Synthesis and some properties of complexones,succinic acid derivatives

Approaches to the synthesis of complexones, succinic acid derivatives, from maleic acid and amino derivatives were considered. Acid-base properties of these complexones were studied.     

Gold-catalyzed multicomponent synthesis of aminoindolizines from aldehydes, amines, and alkynes under solvent-free conditions or in water

A gold(III)-catalyzed multicomponent coupling/cycloisomerization reaction of heteroaryl aldehydes, amines, and alkynes under solvent-free conditions or in water has been developed. This methodology provides rapid access to substituted aminoindolizines with high atom economy and high catalytic efficiency. Especially, the coupling of enantiomerically enriched amino acid derivatives produces the corresponding N-indolizine-incorporated amino acid derivatives without loss of enantiomeric purity.     

Expedient synthesis of threo-beta-hydroxy-alpha-amino acid derivatives: phenylalanine, tyrosine, histidine, and tryptophan

An expedient synthesis of enantiomerically pure threo-beta-hydroxy-alpha-amino acid derivatives of phenylalanine, tyrosine, histidine, and tryptophan is described. The NBS-mediated radical bromination of the N,N-di-tert-butoxycarbonyl protected alpha-amino acids and subsequent treatment with silver nitrate in acetone provided the trans-oxazolidinones predominantly. Cesium carbonate catalyzed hydrolysis then generated the beta-hydroxy amino acid derivatives in excellent overall yield.     

A novel synthesis of N-methyl asparagine,arginine, histidine,and tryptophan

[reaction: see text] N-Methyl amino acid residues in peptides modify several pharmacologically useful parameters, but synthesis of alkylated peptides is hampered by unavailability of N-methylated monomers. The syntheses of four N-methyl amino acids with basic side chains are presented. The side chains of these basic amino acids needed to be specially protected or constructed. This completes the set of 20 common L-amino acid N-methyl derivatives prepared via 5-oxazolidinone intermediates by our group.     

Stable gas-phase radical cations of dimeric tryptophan and tyrosine derivatives

Stable radical cations of dimeric amino acid derivatives of tryptophan and tyrosine were generated by collision-induced dissociation of [Cu(II)(diethylenetriamine)(amino acid derivative)2]*2+. The yields of the dimer radical cations were dependent on both the auxiliary ligand and the tryptophan or tyrosine derivatives used. Amino acid derivatives with an unmodified carboxylic acid group did not generate dimer radical cations. For the amino acid derivatives Ac-Trp-OMe and Ac-Trp-NH2 (Ac is N-acetyl; OMe and NH2 are the methyl ester and amide modifications of the C-terminal carboxylic group), no auxiliary ligand was required for generating the dimer radical cations. Collision-induced dissociation of the [Cu(II)(amino acid derivative)4]*2+ precursor generated the dimer radical cation [(amino acid derivative)2]*+. Stabilizing interactions, most likely involving hydrogen bonding, between the two amino acid derivatives are proposed to account for observation of the dimer radical cations. Dissociation of these ions yields protonated or radical cationic amino acid derivatives; these observations are consistent with the expectation of proton competition between monomeric units, whose proton affinities were calculated using density functional theory.     

Catalytic route to the synthesis of optically active beta,beta-difluoroglutamic acid and beta,beta-difluoroproline derivatives

Beta,beta-difluorinated amino acid derivatives were synthesized via Mg(0)-promoted defluorination of alpha-trifluoromethyl iminoester. Bromination of the difluoroenamine afforded the bromodifluoromethyl iminoester in good yield. Pd-catalyzed asymmetric hydrogenation of the bromodifluoromethyl iminoester and the subsequent transformations provided optically active beta,beta-difluoroglutamic acid and beta,beta-difluoroproline derivatives.     

