Amino Acids, Peptides and Proteins: Volume 42 / Edition 1 available in Hardcover, eBook
Amino Acids, Peptides and Proteins: Volume 42 / Edition 1
- ISBN-10:
- 1788010027
- ISBN-13:
- 9781788010023
- Pub. Date:
- 12/06/2017
- Publisher:
- RSC
Amino Acids, Peptides and Proteins: Volume 42 / Edition 1
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CHAPTER 1
Amino acids: chemistry, diversity and physical properties
Márta Zarándi and János Szolomájer
The occurrence, chemistry, resolution, and analysis of amino acids published in the literature from 2013 finished with the year of 2016 are reviewed in this Chapter which is arranged in sections similar to previous Volumes in this Specialist Periodical report. Scientific Papers published during 2013–2016 have been sourced mainly from the Web of Science databases and Pubmed on the internet and from scanning a selection of major journals.
1 Naturally occurring amino acids
1.1 Occurrence of amino acids
Several naturally occurring amino acid derivatives are more and more in the focus as sources for new agrochemicals. The 53 most important natural products of amino acids are presented in a review together with their natural sources, mode of action, and herbicidal, fungicidal, or insecticidal activities.
It is known that Arg, the most basic amino acid, occurs less frequently than Lys in proteins. The few important proteins abundant in Arg have important roles in biological systems. A review collects the data of occurrence, functions, and the biological significance of these Arg-rich proteins. Leu is a potential signalling molecule to regulate cell growth and metabolism. Structure–activity relationships of Leu derivatives in HeLa S3 cells were investigated for cellular uptake and for the induction of phosphorylation. The results may provide a new insight into therapeutics targeting both L-amino acid transporters 1 and Leu sensor.
Phenyl-Gly-type amino acids occur in a wide variety of natural peptides. The biosynthesis of 4-hydroxyphenyl-Gly, 3,5-dihydroxyphenyl-Gly, and phenyl-Gly was investigated. Structures and properties of phenyl-Gly containing natural products, the biosynthetic origin and incorporation of phenylglycines are discussed in a review. 4-Methyl-Pro (4-mPro) is a rare nonproteinogenic amino acid produced by cyanobacteria. Eight biosynthetic gene clusters were found from available cyanobacteria genomes, showing that 4-mPro is a good marker to discover previously unknown nonribosomal peptides.
Amino acids represent a fraction of organic matter in marine and freshwater ecosystems. The occurrence of D-amino acids is usually linked to the presence of bacteria. The distribution of L- and D-amino acids in the lacustrine environment of Terra Nova Bay, Antarctica was investigated. Microorganisms that utilize various D-amino acids were successfully isolated from deep-sea sediments. Some of the isolates exhibited high enantioselective degradation activities to various D-amino acids. An antialgal compound was isolated from the cultured broth of Streptomyces jiujiangensis JXJ 0074(T). Based on the data of different analytical methods, the active compound was identified as L-Val which showed antialgal activity. This is the first report showing that L-Val is active against cyanobacteria. Diverse D-amino acids have been found in mammalian tissues. The physiological functions of these D-amino acids are being gradually clarified. It has been demonstrated that D-Ser, D-Asp, D-Ala, and D-Cys play important roles in the nervous and endocrine systems. The investigations of metabolism and the physiological functions of D-amino acids provide new therapeutic and diagnostic strategies for diseases related to the nervous and endocrine systems. D-Ser is a key signalling molecule utilized by neurons and astroglia in the mammalian central nervous system. Alterations in the extracellular levels of D-Ser disrupt cell–cell signalling that leads to many chronic or acute neurological and psychiatric disorders, and are associated with addictive behaviour. Experimental data supports that astroglia and neurons use different pathways to regulate levels of extracellular D-Ser. A rare Gln derivative, hemerocallisamine I, was isolated from the flower buds of daylily. It was first reported that a Gln derivative with a pyrrole ring is found in natural plants. Increased reactive oxygen species are accompanied by 2-aminobutyric acid accumulation and compensatory maintenance of myocardial glutathione levels. It was demonstrated for the first time that 2-aminobutyric acid modulates glutathione homeostasis in the myocardium.
