic imide) variant was isolated from thermally stressed recombinant methionyl human growth hormone (hGH) by high performance anion-exchange chromatography, further purified by reversed-phase high performance liquid chromatography, and analyzed by tryptic mapping. A later eluting tryptic peptide, compared with the native T12 peptide (residues 128-134, Leu-Glu-Asp-Gly-Ser-Pro-Arg), was analyzed by mass spectrometry (MS). This variant had a protonated molecular mass of 755.3 atomic mass units (u), as compared with 773.3 u for the native T12 peptide. A difference of 18 u, a loss of water, is consistent with the formation of a succinimide intermediate at Asp-130 of methionyl hGH. MS/MS analysis of the cyclic imide-containing peptide verified that the modification occurred at Asp-130. A difference of 18 u was also observed for the intact cyclic imide methionyl hGH variant (22,238 u), as measured by electrospray mass spectrometry, compared with native methionyl hGH (22,256 u).

Amino Acid Sequence↗

PubMed1987

Deamidation, isomerization, and racemization at asparaginyl and aspartyl residues in peptides. Succinimide-linked reactions that contribute to protein degradation.

Aspartyl and asparaginyl deamidation, isomerization, and racemization reactions have been studied in synthetic peptides to model these spontaneous processes that alter protein structure and function. We show here that the peptide L-Val-L-Tyr-L-Pro-L-Asn-Gly-L-Ala undergoes a rapid deamidation reaction with a half-life of only 1.4 days at 37 degrees C, pH 7.4, to give an aspartyl succinimide product. Under these conditions, the succinimide product can further react by hydrolysis (half-time, 2.3h) and by racemization (half-time, 19.5 h). The net product of the deamidation reaction is a mixture of L- and D-normal aspartyl and beta-transpeptidation (isoaspartyl) hexapeptides. Replacement of the asparagine residue by an aspartic acid residue results in a 34-fold decrease in the rate of succinimide formation. Significant racemization was found to accompany the deamidation and isomerization reactions, and most of this could be accounted for by the rapid racemization of the succinimide intermediate. Replacement of the glycyl residue in the asparagine-containing peptide with a bulky leucyl or prolyl residue results in a 33-50-fold decrease in the rate of degradation. Peptide cleavage products are observed when these Asn-Leu and Asn-Pro-containing peptides are incubated. Our studies indicate that both aspartic acid and asparagine residues may be hot spots for the nonenzymatic degradation of proteins, especially in cells such as erythrocytes and eye lens, where these macromolecules must function for periods of about 120 days and 80 years, respectively.

Amino Acid Sequence↗

PubMed1986

Metabolism of a synthetic L-isoaspartyl-containing hexapeptide in erythrocyte extracts. Enzymatic methyl esterification is followed by nonenzymatic succinimide formation.

The synthetic peptide, L-Val-L-Tyr-L-Pro-L-isoAsp-Gly-L-Ala, is a substrate for the erythrocyte and brain protein carboxyl methyltransferases. These enzymes catalyze the methyl esterification of the free alpha-carboxyl group of the isoaspartyl residue, to which the glycyl residue is linked through the side chain beta-carboxyl group. In this work, we show that the alpha-methyl ester of this peptide was rapidly demethylated (t1/2 = 4 min at 37 degrees C, pH 7.4) in erythrocyte cytosolic extracts and that the product of this reaction appears to be the succinimide ring derivative of the peptide. The rate of demethylation, measured at either pH 6.0 or 7.4, was the same in buffer and erythrocyte extracts, suggesting that succinimide formation was a nonenzymatic reaction. The L-succinimide is more stable than the ester, but can be hydrolyzed in buffer at pH 7.4 (t1/2 = 180 min at 37 degrees C) to give a mixture of about 75% isoaspartyl peptide and 25% normal aspartyl peptide. The metabolism of the succinimide hexapeptide in erythrocyte extracts appears to be more complex, however. The implications of this work for the methylation and demethylation of cellular proteins containing structurally altered aspartyl residues are discussed.

Chemical Phenomena↗

PubMed1987

Structural requirements for affinity and efficacy of N-(4-amino-2-butynyl)succinimides at muscarinic receptors in the guinea-pig ileum and urinary bladder.

The muscarinic activities on the isolated guinea-pig ileum and urinary bladder of some N-(4-amino-2-butynyl)succinimides, modified only in the amino group, were resolved into receptor affinity and efficacy components. The structural requirements for high affinity and high efficacy were quite different. Cyclic tertiary amino moieties generally favoured high affinity, while small acyclic amino and ammonium groups favoured high efficacy. On the ileum, dissociation constants and relative efficacies of the succinimides were highly correlated (r = 0.94-0.97) with those of the identically modified N-(4-amino-2-butynyl)-2-pyrrolidones. This observation suggests that N-(4-amino-2-butynyl)succinimides and 2-pyrrolidones bind to and activate muscarinic receptors in a similar fashion. In spite of their agonist properties on the ileum, the succinimides studied were agonists, partial agonists or competitive antagonists on the urinary bladder. However, dissociation constants and relative efficacies of the compounds showed good agreement in the two tissues. It therefore appears that muscarinic receptors in the guinea-pig ileum and urinary bladder are pharmacologically similar. The large differences observed in agonist potency and relative maximal responses between the two tissues were explained by a greater receptor reserve for muscarinic agonists in the ileum than in the bladder.

