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PubMed2005

Glucose handling in streptozotocin-induced diabetic rats is improved by tyramine but not by the amine oxidase inhibitor semicarbazide.

A soluble form of semicarbazide-sensitive amine oxidase (SSAO) circulating in plasma is known to increase in type 1 and 2 diabetes. This cuproenzyme generates hydrogen peroxide, ammonia, and aldehydes when oxidizing circulating biogenic or exogenous amines. Based on the angiotoxicity of these products, inhibition of SSAO has been proposed to prevent vascular complications of diabetes. However, substrates of SSAO and monoamine oxidase (MAO) have been recently evidenced to activate glucose utilisation in insulin-sensitive tissues and to exhibit antihyperglycemic actions. To determine whether amine oxidase blockade or activation could be beneficial for diabetes, we aimed at comparing the influence of prolonged treatments with semicarbazide (SSAO-inhibitor), pargyline (MAO-inhibitor), or tyramine (amine oxidase substrate) on amine oxidase activities and glycemic control in streptozotocin-induced diabetic rats. The increase in plasma SSAO was confirmed in diabetic rats, while MAO and SSAO were decreased in subcutaneous adipose tissue when compared with normoglycemic controls. Among the diabetic rats, only those receiving tyramine exhibited slightly decreased hyperglycemia and improved glucose tolerance. Adipocytes from untreated or treated diabetic rats shared similar sensitivity to insulin. However glucose uptake activation and lipolysis inhibition in response to amine oxidase substrates combined with vanadate were impaired in rats treated with amine oxidase inhibitors. Thus, amine oxidase inhibition does not improve metabolic control while prolonged administration of tyramine slightly improves glucose disposal. It is therefore concluded that amine oxidase activation by increased substrate supply elicits insulin-like actions that may be more beneficial in diabetes than SSAO inhibition formerly proposed to prevent vascular complications.

Adipocytes↗
PubMed2004

Mechanics of DNA flexibility visualized by selective 2'-amine acylation at nucleotide bulges.

We used selective acylation of 2'-amine-substituted nucleotides to visualize local backbone conformations that occur preferentially at bulged sites in DNA duplexes. 2'-Amine acylation reports local nucleotide flexibility because unconstrained 2'-amino nucleotides more readily reach a reactive conformation in which the amide-forming transition state is stabilized by interactions between the amine nucleophile and the adjacent 3'-phosphodiester group. Bulged 2'-amine-substituted cytidine nucleotides react approximately 20-fold more rapidly than nucleotides constrained by base-pairing at 35 degrees C. In contrast, base-paired 2'-amine-substituted nucleotides flanked by a 5' or 3' bulge react two- or six-fold more rapidly, respectively, than the perfectly paired duplex. The relative lack of 2'-amine reactivity for nucleotides adjacent to a DNA bulge emphasizes, first, that structural perturbations do not extend significantly into the flanking duplex structure. Second, the exquisite sensitivity towards very local perturbations in nucleic acid structure suggests that 2'-amine acylation can be used to chemically interrogate deletion mutations in DNA. Finally, these data support the mechanical interpretation that the reactive ribose conformation for 2'-amine acylation requires that the base lies out of the helix and in the major groove, a mechanistic insight useful for designing 2'-amine-based sensors.

Acylation↗
PubMed2000

Detection of carcinogenic aromatic amines in the urine of non-smokers.