β-Amino acids are components of complex natural products generating significant and unique biological functions. The de novo synthesis of β-amino acids and the mechanisms of β-amino acid incorporation into natural products are summarized.
Mycobacterium tuberculosis (Mtb) is responsible for 9 million active tuberculosis cases annually, resulting in 1.5 million death cases per year worldwide. It is known that Mtb uses Arg as a nitrogen source in vitro, but the metabolic pathways have not been identified. It was found that, both nitrogen and carbons from Arg can be incorporated into the central metabolism of Mtb. The highly induced pathway for Arg utilization in Mtb differs from that of other bacteria including non-tuberculous mycobacteria.
1.2 New amino acids and derivatives
The increasing interest of modified peptides in chemical engineering of proteins and also as therapeutic agents has refreshed research toward the development of derivatives of new natural and non-natural amino acids.
Oxidative stress plays an important role in the development of atrial fibrillation. Derivatives of Arg including asymmetric dimethyl-Arg (ADMA) are central to nitric oxide metabolism and nitrosative stress. The circulating levels of ADMA, L-Arg, symmetric dimethyl-Arg (SDMA), and the ratio of L-Arg/ADMA to incidence of atrial fibrillation were investigated. The results revealed that circulating ADMA is not strongly associated with new-onset atrial fibrillation, and L-Arg and SDMA are also not predictive of long-term incidence of atrial fibrillation. A growing number of studies showed elevated concentrations of circulating ADMA and SDMA leading to mortality and cardiovascular diseases. A systematic review summarizes the evidence from studies of ADMA and SDMA with the risks of all-cause mortality and incident cardiovascular disease in meta-analyses. It was concluded that ADMA and SDMA are independent risk markers for all-cause mortality and cardiovascular disease across different populations and methodological approaches. In search for new drugs lowering arterial blood pressure, novel potential renin inhibitors based on human angiotensinogen, were designed and synthesized. All these inhibitors contain unnatural amino acids that are derivatives of N-alkylleucyl-β-hydroxy-γ-amino acids. In vitro renin inhibitory activity of all obtained compounds was within the range 10-6–10-9 M.
A series of different amino acid-bearing thieno[2,3-D]pyrimidine moiety and a tricyclic imidazothienopyrimidine of the Gly derivative were synthesized. All the obtained amino acid-derivatives were screened for their post-irradiation protective efficacy. Most of the newly synthesized derivatives showed significant protective effects against injuries induced by γ-irradiation exposure, and they may be promising curative agents against γ-irradiation induced oxidative stress and physiological disturbance in different organs.
A novel series of biaryl-based phenylalanines with a carboxyl-benzene (or a carboxyl-thiophene ring) was designed, synthesized, and pharmacologically characterized in vitro. The structural modifications were focused on positions 5- and 4- of the Phe ring. Various combinations of small-sized groups, both polar and lipophilic, hydrogen bond donors and acceptors, were investigated. All the target amino acids were pharmacologically characterized by radioligand binding at native AMPA, kainate, and NMDA receptors, and the structure–activity relationships were also studied.
Thiazolides are polypharmacologycal agents with at least three mechanisms of action against a broad spectrum of parasites, bacteria and viruses. New amino-acid ester thiazolide prodrugs were synthesized in order to improve their systemic absorption and tested. Oxazolidinone derivatives serve as important drugs among antibiotics, since they act on multidrug-resistant bacteria. A small library of compounds based on isoxazolidinone and dehydro-β-Pro was designed with the aim to obtain antibacterial agents and monoaminooxidase(MAO)-inhibitors. Substituted indolizidine and quinolizidine derivatives are readily assembled from cyclic amino acids (Pro or pipecolic acid) and γ-nitroaldehydes by a simple decarboxylative annulation process.
