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1.
J Agric Food Chem ; 68(4): 989-997, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31909616

RESUMO

In the previous studies, gemini lipoamino acids (GLAA) were always synthesized by complex multistep organic synthesis, which involved a large number of byproducts and organic solvents. To develop a straightforward, efficient, and renewable synthesis strategy for GLAA, in this study, a type of novel green solvents, natural deep eutectic solvents (NADESs), were adopted as the solvents for these reactions. Five commercial enzymes were involved in the enzyme screening section, and Candida antarctica lipase B (CALB) tended to have the best performance in NADESs systems. The optimization procedure was performed using the Taguchi crossed array method and the highest yield of GLAA (59.14 ± 0.51%) was obtained in choline chloride-glycerol (C-Gly). The purification procedure was carried out with ethyl acetate and water, and the isolate yield ranged from 86.31 ± 2.36 to 91.34 ± 2.26%. With 10 times recycling, the yield of GLAA in C-Gly decreased from 59.14 ± 0.51 to 51.31 ± 0.68%. Interestingly, a synergistic effect of CALB and NADESs was found in the enzymatic synthesis of GLAA, which can be attributed to fatty acids being activated by chloride ions via hydrogen-bonding interactions and resulting in an enhancement in its electron-attracting ability.


Assuntos
Aminoácidos/síntese química , Proteínas Fúngicas/química , Lipase/química , Aminoácidos/química , Catálise , Glicerol/química , Ligações de Hidrogênio , Solventes/química
2.
J Enzyme Inhib Med Chem ; 35(1): 489-497, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31914827

RESUMO

A series of amino acid-sulphonamide conjugates was prepared through benzotriazole mediated coupling reactions and characterised by 1H-NMR, 13C-NMR, MS, and FTIR spectroscopic techniques as well as elemental analysis. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was determined against four human (h) isoforms, hCA I, hCA II, hCA VA, and hCA XII. Most of the synthesised compounds showed effective in vitro CA inhibitory properties. The new amino acid-sulphonamide conjugates showed potent inhibitory activity against hCA II, some of them at subnanomolar levels, exhibiting more effective inhibitory activity compared to the standard drug acetazolamide. Some of these sulphonamides were also found to be effective inhibitors of hCA I, hCA VA, and hCA XII, with activity from the low to high nanomolar range.


Assuntos
Aminoácidos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Sulfonamidas/farmacologia , Aminoácidos/síntese química , Aminoácidos/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Sulfonamidas/síntese química , Sulfonamidas/química
3.
Eur J Med Chem ; 186: 111826, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31740056

RESUMO

Fluorine-containing amino acids are becoming increasingly prominent in new drugs due to two general trends in the modern pharmaceutical industry. Firstly, the growing acceptance of peptides and modified peptides as drugs; and secondly, fluorine editing has become a prevalent protocol in drug-candidate optimization. Accordingly, fluorine-containing amino acids represent one of the more promising and rapidly developing areas of research in organic, bio-organic and medicinal chemistry. The goal of this Review article is to highlight the current state-of-the-art in this area by profiling 42 selected compounds that combine fluorine and amino acid structural elements. The compounds under discussion represent pharmaceutical drugs currently on the market, or in clinical trials as well as examples of drug-candidates that although withdrawn from development had a significant impact on the progress of medicinal chemistry and/or provided a deeper understanding of the nature and mechanism of biological action. For each compound, we present features of biological activity, a brief history of the design principles and the development of the synthetic approach, focusing on the source of tailor-made amino acid structures and fluorination methods. General aspects of the medicinal chemistry of fluorine-containing amino acids and synthetic methodology are briefly discussed.


Assuntos
Aminoácidos/síntese química , Desenho de Drogas , Flúor/química , Aminoácidos/química , Indústria Farmacêutica
4.
Eur J Med Chem ; 186: 111901, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31771826

RESUMO

Development of novel antimicrobial agents combating drug resistance is in an urgent need. Herein we report the design and synthesis of a series of short lipo-α/sulfono-γ-AA hybrid peptides. Several short peptides exhibit potent and broad-spectrum antimicrobial activity toward both Gram-positive and Gram-negative bacteria. Membrane depolarization and fluorescence microscopy studies indicate that these short lipo-α/sulfono-γ-AA hybrid peptides can mimic the mechanisms of HDPs to kill bacteria by disrupting bacterial membranes. In addition, these short peptides also show capability to eradicate the biofilm formation of E. coli even at very low concentration. The further development of lipidated α/sulofono-γ-AA hybrid peptides may lead to a new class of antibiotic agents to combat drug resistance.