Amino acid, fatty acid, and carbohydrate content of Artocarpus altilis (breadfruit)

A study is conducted to determine the amino acid, fatty acid, and carbohydrate content of breadfruit using high-performance liquid chromatography (HPLC) and gas chromatography (GC). An HPLC method is used for the determination of amino acids and fatty acids in breadfruit. Representative amino acid samples are derivatized with phenylisothiocianate and the resulting phenylthiocarbamyl derivatives are separated on a reversed-phase column by gradient elution with a 0.05M ammonium acetate buffer and 0.01M ammonium acetate in acetonitrile-methanol-water (44:10:46, v/v). Representative fatty acid samples are derivatized with phenacyl bromide and the resulting fatty acid phenacyl esters are separated on a reversed-phase column by gradient elution with acetonitrile and water. Amino acid and fatty acid derivatives are detected by ultraviolet detection at 254 nm. The analysis of the carbohydrates in breadfruit employs a GC method. Carbohydrates are derivatized using trimethylchlorosilane and hexamethyldisilazane to form trimethylsilyl ethers. Compounds in the samples are separated by the temperature programming of a GC using nitrogen as the carrier gas. Percent recoveries of amino acids, fatty acids, and carbohydrates are 72.5%, 68.2%, and 81.4%, respectively. The starch content of the breadfruit is 15.52 g/100 g fresh weight.     

Convenient synthesis of 3,4-methano-1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid and its derivatives as doubly constrained nonproteinogenic amino acid derivatives

Three strategies for the synthesis of the novel, doubly constrained, 3,4-methano-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and its derivatives were evaluated. Only cyclocondensation of the mono(triphenyl)phosphonium salt derived from 1, 2-bis(bromomethyl)benzene with N-alkoxycarbonyloxamates in 1, 2-dimethoxyethane in the presence of potassium carbonate and subsequent cyclopropanation with dimethylsulfoxonium methylide in dimethyl sulfoxide furnished suitable O- and N-protected derivatives of 3,4-methano-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in a convenient way. A detailed 2D DQF-COSY and 2D NOESY NMR analysis of the rotational isomerism of the latter bicyclic amino acid derivatives was performed. Various O- and N-protection protocols were worked out to afford access to a whole range of new derivatives of the title amino acid, suitable for peptide synthesis.     

Separation, identification, and quantification of amino acids in L-lysine fermentation potato juices by gas chromatography-mass spectrometry

The amino acid composition of L-lysine fermentation juices from potatoes and cane molasses from a green biorefinery has been determined by gas chromatography-mass spectrometry. N-Methyl-N-tert(butyldimethylsilyl)tri-fluoroacetamide (MTBSTFA) was used as derivatization reagent to prepare the t-butyldimethylsilyl derivatives of the amino acids present in the juices. The amino acids in these derivatives were identified from both their EI and CI mass spectra and their retention times in the gas chromatogram, and they were quantified employing the GC response signals relative to cycloleucine as internal standard.     

Synthesis, characterization and photodynamic activity of amino-substituted hypocrellin derivatives

Three new hypocrellin derivatives, amino- or amino acid-substituted on the side ring of hypocrellin B (HB), were synthesized by the reactions of HB with 3-methoxypropylamine, 6-aminohexanoic acid and gamma-amino-n-butyric acid, respectively. The structures of these compounds were characterized with proton nuclear magnetic resonance spectra, infrared spectra and mass spectra. The UV-visible absorption spectra, singlet oxygen-generating quantum yield and amphiphilicities of hypocrellin derivatives were measured and compared with HB, the parent compound. These derivatives showed strong absorption in the domain of the phototherapeutic window (600-900 nm) and improved amphiphilicity. HB and the derivatives were preliminarily tested for their photodynamic effects on human oral cavity epithelial carcinoma KB cell line in vitro. Two amino acid-substituted hypocrellins showed phototoxicity to the KB cell line. At an inhibitory dosage of 50% killing only 0.51 mumol L-1 compound 3 (or 0.88 mumol L-1 compound 2) and 0.5 J cm-2 irradiation were required. The hypocrellins exhibited some dark toxicity to the KB cell line. HB and amino acid-substituted hypocrellins showed lower dark toxicity to the KB cell line than amino-substituted hypocrellins in the assessment of cell survival.     

A GC-ECD method for estimation of free and bound amino acids, gamma-aminobutyric acid, salicylic acid, and acetyl salicylic acid from Solanum lycopersicum (L.)

