Synthesis of Tenuilobine,a Bis-polyamine Alkaloid from Oncinotis tenuiloba,and Its Transamidation to Isotenuilobine

From the leaves of Oncinotis tenuiloba STAPF , a novel polyamine alkaloid, tenuilobine ( 9 ), was isolated. This paper presents the synthesis of 9 , as well as the base-catalyzed Zip reaction of 9 , leading to the transamidation product isotenuilobine ( 10 ). The structure of 10 was further confirmed by 2D-NMR correlation spectroscopy. For analytical purposes, the bis-polyamines 9 and 10 were converted into their pentaacetyl derivatives 12 and 11 , respectively, which were readily separable by reverse-phase HPLC.     

Synthetische Analoga von niedermolekularen Spinnentoxinen mit Acyl-polyamin-Struktur

Synthetic Analogues of Low-Molecular-Weight Acyl-polyamine Spider Toxins Low-molecular-weight spider and wasp toxins are selective inhibitors of glutamate receptors of the central nervous system and consist of a polyamine backbone and one or several carboxylic acids and/or amino acids linked by a peptide-like bond. The syntheses of twelve analogues of spider and wasp toxins are described ( 10a – c , 15a – c , 20a – c , 25a – c ) having the general structure of acyl, arylacyl, or heteroarylacyl → DL -alanyl → ω-aminoacyl → N¹-spermidine, with variation in the acyl and the ω-aminoacyl part.     

Solid‐Phase Synthesis of Polyamine Spider Toxins and Correlation with the Natural Products by HPLC‐MS/MS

A recently developed new and divergent approach for the solid‐phase synthesis of polyamines and polyamine derivatives was extended to the preparation of linear pentamines, and it was applied to the synthesis of three quartets of isomeric polyamine spider toxins. The twelve synthetic acylpolyamines were investigated by HPLC‐UV(DAD)‐MS and HPLC‐UV(DAD)‐MS/MS and compared with the natural products in the complex mixture of the venom of Agelenopsis aperta. The comparative investigation supported the structures and assignments of seven previously found toxins and allowed the identification of an additional five polyamine derivatives in the natural sample. The MS/MS study of the isomerically pure polyamine derivatives revealed furthermore a characteristic pattern for the fragmentation of these compounds, which can possibly be used as evidence in the trace analysis of other polyamine derivatives.     

Synthesis of polyamines and polyamine toxins. An improved alkylation procedure

Polyamines and polyamine toxins are biologically important molecules, having modulatory effects on nucleotides and proteins. Here we present an improved alkylation procedure, which allows sequential synthesis of polyamines and polyamine toxins on solid phase using N-protected aminoalkyl halides and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) as base. The feasibility of the procedure is demonstrated with the synthesis of the native polyamine toxin, PhTX-433, as well as an analogue, PhTX-56, which is a very potent and subtype selective glutamate receptor antagonist.     

Herstellung von Analoga von Polyamin-Spinnentoxinen

Synthesis of Polyamine Analoga of Spider Toxins Within the last few years, polyamine toxins derived from various arthropods raised increasing interest due to their interaction with glutamate receptors of insects and invertebrates. Compounds 51 and 52 (Scheme 5) were prepared together with 53–58 to study a new pathway to Ala-, Lys-, and Gln-derived polyamine toxins according to Scheme 6.     

The total synthesis of argiotoxins 636, 659 and 673

Practical syntheses of three polyamine spider toxins isolated from the venom of Argiope aurantia are described.     

Philanthotoxins. A mass spectrometric investigation

A method employing liquid secondary-ion mass spectrometry (SIMS) in conjunction with metastable-ion measurements (linked scanning at constant B/E) to obtain sequence-specific information for three synthetic polyamine isomers was developed. The normal liquid SIMS spectra gave molecular weight information, but important sequence ions were of low intensity or obscured by the background. The metastable-ion spectra contained important fragment ions in particular due to cleavage along the polyamine chain. One of the three synthetic isomers was identical with a toxin present in the venom of the digger wasp. In conjunction with nuclear magnetic resonance spectroscopic studies, this should be a powerful method for the structural characterization of other closely related toxins present in the venom of this wasp.     