Animals↗

PubMed1992

Renal effects of N-(3,5-disubstitutedphenyl)-succinimides in the Fischer 344 rat.

Previous studies have demonstrated the importance of substitution at the 3- and 5-positions of the phenyl ring in N-phenylsuccinimides for the production of nephrotoxicants in this series of compounds. The purpose of this study was to determine if the electronic nature of the 3,5-substituents is an important determinant for nephrotoxic potential. Male Fischer 344 rats (four rats per group) were administered a single intraperitoneal injection of a succinimide (0.4 or 1.0 mmol kg-1) or vehicle, and the renal function was monitored for 48 h. Only N-(3,5-dichlorophenyl)succinimide (0.4 or 1.0 mmol kg-1) induced marked changes in renal function. Urine volume, BUN concentration and proteinuria were increased following N-(3,5-dinitrophenyl)succinimide (1.0 mmol kg-1) treatment but other renal parameters and renal morphology were unchanged in this treatment group. These results indicate that the presence of halogen atoms at the 3- and 5-positions of the phenyl ring in N-phenylsuccinimides is more important for nephrotoxic potential than the presence of non-halogen substituents. The reason why halogen substitution is an important determinant for N-phenylsuccinimide nephrotoxicity is unknown.

Animals↗

PubMed1992

Isolation and characterization of porcine somatotropin containing a succinimide residue in place of aspartate129.

Aspartate129 in porcine somatotropin was converted into a cyclic imide residue (succinimide) under acidic solution conditions. Reversed-phase high performance liquid chromatography was utilized to isolate and quantitate this altered species, which accounted for approximately 30% of the total protein. The molecular mass of this modified species was determined by electrospray mass spectrometry to be 18 Da less than normal porcine somatotropin, indicative of a loss of 1 H2O molecule. Tryptic peptide mapping demonstrated that the peptide composed of residues 126-133 was altered in this modified protein. Amino acid analysis, amino acid sequencing, mass spectrometry, and capillary zone electrophoresis were used to demonstrate that aspartate129 in this peptide had been converted into a succinimide residue. Further confirmation that this peptide contained a succinimide was obtained by hydrolyzing the modified peptide at pH 9.0, which yielded both the aspartate and isoaspartate peptides.

Amino Acid Sequence↗

PubMed1998

Succinimide and isoaspartate residues in the crystal structures of hen egg-white lysozyme complexed with tri-N-acetylchitotriose.

The isomerization of Asp101 to isoaspartate autocatalytically proceeds via a succinimide intermediate in hen egg-white lysozyme at a mildly acidic condition. The crystal structures of succinimide and isoaspartate forms of the lysozyme proteins, each complexed with a tri-N-acetylchitotriose ligand, have been determined at 1.8 A resolution, and distinctively elucidate coplanar cyclic aminosuccinyl and beta-linked isoaspartyl residues. Compared with the liganded native protein with normal Asp101, succinimide 101 protrudes toward the ligand, and isoaspartate 101 extends away from the ligand. The formations of these residues caused the loss of three hydrogen-bonds between the ligand and the side-chains of Asp101 and Asn103 along with 0.5 A displacement of the ligand location.

Animals↗

PubMed1983

Effects of alkyl-substituted gamma-butyrolactones and succinimides on the evoked and spontaneous activity of hippocampal slices in vitro.

Alkyl-substituted and unsubstituted derivatives of gamma-butyrolactone (GBL), gamma-hydroxybutyrate (GHB), and succinimide were tested for their effects on the evoked potential (EP) and spontaneous activity of hippocampal slices incubated in vitro. When tested alone, only beta-ethyl-beta-methyl-GBL (beta-EMGBL) and tetramethylsuccinimide (TMSM) had any effect, producing greatly augmented EPs and spontaneous epileptiform discharges. The nonexcitatory drugs were also tested for the ability to block the excitation produced by beta-EMGBL, TMSM, and penicillin. The unsubstituted compounds had no effect on the augmented EP induced by any of the convulsants. The alpha-ethyl-alpha-methyl-substituted GBL (alpha-EMGBL) and ethosuximide (ESM), blocked the augmented EP induced by beta-EMGBL and TMSM but not that induced by penicillin. The spontaneous activity induced by all three excitatory agents was blocked by GHB. Unsubstituted succinimide had no effect on spontaneous activity. The spontaneous activity produced by beta-EMGBL and TMSM was blocked by alpha-EMGBL, but ESM blocked only that induced by TMSM. Neither alpha-EMGBL nor ESM blocked the spontaneous activity produced by penicillin. We conclude that the ability to block the EP more closely parallels in vivo anticonvulsant activity whereas effects on the spontaneous activity may be more related to neuronal depressant effects. The alkyl-substituted GBLs and succinimides had very similar, albeit not identical, effects on incubated hippocampal slices. That may indicate that they have a similar but not a common mechanism of action.

