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At least 703 records · Page 39Linked to original sources
PubMed1999

Aryliminopropadienone-C-Amidoketenimine- Amidinoketene-2-Aminoquinolone Cascades and the Ynamine-Isocyanate Reaction.

Imidoylketenes 11 and oxoketenimines 12 are generated by flash vacuum thermolysis of Meldrum's acid derivatives 9, pyrrolediones 17 and 18, and triazole 19 and are observed by IR spectroscopy. Ketenimine-3-carboxylic acid esters 12a are isolable at room temperature. Ketenes 11 and ketenimines 12 undergo rapid interconversion in the gas phase, and the ketenes cyclize to 4-quinolones 13. When using an amine leaving group in Meldrum's acid derivatives 9c, the major reaction products are aryliminopropadienones, ArN=C=C=C=O (15). The latter react with 1 equiv of nucleophile to produce ketenimines 12 and with 2 equiv to afford malonic acid imide derivatives 16. N-Arylketenimine-C-carboxamides 12c cyclize to quinolones 13c via the transient amidinoketenes 11c at temperatures of 25-40 degrees C. This implies rapid interconversion of ketenes and ketenimines by a 1,3-shift of the dimethylamino group, even at room temperature. This interconversion explains previously poorly understood outcomes of the ynamine-isocyanate reaction. The solvent dependence of the tautomerism of 4-quinolones/4-quinolinols is discussed. Rotational barriers of NMe(2) groups in amidoketenimines 12c and malonioc amides and amidines 16 (24) are reported.

Journal Article↗
PubMed2000

Biosynthesis of cylindrospermopsin.

Studies on the biosynthesis of cylindrospermopsin (1), a potent hepatotoxin associated with the cyanobacterium Cylindrospermopsis raciborskii, indicate that 1 is an acetogenin with guanidinoacetic acid serving as the starter unit of the polyketide chain. Feeding experiments show that C14 and C15 of 1 are derived from C1 and C2 of glycine, respectively, and C4 through C13 arise from five contiguous acetate units attached head to tail. The methyl carbon on C13 originates from the C(1) pool. The starter unit, established by the incorporation of [guanidino-(13)C,alpha-(15)N]-guanidinoacetic acid into N16 and C17 of 1, does not appear to be formed from glycine by known amidination pathways. The origin of the NH-CO-NH segment in the uracil ring is also unknown.

Alkaloids↗
PubMed2000

Catalysis of a Diels-Alder Reaction by Amidinium Ions.

Amidines and guanidines are important functional groups in molecular recognition and host-guest chemistry. Here it is shown that lipophilic amidinium ions catalyze a cycloaddition reaction representing the key step of the Quinkert-Dane estrone synthesis. Hydrogen-bond-mediated association with the organic cation leads to an electrophilic activation of the dienophile and to enhanced rates of the Diels-Alder reaction. The observed effects are similar to those expected from mild Lewis acids. In competition experiments, amidinium catalysis favors the reaction of the less electron deficient dienophile.

Journal Article↗
PubMed2000

Total synthesis of the fumiquinazoline alkaloids: solution-phase studies.

Biomimetic total syntheses of glyantrypine, fumiquinazoline F, fumiquinazoline G, and fiscalin B were achieved in four steps from tryptophan methyl ester. In the key step, the anthranilamide residue in a linear tripeptide is dehydrated to a benzoxazine by reaction with triphenylphosphine, iodine, and a tertiary amine. The benzoxazines subsequently undergo rearrangement to the natural products via an amidine intermediate. This dehydrative oxazine to quinazoline route is applicable to a broad range of N-acylanthranilamides, including sterically hindered cases.

Alkaloids↗
PubMed2006

Imidazo[1,2-a]pyrazine-3,6-diones derived from alpha-amino acids: a theoretical mechanistic study of their formation via pyrolysis and silica-catalyzed process.