Assuntos
Aminoácidos/farmacologia , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Peptídeos/farmacologia , Peptidomiméticos/farmacologia , Aminoácidos/síntese química , Aminoácidos/química , Antibacterianos/síntese química , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Peptidomiméticos/síntese química , Peptidomiméticos/química , Relação Estrutura-Atividade
5.
Chem Asian J ; 15(1): 79-84, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31778028

RESUMO

ß-Amino acid N-carboxy anhydrides (ß-NCAs) are rarely used in the synthesis of ß-peptides, which is due mainly to the poor availability of these potentially useful substrates. Herein, we describe the heretofore challenging synthesis of ß-NCAs via a single-step, rapid, and mild formation using pH flash switching and flash dilution, which are aspects of micro-flow technology. We synthesized 15 ß-NCAs in good to excellent yields that included acid-labile ß-NCAs that cannot be readily synthesized using the conventional Leuchs approach. Scaled-up synthesis using this process can be readily achieved via continuous operation.


Assuntos
Aminoácidos/síntese química , Anidridos/síntese química , Técnicas Analíticas Microfluídicas , Aminoácidos/química , Anidridos/química , Técnicas Analíticas Microfluídicas/instrumentação , Estrutura Molecular
6.
Chem Commun (Camb) ; 56(4): 579-582, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31830176

RESUMO

The highly enantioselective (>99.5% ee) synthesis of a new class of densely functionalized ß2,2-amino acid derivatives by reacting isoxazolidin-5-ones with para-quinone methides in the presence of chiral ammonium salt phase-transfer catalysts was developed. The reaction proceeds with exceptionally low catalyst loadings down to 20 ppm on gram scale and the utilization of the primary addition products towards further manipulations was demonstrated for selected examples.


Assuntos
Aminoácidos/síntese química , Indolquinonas/química , Isoxazóis/química , Aminoácidos/química , Estrutura Molecular , Estereoisomerismo
7.
Chem Commun (Camb) ; 55(98): 14721-14724, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31670353

RESUMO

Seven amino acids were electrochemically synthesized from biomass-derivable α-keto acids and NH2OH with faradaic efficiencies (FEs) of 77-99% using an earth-abundant TiO2 catalyst. Furthermore, we newly constructed a flow-type electrochemical reactor, named a "polymer electrolyte amino acid electrosynthesis cell", and achieved continuous production of alanine with an FE of 77%.


Assuntos
Aminoácidos/síntese química , Titânio/química , Alanina/síntese química , Hidróxido de Amônia/química , Biomassa , Catálise , Técnicas Eletroquímicas , Cetoácidos/química
8.
J Enzyme Inhib Med Chem ; 34(1): 1652-1659, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31530034

RESUMO

Eight genetically distinct carbonic anhydrase (EC 4.2.1.1) enzyme families (α-, ß-, γ- δ-, ζ-, η-, θ- and ι-CAs) were described to date. On the other hand, 16 mammalian α-CA isoforms are known to be involved in many diseases such as glaucoma, edema, epilepsy, obesity, hypoxic tumors, neuropathic pain, arthritis, neurodegeneration, etc. Although CA inhibitors were investigated for the management of a variety of such disorders, the activators just started to be investigated in detail for their in vivo effects. This review summarizes the activation profiles of α-, ß, γ-, δ-, ζ- and η- CAs from various organisms (animals, fungi, protozoan, bacteria and archaea) with the most investigated classes of activators, the amines and the amino acids.


Assuntos
Aminas/farmacologia , Aminoácidos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Aminas/síntese química , Aminas/química , Aminoácidos/síntese química , Aminoácidos/química , Bactérias/enzimologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Entamoeba histolytica/enzimologia , Fungos/enzimologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular
9.
Chem Pharm Bull (Tokyo) ; 67(10): 1046-1049, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31341115

RESUMO

A new catalytic system comprising chiral Ag complex and Li aryloxide/bisphosphine oxide is developed for the synthesis of ß2,2-amino acids via direct asymmetric Mannich-type reaction of 4-subsituted isoxazolidin-5-ones. The Mannich adduct is a direct precursor of ß-peptidic compounds otherwise difficult to obtain.


Assuntos
Aminoácidos/síntese química , Carbonatos/química , Complexos de Coordenação/química , Bases de Lewis/química , Lítio/química , Aminoácidos/química , Catálise , Complexos de Coordenação/síntese química , Isoxazóis/química , Estrutura Molecular , Prata/química
10.
Molecules ; 24(12)2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31226791