Derivatives of aminobenzoic acid were functionalized via a chemoselective carbene insertion manner without implementing protection and deprotection strategy under mild reaction conditions leading to carboxy and hydroxy functionalized a-amino esters (27 examples). The neurotrophic effects of L-Glu and β-phenyl-Glu hydrochloride were compared. It was found that β-phenyl-Glu hydrochloride was more potent than L-Glu in neuroprotection and increasing survival rate. A new member of the dimethylallyl-Trp synthase superfamily catalyzes prenylations of both Tyr and Trp derivatives. The results enhance the relationship of Tyr O- and Trp C7-prenyltranferases and provide a new enzyme for production of prenylated derivatives.
Arctigenin, a traditional medicine with many pharmacological activities, has been restricted due to its poor solubility in water. Five amino acid derivatives of arctigenin have been synthesized using Gly, Ala, Val, Leu, and Ile. The results showed that the amino acid derivatives have better solubility and exhibit higher anti-tumour activity than arctigenin.
New amino acid derivatives with carbocycles of adamantine and quinaldic acid were developed; their in vitro antiviral activity against highly pathogenic influenza A virus (H5N1) was evaluated; and found that they suppressed viral replication.
New N-(4-substituted phenyl)Gly derivatives have been synthesized. The intermediates (the chalcone and the thiosemicarbazone derivative) were derivatized and/or cyclized into different heterocyclic target derivatives and evaluated as potential anti-inflammatory agents. Novel rifamycins containing L-amino acid esters were produced, and their structure–activity relationships in solution were studied. The presence of the rifamycins' structures influenced antibacterial properties. Schiff base compounds of cinnamaldehyde and amino acids have been synthesized and investigated for their antimicrobial activities. A total of 24 Schiff base compounds were synthesized using a simple approach with 3 cinnamaldehyde derivatives and 8 amino acids. Results from the structure–activity relationship suggest that both –p–Cl on benzene ring of cinnamaldehyde and the number of –COOK of amino acid salts significantly contributed to antimicrobial activity.
A series of bile acid (cholic acid and deoxycholic acid) aryl/heteroaryl amides linked via α-amino acid were synthesized and tested against 3 human cancer cell-lines. Some of the conjugates showed promising results to be new anticancer agents with good in vitro results. They showed fairly good activity against the breast cancer cell line with respect to Cisplatin and comparable with respect to Doxorubicin and showed better activity against glioblastoma cancer cell line with respect to both Cisplatin and Doxorubicin drugs used as standards.
A series of red-shifted azobenzene amino (Scheme 1) acids have been synthesized via a two-step procedure. Derivatives of Tyr were first oxidized to the corresponding quinonoidal spirolactones followed by the unsymmetrical azo formation with the substituted phenylhydrazines in the presence of the ceric ammonium nitrate catalyst.
Kojic acid (5-hydroxy-2-hydroxymethyl-4H-pyran-4-one) is a natural product that is produced by many species of fungi. A simple and efficient method for the preparation of dialkylated kojic acid based α-amino acid derivatives was described. The novel derivatives might find application as tyrosinase inhibitors.
Oleanolic acid or oleanic acid (3β-hydroxy-olean-12-en-28-oic acid) is a naturally occurring pentacyclic triterpenoid related to betulinic acid. It is widely distributed in food and plants where it exists as a free acid or as an aglycone of triterpenoid saponins and exhibits a wide range of pharmacological and biological activities. Four known and two new amino acid conjugates of oleanolic acid were prepared, and investigated for their cytotoxic effects. The results revealed that two derivatives showed significantly increased inhibition rates than the parent oleanolic acid. Novel derivatives of ligustrazine-oleanolic acid were designed, and synthesized by conjugating amino acids to the 3-hydroxy group of ligustrazine-oleanolic acid by ester bonds. Their cytotoxicity was evaluated on four cancer cell lines. Hepatic fibrosis is a naturally occurring wound-healing reaction, with an imbalance of extracellular matrix during tissue repair response, which can further deteriorate to hepatocellular carcinoma without timely treatment. It was found that Gly derivative of ligustrazine-oleanolic acid selectively inhibited the proliferation and induced apoptosis indicating that Gly derivative of ligustrazine-oleanolic acid might be a potential antifibrosis agent for the therapy of hepatic fibrosis.