Smoking is thought to be one of the most important anthropogenic risk factors involved in the development of urinary bladder cancer in humans. Tobacco smoke contains a complex mixture of chemicals including potent carcinogens such as aromatic amines. In the present study the amounts of several freebase aromatic amines including the potent carcinogens 2-aminonaphthalene and 4-aminobiphenyl have been analyzed in the urine of 48 German urban living smokers and non-smokers. The results indicate that (i) both groups excrete the identical set of four aromatic amines; (ii) smokers excrete approximately twice the total amount of these amines, but similar amounts of 2-aminonaphthalene and 4-aminobiphenyl are found in non-smokers; and (iii) the excreted aromatic amines are decomposed in the urine within a few hours thus, explaining why aromatic amines are difficult to detect in this matrix. Their decomposition could be prevented by adding small amounts of p-toluidine to the freshly collected urine. Unlike smokers the origin of aromatic amines detected in the urine of non-smokers is at present unknown. Based on the cotinine levels found in the urine of non-smokers environmental tobacco smoke can be excluded as a major source of aromatic amines. In addition, neither diesel exhaust-related nitroarenes nor the corresponding amino-derivatives, to which they may be metabolically converted, were found. The detected urinary levels of aromatic amines arising from sources other than tobacco smoke or diesel exhaust may play a role in the bladder cancer etiology of non-smokers.

2-Naphthylamine↗
PubMed1999

Cleavage of abasic sites in DNA by intercalator-amines.

Anthraquinone and naphthalene diimide intercalators with amine-containing side chains cleave plasmid DNA at abasic sites (apurinic or apyrimidinic (AP) sites). The intercalator-amine is substantially more effective than the amine itself; many intercalators with diamine side chains cleave most of the abasic sites at micromolar concentration (30 min at 37 degrees C). Intercalators with two amino moieties in the side chain are more efficient than those with one, arguing for a role for each of two amines in the cleavage mechanism. Side chains ending in tertiary amines are somewhat more effective than those ending in primary amines, indicating that imine formation is not required for cleavage at the abasic site. We also report a systematic study of abasic site cleavage by polyamines, including piperidine, spermine, spermidine and 12 other di-, tri- and tetra-amines. For polyamines as well as intercalator-amines, examples with three carbon atoms between neighboring nitrogens atoms cleave most efficiently. This may reflect a particularly favorable geometry for proton abstraction for these species. The effect of nitrogen-nitrogen spacing on the pKa values of the nitrogens may contribute as well. Overall, cleavage of plasmid DNA at adventitious abasic sites by intercalator-amines bearing two nitrogens in a single side chain occurs readily.

Amines↗
PubMedDate not supplied

Fluorescent labeling of drugs and simple organic compounds containing amine functional groups, utilizing dansyl chloride in Na(2)CO(3) buffer.

Fluorescent labeling of amine functional groups using dansyl chloride (DNS-Cl), and in sodium carbonate buffer, allowed the detection of 1 microg amounts of analytes. The methodology presented allows dansylation of primary, secondary, and tertiary amine groups at a temperature of 25 degrees C. The dansylation of tertiary amines involves a chemical reaction which removes one substituent (or branch) of the amine group. A one molar working concentration of Na(2)CO(3) is used, and is at pH 11.0. Compounds such as isopropylamine, dipropylamine, diethylamine, triethylamine, triisooctylamine, and N,N-dimethylaniline were labeled by use of DNS-Cl from samples obtained from a complex mixture of alkanes. The compound p-chloroaniline contains a primary amine group and is a solid at 25 degrees, quickly dissolves in the one molar sodium carbonate buffer and is dansylated in 15 min. Heroin, which contains a tertiary amine group, was extracted into ethyl acetate from an aqueous solution, then reacted with DNS-Cl. Benzocaine, a local anesthetic, was dansylated in 15 min. Tertiary amine groups incorporated in a rigid ring system, such as for caffeine, strychnine, and the ionic salt form of cocaine hydrochloride did not react with DNS-Cl under these conditions. The reaction time for tertiary amines was 2 h or less, and 15 min for compounds having primary and secondary amine groups. Separation of the dansylated compounds from unreacted DNS-Cl was accomplished by diethyl ether extraction of the aqueous reaction solution, followed by thin layer chromatography using various organic solvents such as acetone and methylene chloride.

Amines↗
PubMed2006

Formation of amines and aldehydes from parent amino acids during thermal processing of cocoa and model systems: new insights into pathways of the strecker reaction.

