Tyrosine Derivatives Research Articles

A Bioinspired Synthesis of Polyfunctional Indoles

AbstractPolyfunctional indoles bearing substituents at C5 and C6 are prevalent in natural products, pharmaceuticals, agrochemicals, and materials. Owing to the remoteness of the C5 and C6 positions, indoles of this family can be difficult to prepare, and often require multistep syntheses. Herein, we describe a concise process that converts simple derivatives of tyrosine into 5,6‐difunctionalized indoles by direct oxidation of C−H, N−H, and O−H bonds. Our work draws inspiration from the biosynthetic polymerization of tyrosine to make melanin pigments, but makes an important departure to provide well‐defined indole heterocycles.

Photosensitized Cross-Linking of Tryptophan and Tyrosine Derivatives by Rose Bengal in Aqueous Solutions.

Photosensitized cross-linking of N-acetyl derivatives of tryptophan and tyrosine by rose bengal in phosphate buffer saline was studied by steady-state absorption and emission spectroscopy, nanosecond transient absorption spectroscopy, and chemical analyses. These amino acids undergo cross-linking to form dimeric and higher oligomeric products under anoxic conditions with rose bengal as a sacrificial oxidant, whereas they react predominantly with singlet oxygen produced by rose bengal in aerated solutions. This investigation provides a comprehensive view into the first steps of rose bengal photosensitized cross-linking of these two amino acids. The results can be helpful for future applications of rose bengal and related dyes, such as photochemical tissue bonding or visible light photocatalysis.

Insect Arylalkylamine N-Acyltransferases: Mechanism and Role in Fatty Acid Amide Biosynthesis.

Arylalkylamine N-acyltransferases (AANATs) catalyze the formation of an N-acylamide from an acyl-CoA thioester and an amine. One well known example is the production of N-acetylserotonin from acetyl-CoA and serotonin, a reaction in the melatonin biosynthetic pathway from tryptophan. AANATs have been identified from a variety of vertebrates and invertebrates. Considerable efforts have been devoted to the mammalian AANAT because a cell-permeable inhibitor specifically targeted against this enzyme could prove useful to treat diseases related to dysfunction in melatonin production. Insects are an interesting model for the study of AANATs because more than one isoform is typically expressed by a specific insect and the different insect AANATs (iAANATs) serve different roles in the insect cell. In contrast, mammals express only one AANAT. The major role of iAANATs seem to be in the production of N-acetyldopamine, a reaction important in the tanning and sclerotization of the cuticle. Metabolites identified in insects including N-acetylserotonin and long-chain N-fatty acyl derivatives of dopamine, histidine, phenylalanine, serotonin, tyrosine, and tryptophan are likely produced by an iAANAT. In vitro studies of specific iAANATs are consistent with this hypothesis. In this review, we highlight the current metabolomic knowledge of the N-acylated aromatic amino acids and N-acylated derivatives of the aromatic amino acids, the current mechanistic understanding of the iAANATs, and explore the possibility that iAANATs serve as insect “rhymezymes” regulating photoperiodism and other rhythmic processes in insects.

Synthesis of the Entomopathogenic Fungus Metabolites Militarinone C and Fumosorinone A.

Militarinone C and fumosorinone A, 3-oligoenoyltetramic acids produced by insect pathogenic fungi, were synthesized for the first time. The pyrrolidine-2,4-dione ring was closed through a late-stage Dieckmann condensation of N-(β-ketoacyl) derivatives of tyrosine, obtained by its acylation with either thioesters or Meldrum's acid derivatives bearing the all- trans-polyene side chain. The latter was built up from ( S)-citronellol via an Evans methylation and Wittig or HWE olefinations.