Imidazo[1,2-a]pyrazine-3,6-diones are unusual compounds composed of three alpha-amino acid fragments. These bicyclic amidines (BCAs) form under high temperatures or with the use of strong dehydrating reagents. We gave insight into the mechanisms of BCA formation via gas-phase pyrolytic and silica-catalyzed reactions of glycine (Gly) and alpha-aminoisobutyric acid (AIB) with related diketopiperazines (DKPs), using quantum chemical calculations. The entire process requires four steps: (1) O-acylation of DKP with free or silica-bonded amino acid, (2) acyl transfer from the oxygen to the nitrogen atom, (3) intramolecular condensation of the N-acyl DKP into a cyclol, and (4) elimination of water. To study step (1) at silica surface (modeled by H7Si8O12-OH cluster), we employed two-level ONIOM calculations (AM1:UFF, B3LYP/3-21G:UFF and B3LYP/6-31G(d):UFF); all gas-phase reactions were studied at the AM1, B3LYP/3-21G and B3LYP/6-31G(d) levels. The catalytic effect of silica was observed for both Gly and AIB: the activation energy in the O-acylation at the surface was lower by more than 9 kcal mol(-1) as compared to the gas-phase process. Contrary to the exothermic O-acylation, the gas-phase transfer reaction (step 2) was exothermic in both cases, but more favorable for Gly. The cyclocondensation of N-acylated DKPs into BCAs (steps 3 and 4) is endothermic for Gly and exothermic for AIB.

Amino Acids↗
PubMed1999

Chemical stability of an ester prodrug of a glycoprotein IIb/IIIa receptor antagonist in solid dosage forms.

DMP 754 is an ester prodrug of a glycoprotein IIb/IIIa receptor antagonist that undergoes ester and amidine hydrolysis in the presence of excipients. A means for the stabilization of DMP 754 was needed for the formulation of a stable drug product. Incorporation of a pH modifier in the formulation was used to control the microenvironment pH to coincide with that of maximum stability for DMP 754. Stability of tablets and capsules manufactured by (a) trituration process, (b) dry granulation process, and (c) wet granulation process was evaluated in HDPE bottles. Formulations manufactured by the dry and wet granulation processes contained disodium citrate as the pH modifier. Although aqueous wet granulation of a hydrolyzable drug is usually avoided, tablets and capsules manufactured by wet granulation were more stable in this case than those manufactured by the dry granulation process. This was attributed to the more uniform distribution of the pH modifier. Although the compression process resulted in enhanced degradation of the binary blend of DMP 754 and anhydrous lactose, tablets manufactured by the wet granulation process were more stable than capsules manufactured by the same process. Decreasing excipient-to-drug ratio enhanced the stability of tablets manufactured by the wet granulation process.

Amino Acids↗
PubMed2004

Colloid stability of lipid/polyelectrolyte decorated latex.

The colloid stability of supramolecular assemblies composed of the synthetic cationic lipid dioctadecyldimethylammonium bromide (DODAB) on carboxymethyl cellulose (CMC) supported on polystyrene amidine (PSA) microspheres was evaluated via turbidimetry kinetics, dynamic light scattering for particle sizing, zeta-potential analysis, and determination of DODAB adsorption on CMC-covered particles. At 0.1 g L(-1) CMC and 2 x 10(11) PSA particles/mL, CMC did not induce significant particle flocculation, and a vast majority of CMC-covered single particles were present in the dispersion so that this was the condition chosen for determining DODAB concentration (C) effects on particle size and zeta potentials. At 0.35 mM DODAB, charge neutralization, maximal size, and visible precipitation indicated extensive flocculation and minimal colloid stability for the DODAB/CMC/PSA assembly. At 0.1 g L(-1) CMC, isotherms of high affinity for DODAB adsorption on CMC-covered particles presented a plateau at a limiting adsorption of 700 x 10(17) DODAB molecules adsorbed per square meter PSA which was well above bilayer deposition on a smooth particle surface. The polyelectrolyte layer on hydrophobic particles was swelled and fluffy (ca. 11-nm hydrodynamic thickness), and maximal adsorption of DODAB lipid onto this layer produced a compressed composite cationic film with 20 mV of zeta potential and about 10-nm mean thickness. The assembly of cationic lipid/CMC layer/polymeric particle was stable only well above charge neutralization of the polyelectrolyte by the cationic lipid, at relatively large lipid concentrations (at and above 1 mM DODAB) with charge neutralization leading to extensive particle aggregation.

Adsorption↗
PubMed2006

Heteroaggregation in binary mixtures of oppositely charged colloidal particles.