1.3 Miscellaneous
Methylation of Lys is one of the important post-translational modifications of histones that produces N(e)-mono-, di-, or trimethyl Lys residues. Multiple, site-specific Lys methylations of histones are essential to define epigenetic statuses and control heterochromatin formation, DNA repair, and transcription regulation. A new method was developed for preparing histones bearing multiple N(ε)-monomethyl Lys residues at specified positions that enables the installation of authentic N(ε)-monomethyl Lys at multiple positions within a protein for large-scale production.
All 20 common natural proteinogenic and 4 other α-amino acidisosteric α-amino tetrazoles have been synthesized. Since the tetrazole group is bioisosteric to the carboxylic group, these derivatives are widely used in medicinal chemistry and drug design. The synthetic process involves the use of the Ugi tetrazole reaction followed by deprotection (Scheme 2).
Amino acids with their variable side chains are ideal candidates for synthesizing biodegradable functional polyesters. The synthetic methods for poly-α-hydroxy esters derived from amino acids were reviewed. The efficient tRNA-mediated incorporation of the hydroxamate containing amino acid, N(ε)-acetyl-N(ε)-hydroxy-L-Lys into a transcription factor was reported. The tetrahydrofuranyl and tetrahydropyranyl O-protecting groups can be removed using mild acid conditions. These protecting groups can be used as valuable alternative for O-protection. Two new antifouling zwitterionic polymers, poly(lysine methacrylamide) and poly(ornithine methacrylamide) derived from natural amino acids Lys and Orn, respectively were developed and investigated. The super low fouling, biomimetic, and multifunctional properties of poly(lysine methacrylamide) and poly(ornithine methacrylamide) make them promising materials for a wide range of applications, such as implant coating, drug delivery and biosensing. Amino-acid-based chiral surfactants with polymerizable moieties are developed for the production of chiral nanoparticles. The synthesized particles are tested for their ability as nucleating agents in the enantioselective crystallization of amino acid conglomerate systems. The results demonstrate that only the chiral nanoparticles made of the polymerizable surfactant are able to act efficiently as nucleation agent in enantioselective crystallization.
The preparation by a direct condensation method, characterization, and cytocompatibility of homo- and hetero-polyesters of α-hydroxy amino acid derivatives with or without lactic acid conjugation has been described. It was concluded that overall selective cytocompatibility and bioactivity might render α-hydroxy amino acid polymers useful as extracellular matrix-mimicking materials for tissue engineering. An asymmetric decarboxylative Csp(3)–Csp(2) cross-coupling has been achieved via a mild, operationally simple protocol with Ni-catalyst. Variety of naturally abundant α-amino acids and aryl halides are transformed into valuable chiral benzyl amines. A highly diastereoselective acid-catalyzed N,O-acetalization/intramolecular transcarbamoylation cascade of reactions between protected α-amino acid derivatives (Ser and Thr) and non-natural α-amino acid derivatives with tetramethoxyalkanes has been reported. The resulting oligocyclic N,O-acetals have been used as excellent chiral building blocks for asymmetric transformations. The complete diastereoselectivity achieved with natural amino acid precursors is completely lost with their non-natural analogues. Incorporation of a non-natural Arg analogue (guanidiniocarbonyl pyrrole) into a cyclic peptide is capable of completely altering the self-assembly properties of the peptide. In contrast to the peptide which does not self-assemble, guanidiniocarbonyl pyrrole-containing peptide forms cationic nanofibers of micrometer length that are capable of gene transfection.
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