Tryptophan Esters Research Articles

Regioselective synthesis of polysaccharide–amino acid ester conjugates

Site-specific conjugation of polysaccharides with proteins is very challenging. Creating the ability to control chemo- and regioselective reaction between polysaccharides and amino acid derivatives can not only create potentially useful and bioactive natural polymer constructs, but should also provide useful guidance for the principles of polysaccharide–protein conjugate synthesis. In this work, we exploited regioselective bromination of the non-reducing end primary dextran hydroxyl using N-bromosuccinimide (NBS) and triphenylphosphine (Ph3P) in the dimethylacetamide (DMAc) and lithium bromide solvent system, thereby enabling a regio- and chemoselective synthetic strategic approach to a variety of polysaccharide-amino acid ester adducts. We demonstrated selective condensation of the α-amino groups of esters of the amino acids tyrosine and proline, displacing the single, terminal C6 bromides of 6-BrDextran, as well as the 6-Br moieties of 6-BrCA320S, with high conversion (71–96%). Histidine ester side group amines were found to react with 6-BrCA320S, while those of tryptophan ester did not. These results provide useful access to polysaccharide–amino acid ester adducts of various architectures, and guide us in designing new pathways to polysaccharide–protein copolymers.

In vitro effects and mechanisms of action of Bidens pilosa in Trypanosoma brucei

Background and aimAfrican trypanosomiasis poses serious health and economic concerns to humans and livestock in several sub-Saharan African countries. The aim of the present study was to identify the antitrypanosomal compounds from B. pilosa (whole plant) through a bioactivity-guided isolation and investigate the in vitro effects and mechanisms of action against Trypanosoma brucei (T. brucei). Experimental procedureCrude extracts and fractions were prepared from air-dried pulverized plant material of B. pilosa using the modified Kupchan method of solvent partitioning. The antitrypanosomal activities of the fractions were determined through cell viability analysis. Effects of fractions on cell death and cell cycle of T. brucei were determined using flow cytometry, while fluorescence microscopy was used to investigate alterations in cell morphology and distribution. Results and conclusionThe solvent partitioning dichloromethane (BPFD) and methanol (BPFM) fractions of B. pilosa exhibited significant activities against T. brucei with respective half-maximal inhibitory concentrations (IC50s) of 3.29 μg/ml and 5.86 μg/ml and resulted in the formation of clumpy subpopulation of T. brucei cells. Butyl (compound 1) and propyl (compound 2) esters of tryptophan were identified as the major antitrypanosomal compounds of B. pilosa. Compounds 1 and 2 exhibited significant antitrypanosomal effects with respective IC50 values of 0.66 and 1.46 μg/ml. At the IC50 values, both compounds significantly inhibited the cell cycle of T. brucei at the G0-G1 phase while causing an increase in G2-M phase. The results suggest that tryptophan esters may possess useful chemotherapeutic properties for the control of African trypanosomiasis.

Synthesis, Biological Evaluation and In silico Studies of Compounds Based on Tryptophan‐Naproxen‐Triazole Hybrids

AbstractA hybrid of three different frameworks e. g. tryptophan, naproxen and triazole has been explored for the identification of potential antibacterial / anticancer agents. A library of new compounds, designed based on this hybrid framework was synthesized via a multi‐step sequence using the Cu(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) as the key reaction step. Thus the terminal alkyne obtained via the reaction of tryptophan ester with naproxen followed by N‐propargylation of the indole ring was coupled with a range of organic azides to give the desired products (through the formation of triazole ring) in good to acceptable yields. The in vitro antibacterial screening of these compounds against S. aureus (Gram‐positive) as well as E. coli and K. pneumoniae (Gram‐negative) strains identified several hits with moderate to good activities with 4‐(4‐((3‐(3‐methoxy‐2‐(2‐(6‐methoxynaphthalen‐2‐yl)propanamido)‐3‐oxopropyl)‐1H‐indol‐1‐yl)methyl)‐1H‐1,2,3‐triazol‐1‐yl)benzoic acid (6 n) being the best (MIC∼25 μg/mL across all the strains). Several compounds e. g. analogues containing a (4‐chlorophenyl)amino)‐2‐oxoethyl moiety (6 e) and (4‐nitrophenyl)amino)‐2‐oxoethyl moiety (6 h) attached to the triazole ring also showed cytotoxic activities when tested against A549 cancer cell line (IC50=39.35 and 28.52 μg/mL, respectively).

