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At least 19 recordsLinked to original sources
PubMed2003

Organoruthenium(II) and (III) amidinates, (eta5-C5Me5)Ru(eta-amidinate) and (eta5-C5Me5)RuCl(eta-amidinate), as unique redox catalysts for the intramolecular Kharasch reactions: facile access to a pyrrolizidine alkaloid skeleton under mild conditions.

A novel organoruthenium(III) amidinate, (eta5-C5Me5)RuCl(eta-iPrN=C(Me)NiPr) (2), has been prepared by oxidation of organoruthenium amidinate, (eta5-C5Me5)Ru(eta-iPrN=C-(Me)NiPr) (1), by organic chlorides; both 1 and 2 are found to be good catalysts for atom-transfer cyclization of N-allyltrichloroacetamides which are useful for successful preparation of a pyrrolizidine alkaloid skeleton under mild conditions.

Journal Article↗
PubMed2005

Racemic N-aryl bis(amidines) and bis(amidinates): on the trail of enantioselective organolanthanide catalysts.

A series of racemic N-aryl-substituted trans-1,2-diaminocyclohexyl (t-1,2-DACH)-linked bis(amidines) were synthesised and their solution behaviour, and solid-state structures were investigated. The amidine functionalities within these compounds were extremely sterically hindered, with ortho-aryl substitution found to hinder N-Ar bond rotation. The results of these studies were used to rationalise the lack of reactivity of these compounds with [Y{N(SiMe(3))(2)}(3)]. Dilithiation of the t-1,2-DACH linked bis(amidines) did, however, proceed easily and the solution behaviour and solid-state structures of the resulting THF-solvated lithium amidinates were investigated. All the compounds showed similar structures in the solid-state, while NMR experiments indicated that the solid-state structures were likely to be maintained in solution. Attempted metathesis reactions with YCl(3) did not, however, yield the desired yttrium chloride complexes.

Amidines↗
PubMed2004

Amidine nitrosation.

The acidic nitrosation chemistry of nine acyclic secondary and tertiary amidines (Ph-N=C(R(1))NR(2)R(3); R(1) = H, CH(3), Ph; R(2), R(3) = H, Ph or (CH(3))(2) or C(CH(2))(4)) and several N-acylamidines was investigated. The principal nitrosation products were amides derived from the amino moiety and compounds derived from the benzenediazonium ion, which was independently trapped for quantitation in several cases. Tertiary amidines also produce nitrosamines in minor, but significant, yields. The benzamidines did not react, and the N-acylamidines hydrolyzed much more rapidly than they nitrosated. The data support the hypothesis that the reaction occurs by nitrosation on the imino nitrogen, followed by the addition of H(2)O to give a tetrahedral intermediate (alpha-hydroxynitrosamine) for which the main decomposition pathway generates an amide and a diazonium ion. In the case of the pyrrolidine-derived amidines, about 25% of the decomposition results in cleavage of the amine moiety, which nitrosates to give N-nitrosopyrrolidine. Pseudo-first-order rate constants for amidine nitrosation in aqueous acetic acid with excess nitrite at 25 degrees C ranged from (3 to 106) x 10(-5) s(-1), while the amidine basicity ranged over 5 pK(a) units. Rate constants corrected for amidine basicity showed the pyrrolidine derived amidines to be most reactive. The lack of benzamidine nitrosative reactivity is attributed to a very slow rate of H(2)O additon to the N-nitrosoamidinium ion and reversible nitrosation.

Amides↗
PubMed2002

Reduction of N-hydroxylated compounds: amidoximes (N-hydroxyamidines) as pro-drugs of amidines.