Regulation of aldose reductase activity by tubulin and phenolic acid derivates

In this work we demonstrate that aldose reductase (AR) interacts directly with tubulin and, was subjected to microtubule formation conditions, enzymatic AR activity increased more than sixfold. Since AR interacts mainly with tubulin that has 3-nitro-tyrosine in its carboxy-terminal, we evaluated whether tyrosine and other phenolic acid derivatives could prevent the interaction tubulin/AR and the enzymatic activation. The drugs evaluated have two characteristics in common: the presence of an aromatic ring and a carboxylic substituent. The 9 drugs tested were able to prevent both the interaction tubulin/AR and the enzymatic activation. In addition, we found that the induction of microtubule formation by high concentrations of glucose and the consequent activation of AR in cultured cells can be inhibited by phenolic acid derivates that prevent the interaction tubulin/AR. These results suggest that tubulin regulates the activation of AR through a direct interaction which can be controlled with phenolic derivates of carboxylic acids.

Design, synthesis, and evaluation of novel l-phenylglycine derivatives as potential PPARγ lead compounds

In accordance with the structural characteristics of thiazolidinedione drugs and highly bioactive tyrosine derivatives, we tentatively designed the l-phenylglycine derivatives TM1 and TM2 based on basic principles of drug design and then synthesized them. The in vitro screening of peroxisome proliferator-activated receptor gamma (PPARγ) activated activity, α-glucosidase inhibitory and dipeptidyl peptidase-4 inhibitory activities showed that the novel molecule M5 had efficient PPAR response element (PPRE) activated activity (PPRE relative activity 105.04% at 10 μg·mL−1 compared with the positive control pioglitazone, with 100% activity). Therefore, M5 was selected as the hit compound from which the TM3 and TM4 series of compounds were further designed and synthesized. Based on the PPRE relative activities of TM3 and TM4, we discovered another new molecule, TM4h, which had the strongest PPRE relative activity (120.42% at 10 μg·mL−1). In addition, the concentration-dependent activity of the highly active compounds was determined by assaying their half-maximal effective concentration (EC50) values. The molecular physical parameter calculation and the molecular toxicity prediction were used to theoretically evaluate the lead-likeness and safety of the active compounds. In conclusion, we identified a potential PPARγ lead molecule and developed a tangible strategy for antidiabetic drug development.

Asymmetric synthesis of highly functionalized tyrosine derivatives for the construction of bistetrahydroisoquinoline alkaloids

A novel and facile synthesis of l-5-hydroxy-2,4-methoxy-3-methylphenylalanine derivatives, which are the key coupling partners for the asymmetric total synthesis of natural bistetrahydroisoquinoline alkaloids, is realized starting from l-tyrosine with 17% overall yield. The synthesis has been carried out on a multigram scale featuring the following key steps: (a) transformation of phenol to dihydroquinone via salcomine-catalyzed oxidation followed by zinc-acetic acid reduction; (b) single TBS-protection of dihydroquinone; (c) Mitsunobu methylation of the newly generated phenolic hydroxyl group.

A direct route for the preparation of Fmoc/OtBu protected iodotyrosine

Herein the synthesis of an Fmoc/OtBu orthogonally protected iodotyrosine derivative is reported. This has been achieved via a simple two-step process in an overall 58% yield from commercially available Fmoc-Tyr(tBu)-OH. The Fmoc/OtBu orthogonally protected iodotyrosine was also shown to be amenable to Suzuki-Miyaura cross-coupling to deliver a novel bi-aryl tyrosine derivative.

Вміст аскорбінової кислоти в печінці і надниркових залозах щурів при коригуванні аліментарного гіпотиреозу йодом різної хімічної природи