A method based on a derivatization with dansyl chloride and LC-MS-MS determination was developed for the quantitation of 2-methylbutyl-, 3-methylbutyl-, 2-phenylethyl-, 3-(methylthio)propyl-, and 2-methylpropylamine. Its application on unfermented, fermented, and roasted cocoas from Ghana and Sulawesi revealed an increase of all amines, except the 3-(methylthio)propylamine, during cocoa fermentation, suggesting an enzymic formation from the parent amino acids isoleucine, leucine, phenylalanine, and valine. However, a much more pronounced formation of most of the amines was measured after roasting of the cocoa, leading to concentrations in the milligrams per kilogram range. This result suggested a new "thermogenic" formation pathway of "biogenic amines". A comparison of the amounts of the amines and the aldehydes in roasted cocoa revealed similar concentrations, for example, for 2- and 3-methylbutanal and the respective amines, whereas the amounts of 2-phenylethylamine were much higher as compared to the amounts of phenylacetaldehyde. Strecker-type model systems, in which each parent amino acid was reacted with 2-oxopropanal, revealed the formation of both the amine and the aldehyde; however, in contrast to cocoa, the concentrations of the aldehydes were always much higher as compared to the amines. The results showed for the first time the thermally induced generation of "biogenic amines" from amino acids. Possible reasons for the different ratios of amines versus aldehydes formed during the roasting of cocoa or the model systems, respectively, are discussed.

Aldehydes↗
PubMed1995

Large steric effect in the substitution reaction of amines with phosphoimidazolide-activated nucleosides.

Aliphatic amines react with phosphoimidazolide-activated derivatives of guanosine and cytidine (ImpN) by replacing the imidazole group. The kinetics of reaction of guanosine 5'-phospho-2-methylimidazolide (2-MeImpG) with glycine ethyl ester, glycinamide, 2-methoxyethylamine, n-butylamine, morpholine, dimethylamine (Me2NH), ethylmethylamine (EtNHMe), diethylamine (Et2NH), pyrrolidine, and piperidine were determined in water at 37 degrees C. With primary amines, a plot of the logarithm of the rate constant for attack by the amine on the protonated substrate, log kSH(A), versus the pKa of the amine exhibits a good linear correlation with a Bronsted slope, beta nuc = 0.48. Most of the secondary amines tested react with slightly higher reactivity than primary amines of similar pKa. Interestingly, some secondary amines show substantially lower reactivity than might be expected: EtNHMe reacts about eight times, and Et2NH at least 100 times, more slowly than Me2NH although all three amines are of similar basicity. For comparison, the kinetics of reaction of guanosine 5'-phosphoimidazolide (ImpG) and cytidine 5'-phosphoimidazolide (ImpC) were determined with Me2NH, EtNHMe, and Et2NH, and similar results were obtained. These results establish that the increased steric hindrance observed with the successive addition of ethyl groups are not due to any special steric requirements imposed by the guanosine or the methyl on the 2-methylimidazole leaving group of 2-MeImpG. It is concluded that addition of ethyl and, perhaps, groups larger than ethyl dramatically increases the kinetic barrier for addition of aliphatic secondary amines to the P-N bond of ImpN. This study supports the observation that the primary amino groups on the natural polyamines are at least 2 orders of magnitude more reactive than the secondary amino groups in the reaction with ImpN.

Amines↗
PubMed2000

Plasma semicarbazide-sensitive amine oxidase (SSAO) is an independent prognostic marker for mortality in chronic heart failure.