In order to examine the importance of metabolic cycles and in particular of reductions of N-hydroxylated compounds, the reversible metabolism at the amidine, guanidine, and amidinohydrazone nitrogen atoms of various drugs and model compounds was investigated. Many of these N-oxygenated metabolites are very easily reduced back into the starting materials. A comparison of the kinetic data for the N-hydroxylation and reduction suggests that the reduction should predominate in vivo. This could be verified by in vivo studies. Thus, N-hydroxylated amidines (amidoximes) can be used as pro-drugs of amidines. Because of their strong basicity, amidines, guanidines, and amidinohydrazones are protonated under physiological conditions, are very hydrophilic, and are usually not absorbed from the gastrointestinal tract. The N-hydroxylated derivatives of amidines (amidoximes), guanidines (N-hydroxyamidines), and amidinohydrazones (N-hydroxyamidinohydrazones) are less basic because of the introduction of the oxygen atom. They are absorbed from the gastrointestinal tract and then reduced to the active amidines, guanidines, and amidinohydrazones. The pro-drug principle was originally developed in our laboratory for pentamidine and then applied to other amidines such as sibrafiban and melagatran (ximelagatran). The enzymatic basis of N-oxidative processes is very well understood, whereas reductions have been less extensively investigated. We purified an enzyme system from pig and human liver consisting of cytochrome b5, its reductase, and a P450 enzyme, which is involved in the reduction of the N-hydroxylated compounds. Similar activities were found in all species studied so far. Furthermore, comparable reductive reactions could also be demonstrated with microsomal fractions from organs other than liver. In addition, mitochondria are highly capable of performing the reductions of these N-hydroxylated compounds. Thus, several organs and cell organelles are involved in the reduction explaining the extensive reduction of the pro-drugs in vivo underlying the suitability of the concept for drug development.

Amidines↗
PubMed1975

[Studies on the osmotic resistance and the viability of amidinated erythrocytes].

The present studies are concerned with properties of amidinated erythrocytes. The reactions of dimethyladipimidate with proteins in solution and red blood cells, respectively, result in an intermolecular cross-linking. Following an amidination of human serum albumin or human gamma-globulin cross-linked products of increased molecular weight have been demonstrated by polyacrylamide gel and immune electrophoresis. Human erythrocytes previously amidinated intensely, exhibit a restricted motility of membrane particles and cross-linked hemoglobin. Intensely amidinated erythrocytes are resistant against distilled water, and they do no longer agglutinate. The findings presumably indicate an increased permeability of the amidinated red cell membrane. The glycolytic activity was found to be normal in moderately amidinated erythrocytes. In comparison with normal red blood cells, previously moderately amidinated erythrocytes of the rat become sequestered more quickly after re-injection into the vascular system.

Amidines↗
PubMed2005

Nitrile-amidine coupling at Pt(IV) and Pt(II) centers. An easy entry to imidoylamidine complexes.

Treatment of trans-[PtCl4(RCN)2] (R = Me, Et, Ph, NEt2) with 2 equiv of the amidine PhC(=NH)NHPh in a suspension of MeCN (R = Me), CHCl3 (R = Et, Ph), or in CHCl3 solution (R = NEt2) results in the formation of the imidoylamidine complexes trans-[PtCl4{NH=C(R)N=C(Ph)NHPh}2] (1-4) isolated in good yields (66-84%). The reaction of soluble complexes 3 and 4 with 2 equiv of Ph3P=CHCO2Me in CH2Cl2 (40 degrees C, 5 h) leads to dehydrochlorination resulting in a chelate ring closure to furnish the platinum(IV) chelates [PtCl2{NH=C(R)NC(Ph)=NPh}2] (R = Ph, 5; R = NEt2, 6), accordingly, and the phosphonium salt [Ph3PCH2CO2Me]Cl. Treatment of 5 with 3 equiv of Ph3P=CHCO2Me at 50 degrees C for 5 d resulted in only a 30% conversion to the corresponding Pt(II) complex [Pt{NH=C(NEt2)NC(Ph)=NPh}2] (15). The reduction can be achieved within several minutes, when Ph2PCH2CH2PPh2 in CDCl3 is used. When the platinum(II) complex trans-[PtCl2(RCN)2] is reacted with 2 equiv of the amidine, the imidoylamidinato complexes [PtCl(RCN){NH=C(R)NC(Ph)=NHPh}] (8-11) and [PhC(=NH)NHPh] x HCl (7) are formed. The reaction of trans-[PtCl2(RCN)2] with 4 equiv of the amidine under a prolonged reaction time or treatment of [PtCl(RCN){NH=C(R)NC(Ph)=NHPh}] (8-11) with 2 more equiv of the amidine yields the complex bearing two chelate rings [Pt{NH=C(R)NC(Ph)=NHPh}2] (12-15). The treatment of cis-[PtCl2(RCN)2] (R = Me, Et) with the amidine gives ca. 50-60% yield of [PtCl2{NH=C(R)NHC(Ph)=NHPh}] (16 and 17). All of the platinum compounds were characterized by elemental analyses; FAB mass spectrometry; IR spectroscopy; 1H, 13C{1H}, and 195Pt NMR spectroscopies, and four of them (4, 6, 8, and 15) were also characterized by X-ray crystallography. The coupling of the Pt-bound nitriles and the amidine is metal-mediated insofar as RCN and PhC(=NH)NHPh do not react in the absence of the metal centers in conditions more drastic than those of the observed reactions. The nitrile-amidine coupling reported in this work constitutes a route to the synthesis of imidoylamidine complexes, some of them exhibiting luminescent properties.