Heteroaggregation (or heterocoagulation) rate constants have been measured in mixtures of well-characterized colloidal particles of opposite charge with multiangle static and dynamic light scattering. This technique permits routine measurements of absolute heteroaggregation rate constants, also in the presence of homoaggregation. Particularly with multiangle dynamic light scattering, one is able to estimate absolute heteroaggregation rate constants accurately in the fast aggregation regime for the first time. Heteroaggregation rate constants have also been measured over a wide range of parameters, for example, ionic strength and different surface charge densities. Amidine latex particles, sulfate latex particles, and silica particles have been used for these experiments, and they were well characterized with respect to their charging and homoaggregation behavior. It was shown that heteroaggregation rate constants of oppositely charged particles increase slowly with decreasing ionic strength, and provided the surface charge is sufficiently large, the rate constant is largely independent of the surface charge. These trends can be well described with DLVO theory without adjustable parameters.

Journal Article↗
PubMed2004

A concise synthesis of siphonodictidine.

Siphonodictidine (1) has been synthesized for the first time in a concise and regiocontrolled manner by using 2-(tert-butyldimethylsiloxy)-3-methylfuran (6) as the crucial building block. The silver trifluoroacetate-induced alkylation of 6 with omega-bromogeranyl acetate 7 gave the key gamma-lactone intermediate 8, which on subsequent reduction, conversion of the hydroxyl into the amino group, and amidination afforded siphonodictidine (1) in an overall yield of 25.7% from 6.

Alkylation↗
PubMed2000

Total syntheses of (-)-fumiquinazolines A, B, and I.

[structure] The first total syntheses of (-)-fumiquinazolines A, B, and I have been accomplished efficiently using the Pd-catalyzed cyclization of an iodoindole carbamate to construct the imidazoindolone moiety and the dehydrative cyclization of a diamide followed by rearrangement through an amidine to construct the quinazolone moiety.

Aspergillus fumigatus↗
PubMed2004

Cyclizations of N-stannylaminyl radicals onto nitriles.

[reaction: see text] Stannylaminyl radicals derived from radical reactions of Bu(3)SnH with azidoalkylmalononitriles exhibit highly efficient 5- and 6-exo cyclization onto either nitrile group to give aminoiminyl radicals that in turn are reduced to amidines or undergo successive 5-exo cyclization onto an internal alkene.

Journal Article↗
PubMed2006

Probing the structure of the Caulobacter crescentus ribosome with chemical labeling and mass spectrometry.

The ribosomal proteins of Caulobacter crescentus were amidinated before and after disassembly of the organelle and the results analyzed by mass spectrometry. Comparison with structural information from previous X-ray crystal studies of other bacterial ribosomes provides insight about the C. crescentus ribosome. In total, 47 of the 54 proteins present in the ribosome of C. crescentus were detected after labeling. The extent of derivatization for each protein is strongly dependent on the solvent accessibility of its target residues. Proteins of the ribosome stalk, which are known to be largely solvent-accessible, were labeled quite extensively. In striking contrast, other proteins that are known to be highly shielded in their subunits were labeled at very few of their potential sites. Furthermore, evidence that protein L12 binds to the ribosome via its N-terminal domain is consistent with previous findings.

Bacterial Proteins↗
PubMed2000

Reduction of amphetamine hydroxylamine and other aliphatic hydroxylamines by benzamidoxime reductase and human liver microsomes.

For the reduction of N-hydroxylated derivatives of strongly basic functional groups, such as amidines, guanidines, and aminohydrazones, an oxygen-insensitive liver microsomal system, the benzamidoxime reductase, has been described. To reconstitute the complete activity of the benzamidoxime reductase, the system required cytochrome b(5), NADH-cytochrome b(5)-reductase, and the benzamidoxime reductase, a cytochrome P450 enzyme, which has been purified to homogeneity from pig liver. It was not known if this enzyme system was also capable of reducing aliphatic hydroxylamines. The N-hydroxylation of aliphatic amines is a well-known metabolic process. It was of interest to study the possibility of benzamidoxime reductase reducing N-hydroxylated metabolites of aliphatic amines back to the parent compound. Overall, N-hydroxylation and reduction would constitute a futile metabolic cycle. As examples of medicinally relevant compounds, the hydroxylamines of methamphetamine, amphetamine, and N-methylamine as model compounds were investigated. Formation of methamphetamine and amphetamine was analyzed by newly developed HPLC methods. All three hydroxylamines were easily reduced by benzamidoxime reductase to their parent amines with reduction rates of 220.6 nmol min(-1) (mg of protein)(-1) for methamphetamine, 5.25 nmol min(-1) (mg of protein)(-1) for amphetamine, and 153 nmol min(-1) (mg of protein)(-1) for N-methylhydroxylamine. Administration of synthetic hydroxylamines of amphetamine and methamphetamine to primary rat neuronal cultures produced frank cell toxicity. Compared with amphetamine or the oxime of amphetamine, the hydroxylamines were significantly more toxic to primary neuronal cells. The benzamidoxime reductase is therefore involved in the detoxication of these reactive hydroxylamines.