AIMS: Experimental evidence has suggested that semicarbazide-sensitive amine oxidase is involved in vascular endothelial damage and in the process of atherosclerosis, through the formation of reactive aldehydes, hydrogen peroxide and ammonia from endogenous substrates. Recent evidence indicates that semicarbazide-sensitive amine oxidase may be identical with the vascular adhesion protein-1. In patients with diabetes mellitus and chronic heart failure the plasma activity is raised relative to the severity of the disease. The prognostic value of plasma semicarbazide-sensitive amine oxidase is not known. METHODS AND RESULTS: Plasma semicarbazide-sensitive amine oxidase activity was measured at baseline in patients with moderate to severe chronic heart failure who participated in a large European study (PRIME-II). The 372 patients who took part in a pre-defined substudy in The Netherlands were investigated and a survival follow-up (maximum 5.4 years, mean 3.4 years) was carried out. Within the follow-up period 195 patients died. Plasma semicarbazide-sensitive amine oxidase was higher at baseline in those who died than in the survivors (653+/-258 vs 540+/-242 mU. l(-1), P<0.001). Dividing the patients into two groups according to plasma values above or below the median value of 550 mU. l(-1), semicarbazide-sensitive amine oxidase was found to be a prognostic parameter for survival, both in univariate (P<0.0001) and in multivariate (P=0.0106) analysis. Semicarbazide-sensitive amine oxidase values >550 mU. l(-1)had a 1. 50 (95% CI, 1.10-2.04) times increased risk of death. CONCLUSION: The finding that plasma semicarbazide-sensitive amine oxidase is an independent prognostic marker for mortality in chronic heart failure supports the concept that an elevated plasma semicarbazide-sensitive amine oxidase level has deleterious effects, possibly due to vascular endothelial damage.

Aged↗
PubMed1976

Anion and amine uptake and uncoupling in submitochondrial particles.

1. Unlike chloroplasts, submitochondrial particles are not uncoupled by nigericin + KCl or NH4Cl. Also the uncoupling effect of lipophilic anions is largely independent of the addition of weak bases. 2. Low concentrations of permeant anions cause a shift of the steady-state energy level rather than a cycle of energy utilization. The degree of inhibition of ATP synthesis by tetraphenylboron is larger than required for the uptake of the anion. 3. Lipophilic anions such as bromthymolblue, bromcresolpurple, and 8-anilino-1-napthalene sulphonate cause a pH-independent, 50% uncoupling in submitochondrial particles at concentrations of 3, 30 and 30 muM, respectively. The passive interaction of bromthymolblue and bromcresolpurple appears as a pH-dependent distribution between two pHases. ATP causes a pH-independent slight shift in the anion distribution, with negligible anion accumulation. 4. Addition of amines to energized submitochondrial particles results in two types of effects; uptake of amines and uncoupling. While in chloroplasts amine uptake and uncoupling are closely associated, this is not the case in submitochondrial particles. The uncoupling effect is observed only with lipophilic and not with hydrophilic amines, and the degree of uncoupling increases with the lipophilicity of the amines. The amine uptake, on the other hand, is accompanied by negligible uncoupling. 5. While the uptake of amines is dependent on the presence of non-permeant anions, such as Cl-, the uncoupling effect is independent of Cl-. Furthermore the amine uncoupling is markedly enhanced by lipophilic anions. 6. The view is discussed that the uncoupling effect of lipophilic anions and lipophilic amines in submitochondrial particles is due to a catalytic energy dissipation rather than to a stoichiometry energy utilization. The molecular mechanism of uncoupling presumably involves a cycling of charges after a perturbation of the membrane structure.

Amines↗
PubMed2000

Influence of hygienic quality of raw materials on biogenic amine production during ripening and storage of dry fermented sausages.