Journal Article↗
PubMed2000

EPC syntheses and structure-activity relationships of hypoglycaemic semicyclic amidines.

A series of homochiral sterically hindered mono- and bicyclic amidines was prepared as hypoglycaemic agents by lethargic reaction of O-methylcaprolactim and 3-ethoxy-2-azabicyclo[2.2.2]oct-2-ene, respectively, with homochiral cis-2-substituted cyclopentane amines provided by asymmetrical reductive amination of racemic 2-substituted cyclopentanones. All compounds, except the cyclohexylmethyl-isoquinuclidone derivative which inhibited secretion at 100 microM, significantly stimulated insulin secretion 2-8-fold at 10 microM and 100 microM in INS-1 cells. The most potent activator was the 2-cyclopentyl-substituted caprolactam derivative 5e. The stimulatory effects on secretion increased with rising steric hindrance of both the amidine alpha-carbon and the bicyclic amidine moiety itself. Enantiomeric discrimination was observed for the 2-¿(cis-2-bulkysubstituted cyclopentyl)iminohexahydroazepine halides 5e and 5f and for the 3-¿(cis-2-substituted cyclopentyl)imino-2-azabicyclo¿2.2.2ŏctane halides 6a and 6c. The amidines depolarized INS-1 cells and generated action potentials, accompanied by a decrease of membrane conductance. Simultaneously [Ca(2+)](i) increased, probably due to Ca(2+)-entry through voltage-dependent Ca(2+)-channels. At high concentrations, where inhibition of secretion was observed, ¿Ca(2+)(i) still rose upon application of the amidines, indicating an additional inhibitory pathway downstream to the elevation of ¿Ca(2+)(i). Even at high concentrations (100 microM), the amidines had no toxic effects on insulin secreting INS-1 cells.

Amidines↗
PubMed1975

Effect of amidination of lysyl residues on the oxygen affinity of human hemoglobin. Specificity of methyl acetimidate for lysine C5(40)alpha.

Treatment of human oxyhemoglobin with methylacetimidate results in selective amidination of the epfilon-amino group of lysin C5(40)alpha. The modified hemoglobin exhibits increased oxygen affinity, high cooperatively, and normal Bohr effect. Hybrid molecules containing amidinated beta chains and normal alpha chains have normal ligand-binding properties, whereas hybrid molecules containing amidinated alpha chains have ligand-binding properties identical with fully amidinated hemoglobin. Amidination of deoxyhemoglobin produces only minimal changes in ligand-binding properties. We propose that amidination of lysine C5(40)alpha prevents its participation in the salt bond with histidine HC3(146)beta in deoxyhemoglobin, thus shifting the allosteric equilibrium in favor of the high affinity oxy conformation.

Amino Acid Sequence↗
PubMed2004

Structural characterization of diC14-amidine, a pH-sensitive cationic lipid used for transfection.

The structure of N-t-butyl-N'-tetradecyl-3-tetradecylaminopropionamidine (diC(14)-amidine) cationic vesicles, used for transfection, was investigated at different pH values and ionic strengths, through the analysis of the electron spin resonance (ESR) spectra of spin labels. Phospholipid derivatives, spin labeled at the 5th and 16th C-atoms along the hydrocarbon chain, incorporated in diC(14)-amidine bilayers, show that the bilayer structure is highly sensitive to the pH value of the medium, due to the two titratable groups present in the amphiphile. Compared with samples at higher pH values, the double charged diC(14)-amidine at pH 3 presents a rather non-organized bilayer gel phase, and a much lower gel-fluid temperature transition, in accord with a strong headgroup electrostatic repulsion. In addition, the structure was found to be highly dependent on the ionic strength of the medium. However, pH 3 diC(14)-amidine bilayer, in the fluid phase, was found to be slightly more closely packed than those at pH 7.4 or 9.0, which are less charged. Parallel to that, the larger isotropic hyperfine splitting measured for nitroxides in the center of the pH 3 diC(14)-amidine bilayer suggests a higher membrane polarity for the highly charged low pH sample.

