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PubMed2006

Formulation considerations for proteins susceptible to asparagine deamidation and aspartate isomerization.

The asparagine (Asn) deamidation and aspartate (Asp) isomerization reactions are nonenzymatic intra-molecular reactions occurring in peptides and proteins that are a source of major stability concern in the formulation of these biomolecules. The mechanisms for the deamidation and isomerization reactions are similar since they both proceed through an intra-molecular cyclic imide (Asu) intermediate. The formation of the Asu intermediate, which involves the attack by nitrogen of the peptide backbone on the carbonyl carbon of the Asn or the Asp side chain, is the rate-limiting step in both the deamidation and the isomerization reactions at physiological pH. In this article, the influence of factors such as formulation conditions, protein primary sequence, and protein structure on the reactivity of Asn and Asp residues in proteins are reviewed. The importance of formulation conditions such as pH and solvent dielectric in influencing deamidation and isomerization reaction rates is addressed. Formulation strategies that could improve the stability of proteins to deamidation and isomerization reactions are described. The review is intended to provide information to formulation scientists, based on protein sequence and structure, to predict potential degradative sites on a protein molecule and to enable formulation scientists to set appropriate formulation conditions to minimize reactivity of Asn and Asp residues in protein therapeutics.

Amides↗
PubMed1978

GLC determination of pemoline in biological fluids.

A specific GLC method for the determination of microgram quantities of the central stimulant pemoline in biological fluids is described. Extraction problems due to the low solubility of pemoline are avoided by acid hydrolysis of the drug to 5-phenyl-2,4-oxazolidinedione, which then can be easily isolated by two-phase extraction with dichloromethane, ether, or chloroform. Amide-imide tautomerism enables a cleanup of the extract. Quantitative determination at the microgram level is done on a methylated fraction of the dichloromethane extract by GLC using a suitable internal standard. For supporting evidence of the GLC method's specificity, the compound is also identified by examining an aliquot of the final dichloromethane extract by TLC.

Chromatography, Gas↗
PubMed1984

Synthesis of deuterium-labeled fluphenazine.

The propylpiperazine side chain of fluphenazine has been labeled with two, four, and six deuterium atoms by lithium aluminum deuteride reduction of the appropriate ester or imide. The gamma-carbon of the propyl group was labeled with two deuterium atoms by reduction of 10- (2-methoxycarbonylethyl) -2-trifluoromethyl-10H-phenothiazine, while four deuterium atoms were incorporated into the piperazine ring by reduction of 10-[3-(3,5-dioxo-1-piperazinyl)propyl]-2-trifluoromethyl-10H-pheno thiazine. The latter reduction gave the d4-labeled N-deshydroxyethyl metabolite of fluphenazine.

Chemical Phenomena↗
PubMed1984

Hypolipidemic activity of 4-phenyl-5,5-dicarbethoxy-2-pyrrolidinone in rodents.

A series of pyrrolidinones have been reported to possess hypolipidemic activity in mice. The most active agent, 4-phenyl-5-5-dicarbethoxy-2-pyrrolidinone, effectively lowered both serum cholesterol and triglyceride levels at 20-30 mg/kg/d. The agent suppressed liver mitochondrial citrate exchange, phosphatidate phosphohydrolase, and sn-glycerol-3-phosphate acyl transferase activities. Lipid content of the liver, small intestine, and serum lipoprotein fractions was reduced by drug treatment, but lipid levels increased in the bile and fecal samples, suggesting the drug accelerated lipid excretion. The mode of action of the pyrrolidinone appears similar to that of the cyclic imides.

Animals↗
PubMed1984

Biological activity of the hypolipidemic agent, N2-n-butylindazolone.

Previously, a series of N-substituted indazolone derivatives proved to be effective hypolipidemic agents in rodents. The most effective agent, N2-n-butylindazolone, at 20 mg/kg/d was shown to suppress the levels of cytoplasm acetyl coenzyme A required for cholesterol and fatty acid synthesis as well as sn-glycerol-3-phosphate acyl transferase and phosphatidate phosphohydrolase activities. Lipid content of the liver, small intestine, and serum lipoprotein fractions was lowered, whereas lipid content was increased in fecal excretions by drug treatment for 14 d. The absorption of orally administered cholesterol from the intestine was severely reduced after drug administration. The mode of action of N2-n-butylindazolone appears to be similar to cyclic imides possessing hypolipidemic activity.