Questioning the γ-gauche effect: stereoassignment of 1,3-disubstituted-tetrahydro-β-carbolines using 1H-1H coupling constants.

The Pictet-Spengler reaction of tryptophan esters and aldehydes has been widely applied in natural product synthesis and medicinal chemistry. To date, the trans- or cis-configuration of 1,3-disubstituted tetrahydro-β-carbolines (THβCs) formed in this reaction has most often been assigned based on the relative 13C chemical shifts of C1 and C3 in the diastereomers. Although the upfield shifts of C1 and C3 in trans-THβCs relative to cis-THβCs has been attributed to steric compression associated with the "γ-gauche" effect, we show that this effect is not borne out experimentally for other carbons that should suffer this same compression. Thus we developed a robust alternative method for stereochemical assignment based on 1H NMR coupling constants (31 examples) and supported by extensive DFT-based conformational analysis and calculation of 1H-1H coupling constants. DFT calculations of 13C NMR chemical shifts also cast doubt upon the role of the "γ-gauche" effect on C1 and C3 chemical shifts in trans-THβCs.

Solvent-Induced Molecular Folding and Self-Assembled Nanostructures of Tyrosine and Tryptophan Analogues in Aqueous Solution: Fascinating Morphology of High Order.

Hydrophobic derivatives of tyrosine and tryptophan, viz. octyl and dodecyl esters of tyrosine and octyl ester of tryptophan, are synthesized, and the interfacial and bulk properties in aqueous media are investigated as models for the membrane proteins. Molecular modeling by the density functional theory method is carried out to understand the molecular conformation and geometry for the purpose of determining the packing parameters. Water-induced molecular folding of the esters of both tyrosine and tryptophan, as observed using rotating frame nuclear Overhauser effect spectroscopy, indicates that the segregation of the hydrophobic and hydrophilic blocks in water is the key to the development of fascinating interfacial property displayed by the aromatic amino acid esters. The unusually high-order morphology of the aggregates, as observed using high-resolution transmission electron microscopy, is highly uncommon for single-chain amphiphiles and points to the fact that the self-assembly behavior of the present systems resembles that of block copolymers. The study of the growth of mesosized hollow aggregates with internal bilayer structures from tyrosine and tryptophan-based model systems would add to the understanding of biochemistry and biotechnology relevant to the cell membrane. The potential of biocompatible nanostructured motifs as the drug carriers is discussed. The highly functional role played by the aromatic amino acids at the membrane-water interface will be considered with the present amphiphilic models for future perspective.

Direct intramolecular amination of tryptophan esters to prepare pyrrolo[2,3-b]indoles.

A metal-free iodine-catalyzed intramolecular amination has been developed for the practical synthesis of pyrrolo[2,3-b]indoles from readily available tryptophan esters. The transformation has been applied to a wide array of substrates and can be performed on gram scale under very mild conditions.

Diastereoselective Synthesis of Bridged Polycyclic Alkaloids via Tandem Acylation/Intramolecular Diels–Alder Reaction

A mild and efficient stereoselective synthesis of hexacyclic indole alkaloids with a tetrahydro-β-carboline motif has been developed by utilizing the Pictet-Spengler reaction and tandem N-acylation followed by intramolecular Diels-Alder cyclization. Initially, a diene unit was installed in the tetrahedron β-carboline skeleton through Pictet-Spengler cyclization of the corresponding aldehyde with tryptophan ester. The dienophile moiety was introduced by N-acylation of tetrahydro-β-carboline. Successive, in situ, [4 + 2] intramolecular Diels-Alder cycloaddition of the activated dienophile and conjugated diene containing intermediate furnished bridged polycyclic heterocycles with high diastereoselectivity. Formation of four new rings, five new covalent bonds, and five new chiral centers with excellent stereoselectivity is the key feature of this strategy. The diastereoselective formation of product was attributed to intramolecular chirality transfer through a chiral amino acid. The stereoselective outcome of this tandem reaction was confirmed by X-ray crystallographic studies. The developed synthetic strategy was also explored on a soluble polymer support to incorporate the advantage of rapid synthesis and a high-throughput workup process toward the development of a green synthetic protocol for polycyclic alkaloids.

ChemInform Abstract: Facile and Efficient One‐Pot Synthesis of β‐Carbolines.