Amidines↗
PubMed1990

Specific adsorption of serine proteases on coated silica beads substituted with amidine derivatives.

Amidine derivatives interact with serine proteases, the inhibition being due to interactions between amidine functions and the active sites of the enzymes. Five different types of amidine (substituted or unsubstituted) were coupled to coated silica beads, which had previously been coated with DEAE-dextran to minimize the non-specific interactions due to silanol groups. Coated silica functionalized with substituted amidines shows a strong affinity towards human plasmin. This affinity is probably due to hydrophobic interactions between the substituted amidine and the human plasmin structure. Coated silica grafted by p-aminobenzamide gives a specific interaction with human plasmin. The importance of ionic strength and the steric conformation of the ligand is discussed. This support was used to purify thrombin from crude preparations by high-performance affinity chromatography.

Adsorption↗
PubMed1984

Histamine H2 receptor antagonists. 1. Synthesis of N-cyano and N-carbamoyl amidine derivatives and their biological activities.

A large number of N-cyano amidine derivatives were prepared as potential histamine H2 receptor antagonists and evaluated for their inhibitory action on histamine-stimulated chronotropic response of isolated right atria from guinea pigs. Several selected compounds were assessed as inhibitors of gastric acid secretion induced by histamine in anesthetized dogs. Of these compounds, furan (8c) and [(diaminomethylene)amino]thiazole derivatives (16c) were found to be more potent than cimetidine in both assays. In contrast to the guanidine series, methyl substitution at the terminal nitrogen of the cyano amidines was detrimental to the activities. Furthermore, acid hydrolysis of the cyano amidines gave carbamoyl amidines, which proved to be more active than the cyano amidines, the converse of the case for guanidines. 3-[[[2-[(Diaminomethylene)amino]-4- thiazolyl]methyl]thio]-N'-carbamoylpropionamidine (16d) was the most potent of all the compounds tested and was approximately 30 times more active in vitro and 50 times more active in vivo than cimetidine.

Amidines↗
PubMed2005

Carbon-bound diazeniumdiolates from the reaction of nitric oxide with amidines.

[reaction: see text] The enediamine tautomer of a variety of substituted amidine free bases reacts with nitric oxide (NO) to produce compounds containing a carbon-bound diazeniumdiolate [R1R2R3C-N(O)=NO-] functional group (previously called "nitrosohydroxylamines"). The new reaction has been shown to be quite general, although the nature of the products does vary. Amidines containing more than one replaceable hydrogen produce polydiazeniumdiolates as intermolecular salts, while those in which only one diazeniumdiolation can occur provide zwitterionic salts. These diazeniumdiolated amidines are shown to be useful NO donor compounds which undergo very slow spontaneous dissociation on dissolution in pH 7.4 phosphate buffer to produce mixtures of NO and nitrous oxide containing mostly NO. The most advantageous manifestation of the new discovery is the preparation of the monodiazeniumdiolated amidine zwitterions. Reaction of the medically relevant alpha-adrenergic agonists tetrahydrozoline and idazoxan produced monodiazeniumdiolated amidine zwitterions from which NO release was observed for up to 28 days and showed little sign of ending. The reaction should be applicable to a variety of pharmaceutical agents, including NO synthase inhibitors, antitumor agents, and antibacterials.

Amidines↗
PubMed2003

Amidines derived from Pt(IV)-mediated nitrile-amino alcohol coupling and their Zn(II)-catalyzed conversion into oxazolines.