RESUMO

Stapled α-helical peptides represent an emerging superclass of macrocyclic molecules with drug-like properties, including high-affinity target binding, protease resistance, and membrane permeability. As a model system for probing the chemical space available for optimizing these properties, we focused on dual Mdm2/MdmX antagonist stapled peptides related to the p53 N-terminus. Specifically, we first generated a library of ATSP-7041 (Chang et al., 2013) analogs iteratively modified by L-Ala and D-amino acids. Single L-Ala substitutions beyond the Mdm2/(X) binding interfacial residues (i.e., Phe3, Trp7, and Cba10) had minimal effects on target binding, α-helical content, and cellular activity. Similar binding affinities and cellular activities were noted at non-interfacial positions when the template residues were substituted with their d-amino acid counterparts, despite the fact that d-amino acid residues typically 'break' right-handed α-helices. d-amino acid substitutions at the interfacial residues Phe3 and Cba10 resulted in the expected decreases in binding affinity and cellular activity. Surprisingly, substitution at the remaining interfacial position with its d-amino acid equivalent (i.e., Trp7 to d-Trp7) was fully tolerated, both in terms of its binding affinity and cellular activity. An X-ray structure of the d-Trp7-modified peptide was determined and revealed that the indole side chain was able to interact optimally with its Mdm2 binding site by a slight global re-orientation of the stapled peptide. To further investigate the comparative effects of d-amino acid substitutions we used linear analogs of ATSP-7041, where we replaced the stapling amino acids by Aib (i.e., R84 to Aib4 and S511 to Aib11) to retain the helix-inducing properties of α-methylation. The resultant analog sequence Ac-Leu-Thr-Phe-Aib-Glu-Tyr-Trp-Gln-Leu-Cba-Aib-Ser-Ala-Ala-NH2 exhibited high-affinity target binding (Mdm2 Kd = 43 nM) and significant α-helicity in circular dichroism studies. Relative to this linear ATSP-7041 analog, several d-amino acid substitutions at Mdm2(X) non-binding residues (e.g., d-Glu5, d-Gln8, and d-Leu9) demonstrated decreased binding and α-helicity. Importantly, circular dichroism (CD) spectroscopy showed that although helicity was indeed disrupted by d-amino acids in linear versions of our template sequence, stapled molecules tolerated these residues well. Further studies on stapled peptides incorporating N-methylated amino acids, l-Pro, or Gly substitutions showed that despite some positional dependence, these helix-breaking residues were also generally tolerated in terms of secondary structure, binding affinity, and cellular activity. Overall, macrocyclization by hydrocarbon stapling appears to overcome the destabilization of α-helicity by helix breaking residues and, in the specific case of d-Trp7-modification, a highly potent ATSP-7041 analog (Mdm2 Kd = 30 nM; cellular EC50 = 600 nM) was identified. Our findings provide incentive for future studies to expand the chemical diversity of macrocyclic α-helical peptides (e.g., d-amino acid modifications) to explore their biophysical properties and cellular permeability. Indeed, using the library of 50 peptides generated in this study, a good correlation between cellular permeability and lipophilicity was observed.


Assuntos
Aminoácidos/química , Peptídeos Penetradores de Células/química , Fragmentos de Peptídeos/química , Conformação Proteica , Sequência de Aminoácidos/genética , Substituição de Aminoácidos/genética , Aminoácidos/síntese química , Peptídeos Penetradores de Células/síntese química , Peptídeos Penetradores de Células/genética , Peptídeos Penetradores de Células/farmacologia , Dicroísmo Circular , Dipeptídeos/química , Humanos , Oligopeptídeos/química , Peptídeos Cíclicos/farmacologia , Permeabilidade/efeitos dos fármacos , Estrutura Secundária de Proteína , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/genética
11.
Spectrochim Acta A Mol Biomol Spectrosc ; 222: 117226, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31181504

RESUMO

Six novel amino acid chromophores were synthesized and their spectroscopic, acid-base, and electrochemical properties are discussed in this work. In studied compounds, selected amino acid residues (l-Aspartic acid, l-Glutamic acid, l-Glutamine, l-Histidine, l-Lysine, l-Arginine) are attached to the 1-(piperazine) 9,10-anthraquinone skeleton via the amide bond between the carboxyl group of amino acid and nitrogen atom of the piperazine ring. All derivatives have been characterized using a variety of spectroscopic techniques (mass spectrometry, 1HNMR, UV-Vis, IR spectroscopy), acid-base (electrochemical and UV-Vis) titrations, and cyclic voltammetry methods. Basing on observed experimental effects, supported by quantum chemical simulations, the structure-properties links were established. They are indicative of the specific interactions within and/or in-between amino acid side groups, which are prone to form both, intra- and intermolecular hydrogen bonds as well as electrostatic interactions with the anthraquinone system.