Introduction. Metabolisms of vitamins, trace elements and hormones are closely linked. The connection between ascorbic acid and hormones, in particular derivatives of tyrosine and steroids, determines its importance for the activity of the thyroid gland, adrenal glands and liver. The most common thyroid pathology is hypothyroidism, caused by iodine deficiency. For its treatment and prevention, compounds that contain iodine of different chemical nature are used.The aim of the study – to compare the effect of the action of organic and inorganic iodine on the content of ascorbic acid (AA) in the liver and adrenal glands.Research Methods. The study was conducted in the model conditions of alimentary hypothyroidism on 80 white nonlinear male rats weighing 0.140–0.160 kg, which for 30 days were in an isocaloric starch-casein ration. Adjustment of iodine deficiency was carried out on three doses of iodine (21, 50, 100 μg/kg body weight), which animals uptaked with potassium iodide (inorganic iodine) and iodine-protein preparation from the Black Sea industrial red algae of Phyllophora nervosa (DС.) Grev (organic iodine). The content of AA in the tissues was determined using Tillman’s reagent.Results and Discussion. In conditions of alimentary hypothyroidism, the level of AA in the investigated organs was significantly reduced, which may indicate a decrease in the activity of metabolic processes. The consumption of both iodine-containing substances at a dose of 21 μg/kg was accompanied by a probable increase in the content of AА in the liver. Under the influence of 50 μg/kg iodine, its level in the rat’s liver and adrenal glands reached the levels of intact rats, but under use organic iodine the level of AA was higher. When receiving 100 μg/kg of iodine, the content of AA in organs was significantly reduced relative to the achieved parameters and in the adrenal glands was at the level of parameters of rats that did not consume iodine-containing compounds.Conclusions. The intake of both inorganic and organic iodine contribute to an increase in the content of AA in the liver and adrenal glands, which is a prerequisite for activating the activity of the thyroid gland, while the effect of organic iodine is more powerful. The effect of both iodine-containing preparations on the liver is greater, which may be a sign of its greater sensitivity to the strengthening of thyroid hormonepoise and indicate an increase in its metabolic activity.

Complete biosynthesis of noscapine and halogenated alkaloids in yeast

Microbial biosynthesis of plant natural products from simple building blocks is a promising approach toward scalable production and modification of high-value compounds. The pathway for biosynthesis of noscapine, a potential anticancer compound, from canadine was recently elucidated as a 10-gene cluster from opium poppy. Here we demonstrate the de novo production of noscapine in Saccharomyces cerevisiae, through the reconstruction of a biosynthetic pathway comprising over 30 enzymes from plants, bacteria, mammals, and yeast itself, including 7 plant endoplasmic reticulum (ER)-localized enzymes. Optimization directed to tuning expression of pathway enzymes, host endogenous metabolic pathways, and fermentation conditions led to an over 18,000-fold improvement from initial noscapine titers to ∼2.2 mg/L. By feeding modified tyrosine derivatives to the optimized noscapine-producing strain we further demonstrated microbial production of halogenated benzylisoquinoline alkaloids. This work highlights the potential for microbial biosynthetic platforms to support the synthesis of valuable and novel alkaloid compounds, which can advance alkaloid-based drug discovery and development.

SM-88 therapy in patients with advanced or metastatic pancreatic cancer.

457 Background: SM-88 (tyrosine derivative, mTOR inhibitor, CYP3a4 inducer and oxidative stress catalyst) is a relatively non-toxic, targeted therapy that utilizes the Warburg Effect in combination with oxidative stress to cause tumor cell death. Previously reported results (Phase I and preliminary Phase II) showed safety and efficacy for SM-88 in metastatic and recurrent cancers. Pancreatic cancer continues to have a poor prognosis with toxic standard of care (SOC) therapies, associated serious adverse events (SAEs), and QOL degradation. SM-88 is being evaluated as a minimally toxic alternative treatment. Methods: Retrospective chart review between 2012-17 of 12 patients with advanced or metastatic pancreatic cancer treated with SM-88 through a Phase 1 study (3/12) or compassionate use (9/12) with 10/12 evaluable. Although treatment regimens specifics varied, all were provided SM-88 therapy five days a week, administered by clinicians, orally or through subcutaneous injection; 7/10 patients received SM-88 mono therapy; and 3/10 received combination therapy (5FU-based). Results: 40% (4/10) of patients achieved survival benefit of greater than one year (mean 12.2 mo) (see table). Monotherapy patients maintained or improved ECOG PS and did not experience drug-related SAEs during treatment. 2/10 patients achieved partial responses. One patient maintained rPFS for 13 months despite positive margins post-surgery and elevated CA19.9 levels. Conclusions: SM-88 appears well tolerated and demonstrated notable survival times in comparison to expected SOC therapies. In addition, several of the patients demonstrating benefit had baseline ECOG PSs of 2, for which current SOC is palliative care only. For further evaluation, a North American Phase II trial in recurrent pancreatic cancer has been initiated. [Table: see text]