Animals↗
PubMed1985

Conformational polymorphism VI: the crystal and molecular structures of form II, form III, and form V of 4-amino-N-2-pyridinylbenzenesulfonamide (sulfapyridine).

The crystal structures of three crystalline forms of 4-amino-N-pyridinylbenzenesulfonamide (sulfapyridine) have been determined by X-ray single crystal structure analysis. Form II crystallizes in space group P2(1)/c with four molecules in the unit cell: a = 0.6722(1) nm, b = 2.0593(5) nm, c = 0.8505(1) nm, beta = 101.14(1) degrees; Form III crystallizes in space group C2/c with eight molecules in the unit cell: a = 1.2830(2) nm, b = 1.1714(3) nm, c = 1.5400(3) nm, beta = 94.12(1) degrees; Form V crystallizes in the orthorhombic space group Pbca with 16 molecules in the unit cell: a = 2.4722(10) nm, b = 1.5710(15) nm, c = 1.2147(7) nm. The three structures were solved by direct methods and refined anisotropically to R factors of 0.045, 0.052, and 0.063, respectively. Bond lengths and bond angles agree well among the molecules in these structures; however, the system exhibits conformational polymorphism since the molecular conformation, as measured by torsion angles, differs significantly among the three forms. Sulfapyridine exhibits the imide configuration in all three structures rather than the amide form present in other sulfonamide compounds. Using the structural data, the powder patterns of the three forms have been computer generated to provide standard diffraction patterns for comparison with the variety of polymorphic forms reported in the literature.

Chemical Phenomena↗
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↗
PubMed1994

Identification of succinimide sites in proteins by N-terminal sequence analysis after alkaline hydroxylamine cleavage.

Under favorable conditions, Asp or Asn residues can undergo rearrangement to a succinimide (cyclic imide), which may also serve as an intermediate for deamidation and/or isoaspartate formation. Direct identification of such succinimides by peptide mapping is hampered by their lability at neutral and alkaline pH. We determined that incubation in 2 M hydroxylamine, 0.2 M Tris buffer, pH 9, for 2 h at 45 degrees C will specifically cleave on the C-terminal side of succinimides without cleavage at Asn-Gly bonds; yields are typically approximately 50%. N-terminal sequence analysis can then be used to identify an internal sequence generated by cleavage of the succinimide, hence identifying the succinimide site.

Amino Acid Sequence↗
PubMed2004

Synthesis and herbicidal activity of novel heterocyclic protoporphyrinogen oxidase inhibitors.

Protox inhibitors are applied as foliar sprays, thus causing very rapid cellular collapse and desiccation of many troublesome weeds in the presence of light. In many respects, they appear to be ideal herbicides, because they act rapidly and do not harm mammals under normal conditions. The main limitation to their widespread adoption is that few crops are naturally resistant to them. Crop tolerance has mainly been pursued with the synthesis of the cyclic imide classes containing 5- and 6-membered heterocycles, including pyrazole, pyridazine, 1,2,4-triazine, triazolinone and trifluoromethyluracil derivatives. Because of their structural novelties and biological performance, active investigations on heterocyclic protox inhibitors have been carried out in our laboratories and we have found 3-arylpyrroles to be a new class of light-activated, membrane-disrupting herbicides. They are active on both grass and broadleaf weeds at low rates. The synthesis and structure-activity relationships are presented.

Herbicides↗
PubMed2005

Hypotensive activity and toxicology of constituents from root bark of Polyalthia longifolia var. pendula.