The reaction between the platinum(IV) complex trans-[PtCl(4)(EtCN)(2)] and the amino alcohols NH(2)CH(2)CH(2)OH, NH(2)CH(2)CH(Me)OH-(R)-(-), NH(2)CH(Ph)CH(2)OH-(R)-(-), NH(2)CH(Et)CH(2)OH-(R)-(-), NH(2)CH(Et)CH(2)OH-(S)-(+), and NH(2)CH(Pr(n)())CH(2)OH proceeds rapidly at room temperature in CH(2)Cl(2) to furnish the amidine complexes [PtCl(4)(HN=C(Et)NH(arcraise;)OH)(2)] (1-6) in good yield (70-80%). The related reaction between the platinum(II) complex trans-[PtCl(2)(EtCN)(2)] and monoethanolamine in a molar ratio of 1:2 in CH(2)Cl(2) results in the addition of 4 equiv of NH(2)CH(2)CH(2)OH per mole of complex to give [Pt(HN=C(Et)NHCH(2)CH(2)OH)(2)(NH(2)CH(2)CH(2)OH)(2)](2+) (7). Formulation of 1-6 is based upon satisfactory C, H, N elemental analyses, electrospray mass spectrometry, IR spectroscopy, and (1)H, (13)C((1)H), (15)N, and (195)Pt NMR spectroscopies, while the structures of trans-[PtCl(4)((Z)-NH=C(Et)NHCH(2)CH(2)OH)(2)] (1), trans-[PtCl(4)((Z)-NH=C(Et)NHCH(2)CH(Me)OH-(R)-(-))(2)] (2), and trans-[PtCl(4)((Z)-NH=C(Et)NHCH(Et)CH(2)OH-(R)-(-))(2)] (4) were determined by X-ray single-crystal diffraction. The Z-amidine configuration of the ligands is preserved in CDCl(3) solutions as confirmed by gradient-enhanced (15)N,(1)H-HMQC spectroscopy and NOE experiments. The amidines, formed upon Pt(IV)-mediated nitrile-amino alcohol coupling, were liberated from their platinum(IV) complexes 1, 3, and 4 by reaction with Ph(2)PCH(2)CH(2)PPh(2) (dppe) giving free NH=C(Et)NHCHRCH(2)OH (R = H 8, Et 9, Ph 10), with the substituents R of different types, and dppe oxides; the P-containing species were identified by (31)P((1)H) NMR spectroscopy. NOESY spectroscopy indicates that the liberated amidines retained the same configuration relative to the C=N double bond, i.e., syn-(H,Et)-NH=C(Et)NHCHRCH(2)OH. The liberated hydroxo-functionalized amidines 8-10 were converted into oxazolines (11-13) in the presence of a catalytic amount of ZnCl(2). A similar catalytic effect has also been reached using anhydrous MSO(4) (M = Cu, Co, Cd), CdCl(2), and AlCl(3).

Journal Article↗
PubMed1997

Human immunodeficiency virus type-1-specific immune responses induced by DNA vaccination are greatly enhanced by mannan-coated diC14-amidine.

Use of mannan-coated N-t-butyl-N'-tetradecyl-3-tetradecylamino-propionamidine (diC14-amidine) as an adjuvant for a DNA vaccine encoding glycoprotein 160 of human immunodeficiency virus type-1 (HIV-1) enhanced the antigen-specific immune responses. The role of interferon-gamma (IFN-gamma) and interleukin-12 in the mechanism of adjuvant action was also evaluated. Coating of diC14-amidine with mannan significantly augmented the HIV-specific delayed-type hypersensitivity reaction induced by the immunogenic DNA. HIV-1-specific cytotoxic T lymphocyte activity was also markedly enhanced by the mannan-diC14-amidine cocktail. An immunomodulatory effect of this cocktail was inhibited by treatment with anti-IFN-gamma monoclonal antibody in vivo, which suggests that IFN-gamma plays an important role in inducing cell-mediated immunity by the DNA vaccine containing this adjuvant. The results of both antigen-specific immunoglobulin isotype analysis and cytokine measurement showed that the immunogenic DNA incorporated into mannan-coated diC14-amidine elicits Th1-biased immune responses.

AIDS Vaccines↗
PubMed1995

Amidines are potent inhibitors of nitric oxide synthases: preferential inhibition of the inducible isoform.