The use of optically active O-alkyl ester hydrochlorides of L-phenylalanine and L-tyrosine as chiral micellar media for the catalysis of diels-alder reactions

The effect of a range of O -alkyl ester hydrochloride surfactants derived from L-phenylalanine and L-tyrosine as catalysts on the Diels-Alder reaction between cyclopentadiene and methyl acrylate was studied. Both chain lengths (C 8 -C 14 ) and head groups of the surfactants were found to influence the yield and selectivity of the Diels-Alder product. The C 10 derivatives of both phenylalanine and tyrosine surfactants gave the highest yields and selectivity. Phenylalanine ester hydrochlorides showed better catalytic activity than the tyrosine derivatives. Adduct optimum yield was obtained at a concentration relating to their critical micelle concentration (CMC) values. The Diels-Alder reaction was also found to be favored in acidic condition (pH 3) as well as in the presence of lithium chloride (LiCl) as salting out agent. KEY WORDS : Diels-Alder, Chiral catalysts, Phenylalanine, Tyrosine, Micelle, CMC Bull. Chem. Soc. Ethiop. 2017 , 31(3), 509-518. DOI: http://dx.doi.org/10.4314/bcse.v31i3.15

Serpulanines A to C, N-Oxidized Tyrosine Derivatives Isolated from the Sri Lankan Fungus Serpula sp.: Structure Elucidation, Synthesis, and Histone Deacetylase Inhibition.

Serpulanines A (1), B (2), and C (3) have been isolated from extracts of the rare Sri Lankan macrofungus Serpula sp. The structures of 1, 2, and 3 were elucidated by a combination of spectroscopic and single-crystal X-ray diffraction analyses. Serpulanines A (1) and B (2) both contain the rare (E)-2-hydroxyimino hydroxamic acid functional group array. A proposed biogenesis for serpulanine B (2) suggests that its (E)-2-hydroxyimino hydroxamic acid moiety arises from a diketopiperazine precursor. Synthetic serpulanine A (1) inhibited class I/II histone deacetylases in murine metastatic lung carcinoma cells with an IC50 of 7 μM.

Tub-Tag Labeling; Chemoenzymatic Incorporation of Unnatural Amino Acids.

Tub-tag labeling is a chemoenzymatic method that enables the site-specific labeling of proteins. Here, the natural enzyme tubulin tyrosine ligase incorporates noncanonical tyrosine derivatives to the terminal carboxylic acid of proteins containing a 14-amino acid recognition sequence called Tub-tag. The tyrosine derivative carries a unique chemical reporter allowing for a subsequent bioorthogonal modification of proteins with a great variety of probes. Here, we describe the Tub-tag protein modification protocol in detail and explain its utilization to generate labeled proteins for advanced applications in cell biology, imaging, and diagnostics.

An auxin–tyrosine derivative based biocompatible supergelator: a template for fabrication of nanoparticles for sustained release of model drugs

This report reveals the supergelating ability of an auxin-tyrosine derivative based biocompatible hydrogel in drug delivery.