The effect of the hygienic status of raw materials on biogenic amine production during ripening and storage (at 4 and 15 degrees C) of fermented sausages was studied. Two portions of fresh lean and back fat pork were stored for 5 days at -20 degrees C (treatment A) and at 4 degrees C (treatment B), respectively. Raw materials of treatment A maintained their hygienic quality high and low amine content. Raw materials of treatment B showed from 1 to 3 log (CFU/g) higher microbial counts and a biogenic amine index near 50 mg/kg, indicating poorer hygienic quality. The quality of raw materials influenced the composition and the concentration of biogenic amines produced during the ripening sausages. Sausages of treatment A (A-sausages) showed a large accumulation of tyramine (up to 100 mg/kg dm) followed by putrescine and cadaverine (<15 mg/kg). In contrast, B-sausages resulted in earlier and much greater amine production, and cadaverine, tyramine, and putrescine levels were 50-, 2.6-, and 6.5-fold higher than those of A-sausages. Other biogenic amines, such as octopamine, tryptamine, phenylethylamine, and histamine were also produced in B-sausages. The higher proteolysis and the lower pH of B-sausages might have favored the decarboxylase activity of microorganisms. Biogenic amine contents of sausages during storage depended on the raw materials used and storage temperature. No significant modification on the amine contents was observed during the storage of A-sausages at either temperature. Greater changes occurred in B-sausages stored at 15 degrees C than in those stored at 4 degrees C. Higher temperatures favored proteolytic and decarboxylase reactions, resulting in increased amine concentrations after storage.

Animals↗
PubMed1990

Metabolism and biodisposition of heterocyclic amines.

The metabolic pathways of activation and detoxification of heterocyclic aromatic amines are similar to those reported for other aromatic amines. In vitro studies have shown that oxidation of the exocyclic amine group by cytochrome P450 results in formation of the mutagenic N-hydroxylamine derivatives. However, metastable conjugates of the hydroxyamino metabolites have not been identified in biological fluids such as bile or urine of rodents. This is in contrast to the aromatic amines 2-acetylaminofluorene and 4-aminobiphenyl in which both the hydroxamic acid and the N-glucuronide of the hydroxylamine have been identified (Miller et al., 1960; Radomski et al., 1973). This suggests that either very low levels of the N-hydroxyamino metabolites of heterocyclic amines are formed or that they are not stable and react rapidly. Phase II conjugation reactions include N-glucuronidation and the unusual pathway of sulfamate formation for several of these amines including IQ and MeIQx. Conjugation to glutathione has not been reported to be a major route of in vivo metabolism and detoxification of heterocyclic amines. Studies conducted in vitro are few and inconclusive. One study has shown that glutathione may serve both to activate as well as to detoxify hydroxyamino-Trp-P-2 (Saito et al., 1983). While a second study demonstrated that depletion of cellular glutathione increased the binding of Trp-P-2 metabolites to DNA in hepatocytes (Mita et al., 1982). Thus the role that glutathione plays in protecting the cell against this class of genotoxins merits further investigation. Much data has been gathered on human exposure to heterocyclic amines and mechanisms of genotoxicity have been elucidated, however, risk estimation of cancer development in humans by these carcinogens is still uncertain. There may be differences between man and rodents in the absorption, metabolism and activation versus detoxification as well as rates of excretion of heterocyclic amines. Humans also are exposed to many other carcinogens and potential tumor promoters (Sugimura, and Sato, 1983). Tumor promoters may enhance the effects of carcinogens. Fortunately, there also are tumor inhibiting factors in the diet which may weaken the biological activity of carcinogens (Wattenberg, 1985). Such variables make it difficult to extrapolate carcinogenicity data from animal experiments to assess risk to human cancer development.(ABSTRACT TRUNCATED AT 400 WORDS)

Amines↗
PubMed1986

Amine sulfate formation in the central nervous system.