A defatted extract of Polyalthia longifolia var. pendula root bark (PRB) in 50% methanol showed a significant ability to reduce blood pressure. It caused a 22% and 47% fall in mean arterial blood pressure (MABP) in rats at doses of 3 mg/kg and 30 mg/kg, respectively. Compounds purified from this extract include kolavenic acid (3), clerodane (1) and its isomer (2), liriodenine (4), lysicamine (5) and bisclerodane imide (6) and its isomer (7). Of these, only kolavenic acid produced a 22% fall in MABP, at a dose of 30 mg/kg. PRB showed a decrease in blood pressure of normotensive and egg yolk induced hypertensive rats. The LD50 of PRB was determined as 100 mg/kg in mice.

Administration, Oral↗
PubMed2006

Doublet-quartet conversion in negative ions as a possible mechanism of the electron autodetachment delay.

Molecular negative ions with abnormally high lifetimes (20 micros) relative to electron autodetachment were registered at 1.65 eV electron energy in pyromellitic acid imide by means of negative ion mass spectrometry with resonant electron capture. Using quantum-chemical calculations, it was shown that the delay of the electron autodetachment may be caused by the conversion of an originally generated molecular ion-doublet into a molecular ion-quartet, as a result of intersystem crossing of the potential energy surfaces of these ions. It was noticed that the ion-quartet cannot decay rapidly into the molecule of the ground state because of the prohibition of the spin flip, which is similar to that for phosphorescence. It can also not decay into the parent triplets, because these triplets are higher in energy than the ion. As a whole, both prohibitions provide the observed effect of the high lifetime of the ions.

Journal Article↗
PubMed1995

Aminoacylpyrrolidine-2-nitriles: potent and stable inhibitors of dipeptidyl-peptidase IV (CD 26).

Dipeptidyl-peptidase IV (EC 3.4.14.5) also known as CD26 is a membrane-bound serine peptidase which cleaves N-terminal dipeptides from a peptide chain containing a proline residue in the penultimate position. The enzyme is believed to play an important role in neuropeptide metabolism and T-cell activation. A series of aminoacylpyrrolidine-2-nitriles, in which the carboxyl group of proline is replaced by a nitrile group, was synthesized as inhibitors of dipeptidyl-peptidase IV. All compounds were found to competitively inhibit a homogeneous preparation of the rat kidney enzyme with Ki values in the low to submicromolar range. The nitriles presumably react with the active-site serine to form an imidate adduct. The compounds were stable following incubation either for 20 h at 37 degrees C or 72 h at room temperature. They proved to be poor inhibitors of dipeptidyl-peptidase II and prolyl oligopeptidase. These studies demonstrate that the generally held concept that nitriles are poor inhibitors of serine proteinases needs to be reconsidered. Amino-acylpyrrolidine-2-nitriles by virtue of their ease of synthesis, stability, specificity, and inhibitory potency appear to be superior to other described dipeptidyl-peptidase IV inhibitors.

Animals↗
PubMed1994

Guinea pig membrane-bound aminopeptidase P is a member of the proline peptidase family.

Members of the newly recognized proline peptidase family share the ability to hydrolyze imide bonds and share six blocks of highly homologous amino acid sequences. We have found that guinea pig lung and kidney forms of aminopeptidase P, both forms bound to membranes via glycosyl phosphatidylinositol lipid anchors, share at least three of the six conserved blocks of amino acid sequences. In addition, aminopeptidase P acts as an aminoacylproline hydrolase and thus appears to be a member of the proline peptidase family.

Amino Acid Sequence↗
PubMed1998

Adsorption and Heat of Adsorption onto Polymer Particular Surface by Inverse Gas Chromatography

A theory of nonlinear inverse chromatography for arbitrary adsorption isotherms has been developed. Methods of investigating adsorption isotherms and heat of adsorption based on the analysis of chromatograms for different temperatures are suggested. Simple formulae for calculating of adsorption isotherms and heat of adsorption are derived. The adsorption isotherm and heat of adsorption of pyridine on particular poly(imide)siloxane have been investigated by inverse chromatography. Copyright 1998 Academic Press. Copyright 1998Academic Press

Journal Article↗
PubMed1986

Carboxyalkyl peptide inhibitors of kininase II: chiral synthesis.