Photoinduced electron transfer-promoted debenzylation of phenylalanine and tyrosine derivatives using dicyanoarene

Photoinduced debenzylations of phenylalanine and tyrosine derivatives with dicyanoarenes afford glycine derivatives by the generation of radical cations. Despite the limited substrate scope, the radical cation of phenylalanine and tyrosine derivatives bearing both a carbamate (without an aromatic group) at the N-terminal and an amide at the C-terminal could promote the breaking C–C bond at the benzylic position by a photoinduced electron transfer. It is important to understand the chemical behavior of the radical cations of phenylalanine and tyrosine in enzymes involving electron transfer.

(+)- and (-)-Itampolin A: First Total Synthesis, Anticancer Effect Through Inhibition of Phospho p38 Expression

Aim and Objective: The brominated tyrosine alkaloids which have broad biological activity are commonly found in marine sponges of the Verongida order, However, with the discovery of itampolin A and B from the Madagascan sponge, Iotrochota purpurea, a plurality of brominated tyrosine derivatives have been found in the sponge Iotrochota purpurea. This study was undertaken to study antitumor activity of itampolin A and to explore the possible mechanism. Material and Method: The total synthesis of itampolin A was first performed to obtain purified brominated tyrosine alkaloid, then the cytotoxicities of itampolin A were evaluated by MTT method against H460 and A549 cells. To explore the possible mechanism, potential target identification by latest integrated pharmacophore matching platform of itampolin A was carried out using PharmMapper Server. Finally, expression of phospho p38α protein was studied using the western blot analysis. Results: Itampolin A and enantiomer of itampolin A were obtained, the latter is a novel compound named (-)- itampolin A, which exhibited significant anticancer activity in the biological tests. After potential target identification by latest integrated pharmacophore matching platform of itampolin A, p38α was screened out as the target protein. Then in the Western-blot analysis, it was proposed that (-)-itampolin A inhibited tumor cells by reducing the phospho-p38α expression. Conclusion: (+)-itampolin A was a brominated tyrosine derivative, isolated from the sponge Iotrochota purpurea. For the first time, the total synthesis of itampolin A was achieved. The enantiomer, (-)-itampolin A was found to show inhibitory activity on the cultured lung cancer A549 cells. The underlying anticancer mechanisms may be associated with its binding to p38α and then decrease in the phospho-p38 expression.

Autobronzants et bronzants artificiels

Practically all currently available self-tanning products have as their active ingredient dihydroxyacetone (DHA), which may or may not be combined with erythrulose, tyrosine derivatives, and occasionally a naphthoquinone. The resulting skin tone, which resembles a natural tan, is due to chemical combination of the DHA with amino acids in the skin through the Maillard reaction. Polymer pigments known as melanoidins are formed and are fixed in the stratum corneum, where they remain until corneocyte desquamation occurs. The colouring thus achieved is semi-permanent and is well tolerated by skin. While the formulation of such products is complex and their storage difficult, no other substances provide more satisfactory or more lasting results.

Nano Cu interaction with single amino acid tyrosine derived self-assemblies; study through XRD, AFM, confocal Raman microscopy, SERS and DFT methods

3,5-Bis(trifluoromethyl)benzylamine derivatives of single amino acid tyrosine produced self-assembled nanotubes (BTTNTs) as simple Phe-Phe. It has been observed that tyrosine derivative gives exclusively micro and nano tubes irrespective of the concentration of the precursor monomer. However, the introduced xenobiotic trifluoromethyl group (TFM) present in key backbone positionsof the self assembly gives the specific therapeutic function has been highlighted. Herein this work study of such self assembled nanotubes were studied through experimental and theoretical methods. The interaction of nanocopper cluster with the nanotubes (Cu@BTTNTs) were extensively studied by various methods like XRD, AFM, confocal Raman microscopy, SERS and theoretical methods like Mulliken's atomic charge analysis. SERS reveals that the interactions of Cu cluster with NH2, OH, NH and phenyl ring π-electrons system of BTTNTs. DFT studies gave the total dipole moment values of Cu@BTTNTs and explained the nature of interaction.

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.