The sulfates of norepinephrine, dopamine (DA), and serotonin (5-hydroxytryptamine [5HT]) are present in the cerebrospinal fluid (CSF) of laboratory animals and humans. The amounts of sulfated amines in human CSF always greatly exceed the amounts of the free amines. The enzyme responsible for sulfation, phenol sulfotransferase (PST) (EC 2.8.2.1), has been detected in the brain tissue of several species, including humans. PST in the human brain has a high affinity for the amines but it is a low-capacity enzyme. Accordingly, sulfation appears to be of greater significance in the economy of the amines under quiescent conditions than during conditions of increased release of transmitter. Recent evidence suggests that a fraction of the conjugated amines in CSF enters from plasma because in the African green monkey, DA sulfate and 5HT sulfate cross the blood-CSF barrier after i.v. injection. In addition, in humans there are no increases in the concentration of amine sulfates from lumbar to ventricular CSF that would also be compatible with a partly peripheral origin for the amine sulfates. However, it appears that at least a portion of the amine sulfates in CSF originate in the central nervous system because the ratios of [CSF amine sulfates]/[plasma sulfates] are never as high after i.v. injection as under basal conditions.

Animals↗
PubMed1984

Alterations of the intestinal microflora by diet, oral antibiotics, and Lactobacillus: decreased production of free amines from aromatic nitro compounds, azo dyes, and glucuronides.

F344 rats were fed compounds containing a nitro, azo, or amine-glucuronide group-2-nitronaphthalene (CAS: 581-89-5), 2-nitrofluorene (CAS: 607-57-8; 2-nitro-9H-fluorene), 4-phenylazo-2-naphthol (CAS: 6410-10-2; 1-[(4-nitrophenyl)azo]-2-naphthol), and 2-naphthylamine-N-D-glucuronide--and the formation of free amines was measured in the feces. The effects of diet (mean vs. grain), administration of antibiotic, and the feeding of Lactobacillus acidophilus were evaluated. Meat-fed rats given 2-nitronaphthalene had approximately 4 times higher concentration of free amines in their feces as compared to the concentration in grain-fed rats. In a similar experiment with 2-naphthylamine-N-D-glucuronide, the meat-fed animals had approximately 1.5 times more of the free amines and 50% less of the conjugates in their feces. When meat-fed animals were given L. acidophilus with 2-nitrofluorene or 2-naphthylamine-N-D-glucuronide, they had significantly lower free amines and higher concentrations of conjugates in their feces than did the meat-fed controls. Similarly, erythromycin or tetracycline decreased the fecal amine production in meat-fed animals that had received 2-nitrofluorene or 4-phenylazo-2-naphthol. In another experiment, erythromycin inhibited the production of free amines from 2-naphthylamine-N-D-glucuronide in rats fed a high-fat diet. Studies of fecal enzymes revealed lower levels of beta-D-glucuronidase, nitroreductase, and azoreductase in grain-fed rats and in meat-fed animals also given antibiotics or lactobacilli. These experiments showed that intestinal flora have the ability to convert exogenously administered aromatic nitro and azo compounds and an amine-glucuronide compound to free amines. The rate of these conversions was affected by diet and by oral administration of antibiotics and lactobacilli.

Amines↗
PubMed1995

Complex formation of heterocyclic amines with porphyrins: its use in detection and prevention.

Porphyrins can suppress mutagenicity of heterocyclic amines. We have shown using the Ames Salmonella test that the mutagenicity of heterocyclic amines is efficiently inhibited by addition of hemin, the red blood porphyrin, in the assay mixture. In this suppression, hemin acts in two ways; inhibition of metabolic activation and suppression of the mutagenicity in the metabolically activated heterocyclic amines. In both of these actions, a complex formation between the porphyrin molecule and the planar molecules of heterocyclic amines seems to play a role. Complex formation and its use in detecting heterocyclic amines in various samples can be seen in the case for copper phthalocyanine, a blue pigment with a porphyrin-like structure. Cellulose bearing copper phthalocyanine trisulfonate as ligand was found to be a selective adsorbent for polycyclic compounds. This adsorbent, named blue cotton/blue rayon, adsorbs polycyclics in aqueous media by forming complexes on the ligand molecules, and releases the adsorbed compounds in organic solvents, such as in methanol plus a small amount of ammonia. The ease in manipulation and its high efficiency have made the blue cotton/blue rayon technique a means now widely used in detecting heterocyclic amines and other polycyclic mutagens in crude samples such as food, urine, and even river water. Chlorophyll, a green plant porphyrin, is another example. Chlorophyll and its stable form, chlorophyllin, have been shown to be inhibitory against the mutagenicity of heterocyclic amines. We have prepared Sepharose-supported chlorophyllin and have shown that heterocyclic amines are adsorbable to this ligand in a reversible fashion. Complex formation between chlorophyllin and heterocyclic amines is also suggested from spectrophotometric studies. A preliminary in vivo study has shown that chlorophyllin is effective in diminishing the cooked beef-derived urinary mutagenicity in humans.