Synthetic Analogues of Naturally Occurring Spider Toxins: Synthesis of 2‐(Hydroxyphenyl)propanamides of Spermidine and Spermine

In a study on structure‐activity relationships of spider toxins, six model compounds, namely the spermidine derivatives 6 , 8 , and 16 as well as the spermine derivatives 24 , 27 , and 32 were synthesized. The synthesis proceeds through stepwise construction of the polyamine backbone, including protection and deprotection of the amino functions. The differentiation of the derivatives by analytical and spectroscopic methods is discussed.     

大环多胺的超分子识别作用

就大环多胺及配合物为主体分子对金属离子,磷酸根,氨基酸,肽及核苷酸等的超分子识别作用、影响因素和识别机制进行了简述。     

Side-chain-anchored N(alpha)-Fmoc-Tyr-OPfp for bidirectional solid-phase synthesis

[reaction: see text] A mild resin-immobilization strategy employing a readily prepared trityl bromide resin for anchoring building blocks via a phenol group has been developed. With N(alpha)-Fmoc-Tyr-OPfp as a starter building block, it was possible to prepare asymmetrically substituted hybrids of spider- and wasp-type polyamine toxins using solid-phase peptide synthesis conditions.     

Solid-phase polyamine synthesis using piperazine and piperidine building blocks

[reaction: see text]. Polyamines containing piperidine and piperazine moieties have been synthesized on solid support using SN2 alkylation of resin-bound secondary amines with 2-nitrobenzenesulfonates (nosylates). The effect of solvent on this alkylation was investigated. The methodology was employed for the total synthesis of novel analogues of wasp polyamine toxins (philanthotoxins).     

Solid-phase synthesis of N-labeled acylpentamines as reference compounds for the MS/MS investigation of spider toxins

A solid-phase route for synthesis of ¹⁵N-labeled acylpolyamines is described. Utilizing alkylation at benzylic N-atom as a key step, ¹⁵N-atoms are incorporated by stepwise construction of the polyamine framework on the solid support. The derivatives were used as reference compounds for the investigation of the MS/MS behavior of spider toxins.     

Solid phase syntheses of polyamine toxins HO-416b and PhTX-433. Use of an efficient polyamide reduction strategy that facilitates access to branched analogues

[structure--se text] Polyamine toxins HO-416b (1) and PhTX-433 (2) isolated from the venom of insects are important lead compounds in neuropharmacology. Their total synthesis has been achieved on a trityl derivatized resin in good yield and purity using a mild borane reduction protocol to access the polyamine chains from polyamide precursors. The synthesis of PhTX isomer 3 demonstrates the potential of this strategy for the generation of branched analogues.     

Solid-phase synthesis of rigid acylpolyamines using temporary N-4,4'-dimethoxytrityl protection in the presence of trityl linkers

An N-protection protocol employing the 4,4'-dimethoxytrityl (Dmt) group in combination with borane reduction of resin-bound polyamides was shown to be an efficient methodology that enables synthesis of novel analogues of natural acylpolyamine toxins. Thus, three philanthotoxins containing polyamine chains with piperidyl and cyclohexyl structural elements, which introduce conformational rigidity, increased lipophilicity, and altered proteolytic properties, were obtained in 39-44% overall yield.     

Decomposition of N‐hydroxylated compounds during atmospheric pressure chemical ionization

N‐Hydroxylated polyamine derivatives were found to decompose during the ionization process of liquid chromatography‐atmospheric pressure chemical ionization‐mass spectrometry (LC‐APCI‐MS) experiments. The phenomenon was studied with a model compound, a synthetic N‐hydroxylated tetraamine derivative. It was found that reduction, oxidation and water elimination occurred during APCI to generate the corresponding amine, N‐oxide, and imine. The investigation further revealed that decomposition of hydroxylamines during APCI depends upon the concentration of the analyte and on the acidity of the solution introduced into the ionization source. The pH‐dependence of decomposition was utilized for the development of an MS method that allows for the unambiguous identification of N? OH functionalities. This method was applied for the study of natural products including polyamine toxins from the venom of the spider Agelenopsis aperta and mayfoline, a cyclic polyamine derivative of the shrub Maytenus buxifolia. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthetic Analogues of Naturally Occurring Spider Toxins

Naturally occurring spider toxins are potent inhibitors of glutamate receptors of the central nervous system and have the general structure (hetero)arylacyl→aminoacyl( I )→polyamine→aminoacyl( II ) (the arrow indicates the direction of an amide linkage). In the present paper, the synthesis of the ten spider-toxin analogues 13 , 18 , 21 , 28 , 35 , 37 , 39 , 41 , 45 , and 53 are reported (Schemes 1–12). These compounds differ in their subunits and, in some cases, in the sequence of these moieties.     