A gas chromatograph with electron capture detection method for estimation of selected metabolites--amino acids (free and bound), gamma-aminobutyric acid (GABA), salicylic acid (SA), and acetyl salicylic acid (ASA) from tomato--is reported. The method is based on nitrophenylation of the metabolites by 1-fluoro-2, 4-dinitrobenzene under aqueous alkaline conditions to form dinitophenyl derivatives. The derivatives were stable under the operating conditions of GC. Analysis of bound amino acids comprised perchloric acid precipitation of protein, alkylation (carboxymethylation) with iodoacetic acid, vapor-phase hydrolysis, and derivatization with 1-fluoro-2,4-dinitrobenzene in that order. The metabolites were resolved in 35 min, using a temperature-programmed run. The method is rapid, sensitive, and precise. It easily measured the typical amino acids (aspartate, asparagine, glutamate, glutamine, alanine, leucine, lysine, and phenylalanine) used for identification and quantification of a protein, resolved amino acids of the same mass (leucine and isoleucine), satisfactorily measured sulfur amino acid (methionine, cystine, and cysteine), and quantified GABA, SA, and ASA, as well. The developed method was validated for specificity, linearity, and precision. It has been applied and recommended for estimation of 25 metabolites from Solanum lycopersicum (L.).     

Quantification by selected ion monitoring of pipecolic acid, proline, gamma-aminobutyric acid and glycine in rat brain

A procedure for the simultaneous analysis of brain pipecolic acid, proline, gamma-aminobutyric acid and glycine--amino acids with potent inhibitory actions on the central nervous system--was developed. The identification and quantification of the amino acids were performed with a gas chromatographic--mass spectrometric--computer system using deuterium-labelled amino acids as the internal standards. After separation of the amino acids by high-performance liquid chromatography, the methyl ester heptafluorobutyryl derivatives were prepared. The lower limit of quantification for this method is at the picomole level. The usefulness of this chromatographic procedure has been demonstrated by measurement of trace amounts of pipecolic acid in rat brain.     

α,β-Diketo nitriles as dielectrophiles. Formation of heterocyclic derivatives of amino acids

The reactions of mono Boc-protected amino monocarboxylic acids with phosphoranylideneacetonitrile yield ylido nitriles which on ozonolysis at low temperature form labile α,β-diketo nitriles. These derivatives may be used in situ for reaction with diamines or related dinucleophiles to yield hetero derivatives of interest as unnatural amino acid building blocks.     

Internally stabilized selenocysteine derivatives: syntheses, 77Se NMR and biomimetic studies

Selenocystine ([Sec]2) and aryl-substituted selenocysteine (Sec) derivatives are synthesized, starting from commercially available amino acid l-serine. These compounds are characterized by a number of analytical techniques such as NMR (1H, 13C and 77Se) and TOF mass spectroscopy. This study reveals that the introduction of amino/imino substituents capable of interacting with selenium may stabilize the Sec derivatives. This study further suggests that the oxidation-elimination reactions in Sec derivatives could be used for the generation of biologically active selenols having internally stabilizing substituents.     

Gas chromatographic quantification of amino acid enantiomers in food matrices by their N(O,S)-ethoxycarbonyl heptafluorobutyl ester derivatives

Several amino acid enantiomer derivatives were prepared with different chloroformates and analysed by gas chromatography (GC) on a Chirasil-L-Val GC column, at a temperature below 200 degrees C. Among them the N(O,S)-ethoxycarbonyl heptafluorobutyl esters presented the best compromise between short retention times, high yield responses and good resolution for almost all the tested amino acids. These derivatives proved to be suited for quantification of amino acids in aqueous media, with L-p-chlorophenylalanine as internal standard. The developed procedure was applied to several food samples for determination of their free amino acid profiles.     

The solute molecule—Rigid or partially flexible? calculation of benzodiazepineR F values as an example

Summary The liquid-chromatographic separation of the enantiomers of amino acid esters as benzophenone Schiff-base derivatives on polysaccharide-derived chiral stationary phases (CSPs) is described. The performance of Chiralcel OF was superior to that of the other CSPs for resolution of benzophenone imine derivatives of amino acid ethyl and methyl esters. The enantiomers of most of the amino acid esters examined as their benzophenone imine derivatives were resolved to baseline on Chiralcel OF. The L-(−) enantiomers of all the analytes were preferentially retained on Chiralcel OF. The resolution of several imine derivatives of amino acid esters was investigated, as was the effect of eluent composition on the resolution of amino acid ethyl esters as their benzophenone imine derivatives.     

Stereoselective synthesis of (2s,3s,4r)-4-amino-3-hydroxy-2-methyl-pentanoic acid,an amino acid constituent of bleomycin,by aldold condensation)

(2S,3S,4R)-4-Amino-3-hydroxy-2-methylpentanoic acid, a novel amino acid constituent of bleomycin, has been synthesized stereoselectively through aldol condensation of (R)-2-aminopropionaldehyde derivatives and E-vinyloxyboranes.     