Heretofore, carboxyalkyl peptide inhibitors of kininase II (e.g. N-[1-carboxy-3-phenylpropyl]-Ala-Pro, "enalaprilic acid") have been synthesized by means that yield racemic product. Typically, the secondary amine bond is formed by reacting an amino acid or dipeptide with a 2-keto carboxylic acid ester or imide. The group providing the 2-keto function must be used in excess, and the desired S,S,S isomer must be obtained by resolution procedures. We have developed a procedure whereby enalaprilic acid, RAC-X-64 and related compounds are synthesized stereospecifically and in relatively high yields.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Reaction mechanisms in peptide synthesis. Part 2. Tautomerism of the peptide bond.

We had concluded in previous work that ring opening of a 2-alkyl-5(4H)-oxazolone by water or ammonia leads to transient high-energy imidol intermediates which instantly tautomerize to the native amides. Using the MOPAC molecular orbital program, detailed geometric and energetic characteristics of the tautomerism of a peptide bond have been determined on the AM1 level. The results demonstrate that tautomerism of a peptide bond comprises a three-stage process involving three successive transition states and a bimolecular mechanism: (i) E----Z peptide bond isomerization followed by dimerization, (ii) concerted double-hydrogen exchange leading to an alpha-hydroxyimine (imidic acid) followed by splitting of the dimer, and (iii) Z----E N-methylimine inversion. While pathway (iii----ii----i) is predicted as a feasible route terminating in the formation of a peptide bond, the inverse route (iii----ii----i) is excluded as a possible initial step in the generation of a 5(4H)-oxazolone intermediate.

Ammonia↗
PubMed1993

Sympathoinhibition by rilmenidine in conscious rabbits: involvement of alpha 2-adrenoceptors.

Cardiovascular and sympathetic nervous system effects of the mixed alpha 2-adrenoceptor and imidazoline receptor agonist rilmenidine were studied in conscious rabbits chronically instrumented for the recording of the firing rate of renal sympathetic fibers. Separate experiments were carried out on pithed rabbits with electrically stimulated (2 Hz) sympathetic outflow. Drugs were administered intravenously in a cumulative manner. In conscious rabbits, rilmenidine 0.1, 0.3 and 1.0 mg kg-1 dose-dependently lowered blood pressure, renal sympathetic nerve activity, heart rate and the plasma concentration of noradrenaline and adrenaline. The effect on blood pressure and plasma catecholamines was maximal after 0.3 mg kg-1 whereas heart rate and renal sympathetic nerve activity decreased further after rilmenidine 1.0 mg kg-1. Yohimbine 0.1 and 0.5 mg kg-1, when injected subsequently, attenuated and at the higher dose abolished all effects of rilmenidine. The effects of rilmenidine were also antagonized by the alpha 2-adrenoceptor antagonist 2-(2,3-dihydro-2-methoxy-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imid azole HCl (RX821002; 0.1 and 0.5 mg kg-1). Yohimbine 0.1 and 0.5 mg kg-1 did not attenuate or attenuated only slightly the decrease of heart rate and renal sympathetic nerve activity produced by infusion of vasopressin. In pithed rabbits with electrically-stimulated sympathetic outflow, yohimbine 0.1 submaximally and yohimbine 0.5 mg kg-1 maximally increased the plasma noradrenaline concentration. The experiments show by direct measurement of sympathetic nerve firing and plasma catecholamines that rilmenidine causes sympathoinhibition in conscious rabbits, presumably through central sites of action.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1978

Metabolic and toxic behaviours of phthalimide derivatives in albino rat II. Placental passage of chloromethyl phthalimide, oxymethyl phthalimide and phthalimide--their fetal metabolism.

Chloromethyl phthalimide, oxymethyl phthalimide, and phthalimide are absorbed by the albino rat at a comparatively high rate. Only phthalimide, the metabolic product, will be recordable from fetuses, following oral administration of chloromethyl phthalimide and oxymethyl phthalimide topregnant rats. Those findings, in conjunction with metabolic studies applied to fetuses isolated by caesarian section, appear to suggest the occurrence of an intensive metabolism in fetal tissue. Certain differences established between results of thin-layer chromatography, on the one hand, and 15N studies, on the other, are likely to support the assumption that phthalimide is further metabolised by splitting the imide ring yielding phthalamic acid.

Animals↗