Separation of amino acid enentiomers by adding a chiral complex to the eluent

Amino acid enantiomers are separated by reverse-phase chromatography with an optically active polyamine/Cu(II) complex in the mobile phase. The polyamine was obtained by reaction of ( — )-trans-1,2-diaminocyclohexane with ethylene glycol diglycidyl ether; the complex with copper(II) ions was used in the eluent. Separation factors are reported for ten amino acids and four barbiturates.     

Modular solid-phase synthetic approach to optimize structural and electronic properties of oligoboronic acid receptors and sensors for the aqueous recognition of oligosaccharides

This article describes the design and optimization of the first entirely modular, parallel solid-phase synthetic approach for the generation of well-defined polyamine oligoboronic acid receptors and fluorescence sensors for complex oligosaccharides. The synthetic approach allows an effective building of the receptor polyamine backbone, followed by the controlled diversification of the amine benzylic side chains. This approach enabled the testing, in a modular fashion, of the effect of different arylboronic acid units substituted with unencumbering para electron-withdrawing or electron-donating groups. The feasibility of this approach toward automated synthesis was also investigated with the assembly of a sublibrary of receptors by means of the Irori MiniKan technology. Several sublibraries of anthracene-capped sensors containing two or three arylboronic acids were synthesized, and their binding to a series of model disaccharides was examined in neutral aqueous media. The calculation of association constants by fluorescence titrations confirmed that subtle changes in the structures of the interamine spacers in the polyamine backbone can have a significant effect on the stability of the resulting complexes. Most importantly, this study led to the determination of the preferred electronic characteristics for the arylboronate units, and suggests that a new generation of receptors containing very electron-poor arylboronic acids could lead to a significant improvement of binding affinities.     

Trace analysis of oxidized, nitrated, and chlorinated aromatic amino acids by capillary electrophoresis with electroosmotic flow modification allowing large-volume sample stacking

A capillary electrophoresis method has been developed for the simultaneous analysis of the oxidized, nitrated, and chlorinated aromatic amino acids, as well as their parent compounds. These modifications of the aromatic amino acids in proteins or free form are induced by the attack of reactive, mainly free radical species generated during cell stress, and these stable products may serve as biomarkers of cell damage. The analytes tyrosine, phenylalanine, dihydroxyphenylalanine, tryptophan, 3-nitrotyrosine, 3-chlorotyrosine, ortho-tyrosine, meta-tyrosine, 3-hydroxyphenylacetic acid (internal standard 1), and alpha-methyltyrosine (internal standard 2) were separated in their anionic forms in alkaline borate buffer. The polyamine spermine was used as electroosmotic flow (EOF) modifier. Adsorbing to the capillary wall, spermine can either suppress or even reverse the EOF depending on its concentration and the pH. The effects of the pH of the separation buffer, the spermine concentration, the temperature, and the applied field strength on the separation were examined. The modified aromatic amino acids are present in biological fluids in a much lower concentration than their parent compounds, thus high detection sensitivity of the analytical method is required. To achieve good detection sensitivity, field-amplified sample stacking of large injection volumes was applied. Omitting polyamine from the sample buffer allowed local reversal of the EOF, thus removal of the low conductivity sample buffer at the capillary inlet. In this way, 100% of the capillary to the detection window could be filled with the sample, and the detection limits achieved for the modified aromatic amino acids were in the range of 2.5-10 nM.     

Synthesis of a new tricyclic tetraazatriacetic acid as ligand for gadolinium(III)

Polyazapolycarboxylic acids are known to be efficient ligands for the development of gadolinium-based contrast agents used in magnetic resonance imaging (MRI). Given that rigidification of the ligand structure seems to be an important structural parameter to increase the relaxivity of the corresponding gadolinium complex, we have synthesized a new tricyclic tetraazatriacetate ligand from commercially available trans-2-aminocyclohexanol. In the synthetic routes described here, the 2-nitrobenzenesulfonamide chemistry was used to selectively functionalize the polyamine precursors.