Reversed-phase chromatography of phenylthiocarbamyl amino acid derivatives of physiological amino acids: an evaluation and a comparison with analysis by ion-exchange chromatography.

Reversed-phase chromatography of phenylthiocarbamyl (PTC) amino acid derivatives of physiological amino acids was evaluated and compared with the traditional method of ion exchange. The PTC amino acid derivatives were stable for at least 32 h at ambient temperature before injection. The relationship of detector response to concentration for the PTC derivatives was linear from 39 to 1250 pmol. With few exceptions, the within- and between-run precisions of plasma amino acid retention times were less than 0.2 and 0.3%, respectively; the within- and between-run precisions of their concentrations were less than 4.0 and 5.0%, respectively. Twenty-four plasma samples were quantitated by both reversed-phase and ion-exchange chromatography; fifteen of the twenty amino acids determined had correlation coefficients in the range 0.81-1.00. Nine non-standard amino acids and ten therapeutic drugs were added to plasma; D-glucosaminic acid and alpha-amino-beta-guanidinopropionic acid co-eluted with alpha-aminoadipic acid and threonine, respectively. Of the ten drugs added, only metronidazole and theophylline co-eluted with beta-alanine and histidine, respectively. The precision, stability, and sensitivity of the method render it ideal for the quantitation of plasma amino acids.     

Stereoselectivity and regioselectivity in nucleophilic ring opening in derivatives of 3-phenylisoxazolo[2,3-a]pyrimidine. Unpredicted dimerization and ring transformation. Syntheses of derivatives of pyrimidinylmethylamine, pyrimidinylmethylamino acid amides, and alpha-amino-2-pyrimidinylacetamides

The nucleophilic ring opening of the isoxazolone ring in 2-oxo-3-phenylisoxazolo[2,3-a]pyrimidine derivatives by optically active amino acid amides and ephedrine led to pyrimidinylmethylamino acid amides. Using amides of different L-amino acids and (-)-ephedrine resulted in different degrees of stereoselectivity. The degree of streoselectivity depended mostly on the nucleophile used. When applying hydroxy amines such as ephedrine, the attack via the secondary amino group was found as the favored regioselectivity. Upon replacement of the oxo group in position 2 in the phenylisoxazolo[2,3-a]pyrimidine system by an imino group, it was expected that the spontaneous decarboxylation that follows the ring opening would not take place, thus achieving amino acid amide derivatives of 2-pyrimidinylacetamide, which are closely related to pyrimidoblamic acid, an important constituent of Bleomycins, used in cancer therapy. However, by heating 5,7-dimethyl-2-imino-3-phenylisoxazolo[2,3-a]pyrimidine in solution, it underwent an unprecedented dimerization process that involved both the phenyl and the imino group. After protecting the imino group by acetylation, the ring opening by nucleophiles was possible, resulting in the formation of derivatives of 2-pyrimidinylacetamide. 2-Acetylimino-5,7-dimethyl-3-phenylisoxazolo[2,3-a]pyrimidine also underwent a ring transformation, yielding an interesting indolone derivative. Selectivity in ring opening and mechanisms of dimerization and ring transformation are discussed.     

Synthesis, characterization and cytotoxicity of new rotundic acid derivatives

Rotundic acid (RA, 1), a natural compound, exhibits potent tumor cell growth inhibiting properties. To date there are no reports on derivatives of RA. Furthermore, the 28-COOH position of RA might make it unstable and induced serious gastrointestinal side effects when it was applied in vivo. Therefore, in order to explore and make use of this compound, eight new amino acid derivatives of RA at the 28-COOH position were synthesized and evaluated for their cytotoxicities in vitro on three tumor cell lines including A375, HepG2 and NCI-H446. As a result, a few of these new amino acid derivatives showed stronger cytotoxicity. Compound 5a was found to have the best inhibition activity on the three tested human tumor cell lines with IC(50) values of less than 10 μM compared with RA treatment. Meanwhile, the cytotoxicity of compound 6b was significantly higher than that of RA on the A375 cell line and almost the same as RA on the HepG2 and NCI-H446 cell lines. Hence, compounds 5a and 6b may serve as potential lead compounds for the development of new anti-tumor drugs.