We evaluated the ability of simple alkyl amidines to inhibit the activity of the inducible isoform of nitric oxide (NO) synthase in vitro. In immunostimulated J774 macrophages, 2-iminopiperidine (EC50 = 10 microM) and butyramidine (EC50 = 60 microM) were more potent than NG-methyl-L-arginine (EC50 = 70 microM) in inhibiting nitrite formation. The five amidines tested for their ability to inhibit the conversion of L-arginine to L-citrulline by bovine endothelial cell homogenates (a source of the constitutive, endothelial NO synthase isoform) were less effective than NG-nitro-L-arginine or NG-methyl-L-arginine. The rank-order of the potencies of the amidines against the endothelial NO synthase was, in general, similar to the rank-order of the pressor effects of these agents in anesthetized rats. Thus, certain amidines are potent inhibitors of NO synthase, and are more selective towards the inducible NO synthase than the commonly used L-arginine based NO synthase inhibitors.

Amidines↗
PubMed2003

Effect of amidine derivatives on nitric oxide production by Leishmania amazonensis promastigotes and axenic amastigotes.

The effects of pentamidine isethionate (reference drug) and N,N'-diphenyl-4-methoxy-benzamidine (test compound) on NO. production by Leishmania amazonensis promastigotes and axenic amastigotes were investigated by measuring nitrite, a by-product of nitric oxide released into culture supernatants. The NO. production by infective promastigotes was inhibited by OCH(3)-amidine in about 23.53% and by pentamidine in only 3.78%. In axenic amastigotes, the inhibition of NO. production by OCH(3)-amidine was significantly higher (52.94%; p=0.01) than that by pentamidine, which inhibited this radical production nonsignificantly (25.29%; p=0.1). The mechanism of amidine derivatives, as an antimicrobial agent, is unknown. However, other amidines, such as a diamidine (pentamidine), contain chemical structures shared by the guanidino group of the nitric oxide synthase substrate L-arginine, suggesting the possibility of an interaction with this enzyme or electronic factors (substituent constant) that alter physical and chemical properties significant for biological activity.

Amidines↗
PubMed2005

Mechanism of inactivation of inducible nitric oxide synthase by amidines. Irreversible enzyme inactivation without inactivator modification.

Nitric oxide synthases (NOS) are hemoproteins that catalyze the reaction of L-arginine to L-citrulline and nitric oxide. N-(3-(Aminomethyl)benzyl)acetamidine (1400W) was reported to be a slow, tight-binding, and highly selective inhibitor of iNOS in vitro and in vivo. Previous mechanistic studies reported that 1400W was recovered quantitatively after iNOS fully lost its activity and modification to iNOS was not detected. Here, it is shown that 1400W is a time-, concentration-, and NADPH-dependent irreversible inactivator of iNOS. HPLC-electrospray mass spectrometric analysis of the incubation mixture of iNOS with 1400W shows both loss of heme cofactor and formation of biliverdin, as was previously observed for iNOS inactivation by another amidine-containing compound, N5-(1-iminoethyl)-L-ornithine (L-NIO). The amount of biliverdin produced corresponds to the amount of heme lost by 1400W inactivation of iNOS. A convenient MS/MS-HPLC methodology was developed to identify the trace amount of biliverdin produced by inactivation of iNOS with either 1400W or L-NIO to be biliverdin IXalpha out of the four possible regioisomers. Two mechanisms were previously proposed for iNOS inactivation by L-NIO: (1) uncoupling of the heme peroxide intermediate, leading to destruction of the heme to biliverdin; (2) abstraction of a hydrogen atom from the amidine methyl group followed by attachment to the heme cofactor, which causes the enzyme to catalyze the heme oxygenase reaction. The second mechanistic proposal was ruled out by inactivation of iNOS with d3-1400W, which produced no d2-1400W. Detection of carbon monoxide as one of the heme-degradation products further excludes the covalent heme adduct mechanism. On the basis of these results, a third mechanism is proposed in which the amidine inactivators of iNOS bind as does substrate L-arginine, but because of the amidine methyl group, the heme peroxy intermediate cannot be protonated, thereby preventing its conversion to the heme oxo intermediate. This leads to a change in the enzyme mechanism to one that resembles that of heme oxygenase, an enzyme known to convert heme to biliverdin IXalpha. This appears to be the first example of a compound that causes irreversible inactivation of an enzyme without itself becoming modified in any way.

Amidines↗