Amines↗
PubMed2007

Mechanism of the copper-free palladium-catalyzed Sonagashira reactions: multiple role of amines.

Amines used as bases in copper-free, palladium-catalyzed Sonogashira reactions play a multiple role. The oxidative addition of iodobenzene with [Pd(0)(PPh(3))(4)] is faster when performed in the presence of amines (piperidine>morpholine). Amines also substitute one ligand L in trans-[PdI(Ph)(L)(2)] (L=PPh(3), AsPh(3)) formed in the oxidative addition. This reversible reaction, which gives [PdI(Ph)L(R(2)NH)], is favored in the order AsPh(3)>PPh(3) and piperidine>morpholine. Two mechanisms are proposed for Sonogashira reactions, depending on the ligand and the amine. When L=PPh(3), its substitution by the amine in trans-[PdI(Ph)(PPh(3))(2)] is less favored than that of the alkyne. A mechanism involving prior coordination of the alkyne is suggested, followed by deprotonation of the ligated alkyne by the amine. When L=AsPh(3), its substitution in trans-[PdI(Ph)(AsPh(3))(2)] by the piperidine is easier than that by the alkyne, leading to a different mechanism: substitution of AsPh(3) by the amine is followed by substitution of the second AsPh(3) by the alkyne to generate [PdI(Ph)(amine)(alkyne)]. Deprotonation of the ligated alkyne by an external amine leads to the coupling product. This explains why the catalytic reactions are less efficient with AsPh(3) than with PPh(3) as ligand.

Journal Article↗
PubMed1980

Reactions of the alkylating agent tris(2-chloroethyl)-amine with the erythrocyte membrane. Effects on shape changes of human erythrocytes and ghosts.

The influence of tris(2-chloroethyl)amine on shape changes of human erythrocytes and ghosts was studied in vitro and correlated with alterations in the molecular structure of the membrane. (1) Reaction with 1--2 mM tris(2-chloroethyl)amine, a concentration which caused polymerisation of spectrin as detected by sodium dodecyl sulphate polyacrylamide gel electrophoresis, protected intact erythrocytes against metabolically induced shape changes. (2) When induced by Mg2+-ATP, ghosts porepared from alkylated erythrocytes underwent normal changes in shape. However, when ghosts were treated directly with tris(2-chloroethyl)amine, no Mg2+-ATP-induced shape changes occurred. This fixation in shape appeared to be due to a higher degree of reaction with the alkylating agent. (3) The amount of chlorpromazine necessary for transformation of erythrocytes into stomatocytes was increased for tris(2-chloroethyl)amine-pretreated cells and was dependent on the degree of reaction with tris(2-chloroethyl)amine. (4) Deformability of red cells after reaction with tris(2-chloroethyl)amine was estimated by measuring their rheological behaviour in glass capillary arrays. A slight reduction of the flow rate was observed for cells alkylated with 1--2 mM tris(2-chloroethyl)amine. (5) Extractability of spectrin was diminished and corresponded to the degree of spectrin polymerisation. (6) No difference in the incorporation of 32P by alkylated and untreated cells was found. Sodium dodecyl sulphate polyacrylamide gel electrophoresis and autoradiography of the membrane proteins from 32-P-treated cells showed that the spectrin component 2 and the polymerisation products generated by the reaction with tris(2-chloroethyl)amine were labelled. It is suggested that the observed conservation of cell shape is preferentially caused by the reaction of tris(2-chloroethyl)amine with spectrin.