Abstractusing the Pictet—Spengler reaction of tryptophan ester (I) with aldehydes (II) followed by aromatization using cyanuric chloride

Traceless synthesis of diketopiperazine fused tetrahydro-β-carbolines on soluble polymer support

The Pictet-Spengler reaction, using polyethylene glycol immobilized tryptophan ester with a variety of ketones, was achieved by refluxing condition in acidic chloroform. The linear as well as cyclic ketones were employed. All the ketones were reacted within 6-8 h to furnish soluble polymer-supported tetrahydro-β-carboline in good yields. Further expansion at N-terminus of tetrahydro-β-carbolines was achieved through a reaction with chloroacetyl chloride. Finally, the 2,5-diketopiperazine skeleton was constructed over a β-carboline by amination of the resulting N-chloroacetamides and subsequent intramolecular cyclization leading to cleavage of the polymer; constitutes a traceless synthesis of tetracyclic molecular architecture. Significantly, this strategy affords a straightforward and efficient approach for the construction of biological promising molecules with high purity and good yields.

Mass spectrometric behavior of functionalized calix[4]arenes: the screening ability of host–guest complex formation with amino acid methyl esters

The ESI–MS and MS/MS behavior of functionalized calix[4]arenes (1–5) has been studied in both positive and negative-ion mode. Liquid chromatography coupled to ESI–MS has been successfully used for separation of the byproducts issuing from the functionalization pathways, through the application of a simple reversed phase mechanism. The ability of (1–5) to host methyl esters of amino acids, tyrosine, tryptophan, phenylalanine, cysteine, valine, serine, leucine, isoleucine, and threonine has been evaluated by means of MS identification of the host–guest resulting in protonated molecular ions. The direct infusion within the ESI source of the solutions containing the two partners (i.e., calixarene and amino acid derivative) could act as a fast screening means for the evaluation of hosting capability. Only positive ionization may offer information about the host–guest complexes being formed. The influence of the excess of a partner in the infused solution strongly alters ionization yields, making quantitative approaches meaningless. Attempts to chromatographically isolate the host–guest complexes failed, probably due to the fact that interactions of the partners with the mobile and stationary phases are higher than the inclusion interactions. Structures consisting of combined fragments of the host–guest partners resulting from the collisional induced dissociation have not been observed.

Fluorous and Traceless Synthesis of Substituted Indole Alkaloids

The fluorous traceless synthesis of substituted indole alkaloids is carried out first by attaching the 3-(perfluorooctyl)propanol with Boc protected L-tryptophan. The reaction of perfluoroalkyl (Rfh)-tagged tryptophan esters with various aldehydes undergoes Pictet-Spengler reaction to give cis and trans stereoisomers of tetrahydro-beta-carbolines. The nucleophilic addition of the piperidine nitrogen across various isocyanates is followed by the cyclization of ureas and simultaneous rupture of the fluorous tag to afford the hydantoin ring fused tetrahydro-beta-carbolines. All the fluorous-tag compounds are purified by solid-phase extraction (SPE) through Fluoro Flash cartridges.

Photolysis of carotenoids in chloroform: enhanced yields of carotenoid radical cations in the presence of a tryptophan ester

The presence of an acetyl tryptophan ester gives rise to enhanced yields of carotenoid radical cations in chloroform following 355 nm laser excitation of the carotenoid, even though the tryptophan does not absorb at this wavelength. The increase is attributed to positive charge transfer from semi-oxidized tryptophan itself generated by light absorbed by the carotenoid. The mechanism of these radical processes has been elucidated by pulse radiolysis studies.

Synthesis of the marine alkaloids rhopaladins A, B, C and D

The total synthesis of all four known rhopaladins, A–D, isolated from the Okinawan marine tunicate Rhopalaea sp., in two synthetic steps is described, involving an imidate based cyclization with tryptophan esters as the key step to afford the appropriately substituted imidazolinone unit. A short and efficient new synthesis of indol-3-yl-carbonyl nitriles from indol-3-yl-carboxaldehydes and trimethylsilyl cyanide, followed by oxidation with DDQ is also described.

Extraction Behavior of Amino Acids by Calix[6]arene Carboxylic Acid Derivatives

A series of calixarene carboxylic acid derivatives were synthesized for the extraction of amino acids. A calix[6]arene carboxylic acid derivative showed the highest extractability to the target tryptophan ester. The main driving forcefor the complexation was the interaction between the ammonium cation of the aminoacid and the oxygen atoms of the host molecule. Stripping of amino acids was alsoaccomplished by contacting the organic solution with a fresh acidic solution. Basedon slope and Job method analyses, it was confirmed that the calix[6]arene formsa 1 : 1 complex with the amino acid ester. The structure of the complex between the calix[6]arene and the amino acid was investigated by 1H-NMR and CD spectra. The calix[6]arene includes a guest molecule in the cavity, and the inclusion induces the asymmetrization of the host molecule. This host compound functions as a novel recognition tool for amino acids.