Amphetamines↗
PubMed1990

Chemical stability of pentostatin (NSC-218321), a cytotoxic and immunosuppressant agent.

Pentostatin, an unusual nucleoside of natural origin, has been used for the treatment of hairy cell leukemia, as an immunosuppressant agent, and as an inhibitor of adenosine deaminase. The studies of the physicochemical properties and solution stability of pentostatin are important to the development of a parenteral formulation for extensive preclinical and clinical testing. Pentostatin displayed apparent pKa values at 25 +/- 0.1 degree C and ionic strength of 0.15 M of 2.03 +/- 0.03 and 5.57 +/- 0.14 (spectrophotometric) and 5.50 +/- 0.02 (potentiometric) for N1 and the amidine nitrogen in the seven-membered ring, respectively, which are the most likely protonation sites. The rates of degradation of pentostatin were determined as a function of pH, buffer concentration, and temperature. In the pH range 1.0-4.0, pentostatin undergoes acid-catalyzed glycosidic cleavage leading to the formation of the base compound, and 2-deoxyribose. A carbonium ion mechanism in which C-N bond cleavage was the rate-determining step was consistent with the data. In the pH range 6.5-10.5, the imine bond at C5 position in pentostatin is hydrolyzed to form the corresponding formamide. Pentostatin hydrolysis in this pH range was independent of pH. At pH greater than 11, pentostatin decomposes to nonchromophoric products probably through multiple-step base-catalyzed hydrolytic mechanisms. Pentostatin appears to be quite stable after reconstitution of a lyophilized experimental dosage form. Care must be taken if pentostatin is extensively diluted with 5% dextrose in water, as pentostatin stability is compromised at pH values less than 5.

Buffers↗
PubMed2001

Stoichiometric noncovalent interaction in molecular imprinting.

In this review article the function of the binding site monomers in the molecular imprinting procedure is discussed. Especially, new developments towards stoichiometric noncovalent interactions are highlighted. In stoichiometric noncovalent interactions template and binding site monomer in an 1:1 molar ratio are nearly completely bound to each other. This is only possible if the association constants are considerably high (Kass > 900 M(-1)). Using this type of interaction in molecular imprinting no excess of binding sites is necessary and binding sites are only located inside the imprinted cavity. Since all cavities can be reloaded these polymers show high capacity (e.g., for preparative application) and are especially suited for the synthesis of catalytically active imprinted polymers. Discussed are binding site interactions based on amidines (and guanidines), multiple hydrogen bonding, charge-transfer interactions, and host-guest inclusion. The systematic investigation of the underlying binding reaction is described in detail. With low-molecular weight model substances the thermodynamics of the association can be conveniently investigated, e.g., by NMR spectroscopy.

Binding Sites↗
PubMed2003

Solid-phase synthesis of 2-substituted 4-amino-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidines: an example of cyclization-assisted cleavage.

An efficient solid-phase synthesis of 2-substituted 4-aminopyrido[2,3-d]pyrimidines 12 by cyclization-assisted cleavage from resin is reported. The procedure starts by solid supporting an alpha,beta-unsaturated acid 8 to the Wang resin 13 by using DCC and 4-DMAP in THF. The resulting alpha,beta-unsaturated ester 14 is converted to the Michael adduct by treatment with malononitrile in NaOMe/THF. Such Michael addition constitutes the first example of a Michael reaction with malononitrile in solid-phase. Finally, the Michael adducts 15 are treated with an amidine system in MeOH to yield the corresponding pyridopyrimidines 12. Compounds 12 present three diversity centers R1, R2 and G. Having validated the chemistry on solid support, a 40-membered combinatorial library was obtained using this protocol.

Combinatorial Chemistry Techniques↗
PubMed2003

A one-pot microwave-assisted synthesis of pyrido[2,3-d]pyrimidines.

A high yield multicomponent reaction providing multifunctionalized pyrido[2,3-d]pyrimidines with up to four diversity centers in a one-pot microwave-assisted cyclocondensation of alpha,beta-unsaturated esters, amidine systems and malononitrile (or ethyl cyanoacetate) is described.

Algorithms↗