Alkylating Agents↗
PubMed2001

Concerted mechanisms of the reactions of 2,4,6-trinitrophenyl methyl carbonate and 2,4,6-trinitrophenyl acetate with secondary alicyclic amines.

The reactions of secondary alicyclic amines with 2,4,6-trinitrophenyl methyl carbonate (TNPMC) and 2,4,6-trinitrophenyl acetate (TNPA) are subjected to a kinetic study in aqueous solution, 25.0 degrees C, ionic strength 0.2 (KCl). The reactions are studied by following spectrophotometrically (360 nm) the release of the 2,4,6-trinitrophenoxide anion. Under amine excess, pseudo-first-order rate coefficients (k(obsd)) are found. Plots of k(obsd) vs [amine] are linear, with the slope (kN) independent of pH. The Brönsted-type plots (log k(N) vs pK(a) of the conjugate acid of the amines) are linear, with slopes beta = 0.41 and beta = 0.36 for the reactions of TNPA and TNPMC, respectively. The predicted breaks of the Brönsted plots for stepwise mechanisms are pK(a)0 = 6.8 and 7.3, respectively. The lack of Brönsted breaks for these reactions and the values of the Brönsted slopes are consistent with concerted mechanisms. By comparison of the reactions under investigation among them and with similar aminolysis and pyridinolysis, the following conclusions can be drawn: (i) Secondary alicyclic amines react with TNPA and TNPMC by concerted mechanisms. (ii) TNPA is more reactive toward these amines than TNPMC due to the greater electron release of MeO from the latter substrate. (iii) The change of 2,4-dinitrophenoxy to 2,4,6-trinitrophenoxy in the zwitterionic tetrahedral intermediate (T+/-) formed in the reactions of the title amines with 2,4-dinitrophenyl acetate greatly destabilizes T+/-. (iv) Secondary alicyclic amines destabilize T+/- relative to pyridines. (v) The intermediate T+/- formed in the reactions of the title amines with S-(2,4,6-trinitrophenyl) acetate is greatly destabilized by substitution of S-(2,4,6-trinitrophenyl) by O-(2,4,6-trinitrophenyl) as the leaving group.

Journal Article↗
PubMed2004

Effects of amine nature and nonleaving group substituents on rate and mechanism in aminolyses of 2,4-dinitrophenyl X-substituted benzoates.

Second-order rate constants have been measured for the reactions of 2,4-dinitrophenyl X-substituted benzoates (1a-f) with a series of primary amines in 80 mol % H(2)O/20 mol % DMSO at 25.0 +/- 0.1 degrees C. The Brønsted-type plot for the reactions of 1d with primary amines is biphasic with slopes beta(1) = 0.36 at the high pK(a) region and beta(2) = 0.78 at the low pK(a) region and the curvature center at pK(a) degrees = 9.2, indicating that the reaction proceeds through an addition intermediate with a change in the rate-determining step as the basicity of amines increases. The corresponding Brønsted-type plot for the reactions with secondary amines is also biphasic with beta(1) = 0.34, beta(2) = 0.74, and pK(a) degrees = 9.1, indicating that the effect of amine nature on the reaction mechanism and pK(a) degrees is insignificant. However, primary amines have been found to be less reactive than isobasic secondary amines. The microscopic rate constants associated with the aminolysis have revealed that the smaller k(1) for the reactions with primary amines is fully responsible for their lower reactivity. The electron-donating substituent in the nonleaving group exhibits a negative deviation from the Hammett plots for the reactions of 1a-f with primary and secondary amines, while the corresponding Yukawa-Tsuno plots are linear. The negative deviation has been ascribed to stabilization of the ground state of the substrate through resonance interaction between the electron-donating substituent and the carbonyl functionality.

Journal Article↗