4-Butyrolactone↗

PubMed1984

2-Pyrrolidinone and succinimide endogenously present in several mammalian species.

2-Pyrrolidinone and succinimide were identified in blood plasma of man, rat, and mouse. Dog plasma contained only traces of 2-pyrrolidinone not exceeding significantly the detection limit of our GCMS-method. Succinimide but not 2-pyrrolidinone could also be found in the brains of rat and mouse. Evidence is presented for a metabolic pathway leading from 2-pyrrolidinone to succinimide, with 5-hydroxy-2-pyrrolidinone as an intermediate.

Adult↗

PubMed1986

Deuterium isotope effect in acute N-(3,5-dichlorophenyl)succinimide-induced nephrotoxicity.

Deuterium labelling of the succinimide ring of N-(3,5-dichlorophenyl) succinimide (NDPS) markedly reduced the acute nephrotoxicity produced by NDPS administration to Fischer 344 rats. Administration of the deuterium-labelled derivative, NDPS-d4, to male Fischer 344 rats failed to produce the marked diuresis, increased proteinuria, glucosuria, hematuria, elevated blood urea nitrogen (BUN) concentration and kidney weight, decreased basal p-aminohippurate (PAH) accumulation, and proximal tubular necrosis which are characteristic of NDPS-induced nephrotoxicity. However, lactate-stimulated PAH and tetraethylammonium (TEA) accumulation were decreased by NDPS-d4 (1.0 mmol/kg). The lack of nephrotoxicity produced by NDPS-d4 suggests that oxidation at the carbon-carbon bridge of the succinimide ring is an important biotransformation step in the generation of the nephrotoxic species of NDPS.

Animals↗

PubMed1995

The cytotoxicity of N-Pyridinyl and N-quinolinyl substituted derivatives of phthalimide and succinimide.

The N-pyridinyl and N-quinolinyl substituted derivatives of phthalimides and succinimides demonstrated cytotoxicity against the growth of a number of cultured cell lines. The substituted succinimides were more effective than the unsubstituted succinimide derivative in reducing cell growth. On the other hand, phthalimide demonstrated more potent cytotoxicity than its N-substituted derivatives. Three representative examples N-[2-pyridinyl-1-oxide) methyl] phthalimide 8, 1-[N-2-phthalimidoethyl]-3,4-dihydroiso-quinoline 12, and 1-[N-(2-(1,2,3,4-tetrahydro-2-quinolinyl)] ethylphthalimide 14 were shown to inhibit L1210 leukemia DNA synthesis whereas RNA synthesis was not inhibited at 25-100 uM. All three agents inhibited the activities of DNA polymerase alpha, PRPP-amido transferase, nucleoside kinases, and dihydrofolate reductase. The cellular pool levels of d[GTP], d[CTP], and d[TTP] were reduced after 60 minutes incubation at 100 uM. The DNA molecule itself was not a target of these agents.

Animals↗

PubMed2004

Syntheses, in vitro antibacterial and cytotoxic activities of a series of 3-substituted succinimides.

We have synthesized a series of 3-substituted succinimides and their in vitro antibacterial activities have been tested towards Gram-positive and Gram-negative bacteria from the ATCC collection. Some of them possess significant antibacterial activity against Gram-positive organisms (Staphylococcus aureus ATCC 25923 and Enterococcus faecalis ATCC 29212) but all are poorly active or inactive against Gram-negative organisms (Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853). The compounds with the lowest minimal inhibitory concentrations (esters of 3-hydroxy succinimides) are also the most cytotoxic against green monkey Vero cell line (ATCC CCL-81) and could explain that perhaps apoptosis should be implicated in eukaryotic cell cytotoxicity of succinimides.

Animals↗

PubMed2002

Atomic resolution structure of a succinimide intermediate in E.coli CheY.

Isomerization of aspartate to isoaspartate occurs spontaneously in proteins, causes changes in protein structures, and correlates positively with the aging processes of many organisms, including Alzheimer disease in humans. Aspartate isomerization proceeds through an unstable cyclic succinimide intermediate. There are few protein structure determinations that have characterized the intermediates and products of this isomerization reaction. Here we report the discovery of an unusually stabilized succinimide ring in the 1.1A structure of the Escherichia coli CheY protein, as determined from a crystal eight years old. The ring is formed by the side-chain of aspartate 75 and the backbone nitrogen of glycine 76 in an exposed loop of the molecule. Stabilization of the succinimide is through interaction of a sulfate ion oxygen atom with the imide nitrogen atom. Formation of the ring caused conformational changes in the loop, but did not alter the overall structure of the protein.

Bacterial Proteins↗