Chiral discrimination of permethylated gluco-oligosaccharide toward amino acid ester salts

The chiral discrimination ability of permethylated glucopyrano-oligosaccharides toward amino acid 2-propyl ester hydrochlorides was evaluated using FAB mass spectrometry. In the given permethylated homo-oligosaccharides, permethylated β-cello-oligosaccharide series (II) showed remarkably higher S -selectivity toward tryptophan ester salts (Trp-O- i Pr + ) independent of the numbers ( n ) of the glucopyranose unit ( n =2–5). The hexamer and heptamer of the permethylated β-malto-oligosaccharide series (I) showed the very similar enantioselectivity to permethylated α- and β-cyclodextrin. Graphic

A Novel Thiolate Mediated Cyclization to OPC-15161

An efficient synthetic route to OPC-15161 ( 1) was developed via novel pyrazine ring closure promoted by a lithium thiolate anion. The key intermediate ( 4) was prepared in a one-pot procedure by treating the methyl ester ( 2) with a lithium arylthiolate. This protocol does not require a free acid intermediate and thus can establish the shortest route to pyrazine dioxide skeleton from tryptophan ester derivatives. In the present transformation, lithium arylthiolates could behave like aluminium arylthiolates, and not like lithium alkylthiolates that often cleave esters to the corresponding acids. One-pot reactions that involve lengthy multiple steps in a single flask are of significant importance in contemporary organic synthesis. Utilization of a catalytic or stoichiometric promoter which can facilitate several transformations is a key to the success of such reactions. In this paper, we would like to disclose an interesting one-pot transformation discovered in our process research, which offered us novel information on the reactivity of metal thiolates. Main feature of our one-pot process is a merged deprotection-cyclization sequence.

Enantioselective Construction of Highly Functionalized Indoloquinolizines—congeners to Polycyclic Indole Alkaloids

AbstractIndolo[2,3‐a]quinolizines have been prepared in enantiomerically pure form by a very short and efficient synthetic sequence consisting of a) formation of imines of tryptophan esters, b) their enantioselective reaction with substituted silyloxydienes mediated by a chiral or an achiral boron Lewis acid, and c) subsequent ring closure initiated by conversion of the generated vinylogous amides into vinylogous imidoyl chlorides. With this strategy various substituents can be incorporated directly into the 1‐position of the heterocyclic framework of complex indole alkaloids by the choice of an appropriate silyloxydiene, so that subsequent derivatization of the alkaloid precursor at this position is rendered unnecessary.

Chiral N-substituted 4,5,6,7-tetrahydroindoles

2-Formylmethylcyclohexanone reacts with α-amino esters in dry dichloromethane at room temperature to give homochiral N-substituted 4,5,6,7-tetrahydroindoles in good yield. No Pictet-Spengler products are observed with histidine or tryptophan esters.

3-Aryl-1,2-diacetamidopropane derivatives as novel and potent NK-1 receptor antagonists.

Early structure-activity studies on racemic tryptophan ester and amide NK-1 antagonists 5-7 led to the discovery that the potency of the series could be markedly increased by moving the carbonyl function in these molecules to an off-chain position as in the 3-aryl-1,2-diacetamidopropane 9. Further medicinal chemistry incorporating this change resulted in the discovery of a novel series of highly potent aryl amino acid derived NK-1 antagonists of the R stereoisomeric series (IC50's = 100 pM to > 5 microM). Compounds in this series were shown to be competitive antagonists using an in vitro NK-1 smooth muscle assay, and this data correlated well with observed human NK-1 binding affinities. Two of these agents, (R)-25 and (R)-32, blocked intrathecal NK-1 agonist-driven [Ac-[Arg6,Sar9,Met(O2)11]- substance P 6-11 (Ac-Sar9)] nociceptive behavior in mice. Both compounds potently blocked the neurogenic dural inflammation following trigeminal ganglion stimulation in the guinea pig after intravenous administration. Further, upon oral administration in this model, (R)-32 was observed to be very potent (ID50 = 91 ng/kg) and have a long duration of action (> 8 h at 1 micrograms/kg). Compound (R)-32, designated LY303870, is currently under clinical development as an NK-1 antagonist with a long duration of action.

A general preparation of β-substituted tryptophan esters

The title compounds 6 have been synthesized in 4 steps from indoles, aldehydes and Meldrum's acid.