Assuntos
Aminoácidos/química , Antraquinonas/química , Corantes/química , Aminoácidos/síntese química , Antraquinonas/síntese química , Corantes/síntese química , Técnicas Eletroquímicas , Ligações de Hidrogênio , Modelos Moleculares , Prótons , Espectrofotometria Ultravioleta
12.
Chemistry ; 25(43): 10226-10231, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31161639

RESUMO

A Pd-catalyzed enantiospecific and regioselective ring-opening Suzuki-Miyaura arylation of aziridine-2-carboxylates was developed. The cross-coupling allows for the asymmetric preparation of enantioenriched ß2 -aryl amino acids, starting from commercially available enantiopure d- and l-serine esters. The mechanism and selectivity of the reaction was rationalized based on computational models.


Assuntos
Aminoácidos/química , Aziridinas/química , Paládio/química , Aminoácidos/síntese química , Catálise , Serina/química , Estereoisomerismo , Termodinâmica
13.
Arch Pharm (Weinheim) ; 352(6): e1800354, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081964

RESUMO

Nineteen antioxidant pseudopeptides were designed and synthesized. They were confirmed as mild antioxidants, in which L1-11 was the most active antioxidant with a cellular antioxidant activity (CAA) value of 5.65 ± 0.64 µmol QE/g, and L1-12 was the second most active one (5.58 ± 0.66 µmol QE/g). The existence of nonnatural amino acids in L1-12 increased its stability. Pretreatment with L1-12 dose-dependently extended the lifespan of Caenorhabditis elegans. L1-12 improved resistance against UVB irradiation, oxidative stress induced by paraquat, and thermal shock. It decreased the reactive oxygen species level and upregulated the superoxide dismutase activity inside C. elegans. This pseudopeptide sensitively enhanced the expressions of the Cat-1 and Nhr-8 genes to reduce oxidative damage, leading to an extension of the lifespan. All the evidence support that L1-12 may probably be a potential antiageing agent.


Assuntos
Aminoácidos/síntese química , Antioxidantes/síntese química , Caenorhabditis elegans/efeitos dos fármacos , Desenho de Drogas , Longevidade/efeitos dos fármacos , Peptídeos/síntese química , Aminoácidos/química , Aminoácidos/farmacologia , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/efeitos da radiação , Proteínas de Caenorhabditis elegans/genética , Transportador 1 de Aminoácidos Catiônicos/genética , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Expressão Gênica/efeitos dos fármacos , Longevidade/genética , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Peptídeos/química , Peptídeos/farmacologia , Receptores Citoplasmáticos e Nucleares/genética , Relação Estrutura-Atividade
14.
Org Biomol Chem ; 17(20): 5138-5147, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31073571

RESUMO

A series of amino acid derivatives are successfully synthesized via a metal-free C-N coupling reaction of 5-alkoxy-3,4-dihalo-2(5H)-furanones and amino acids. Their structures are well characterized with 1H NMR, 13C NMR, ESI-MS and elemental analysis. As potential linkers of the 2(5H)-furanone unit with other drug moieties containing a hydroxyl or amino group, the effect of amino acids is investigated by comparison with other 2(5H)-furanone compounds by constructing C-O/C-S bonds. The preliminary results of the biological activity assay by the MTT method on a series of cancer cell lines in vitro reveal that the introduction of amino acids basically has no toxic effect. This can lead to these 2(5H)-furanone derivatives being further well-linked with other bioactive moieties with amino or hydroxy groups as expected. Thus, the biological activity assay gives a direction for the design of bioactive 2(5H)-furanones based on these amino acid linkers.


Assuntos
Álcoois/farmacologia , Aminoácidos/farmacologia , Antineoplásicos/farmacologia , Furanos/farmacologia , Álcoois/química , Aminoácidos/síntese química , Aminoácidos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/química , Humanos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
15.
Amino Acids ; 51(7): 991-998, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079215

RESUMO

DMDP acetic acid [N-carboxymethyl-2,5-dideoxy-2,5-imino-D-mannitol] 5 from Stevia rebaudiana is the first isolated natural amino acid derived from iminosugars bearing an N-alkyl acid side chain; it is clear from GCMS studies that such derivatives with acetic and propionic acids are common in a broad range of plants including mulberry, Baphia, and English bluebells, but that they are very difficult to purify. Reaction of unprotected pyrrolidine iminosugars with aqueous glyoxal gives the corresponding N-acetic acids in very high yield; Michael addition of both pyrrolidine and piperidine iminosugars and that of polyhydroxylated prolines to tert-butyl acrylate give the corresponding N-propionic acids in which the amino group of ß-alanine is incorporated into the heterocyclic ring. These easy syntheses allow the identification of this new class of amino acid in plant extracts and provide pure samples for biological evaluation. DMDP N-acetic and propionic acids are potent α-galactosidase inhibitors in contrast to potent ß-galactosidase inhibition by DMDP.


Assuntos
Acetatos/síntese química , Aminoácidos/química , Glicosídeo Hidrolases/antagonistas & inibidores , Imino Açúcares/isolamento & purificação , Propionatos/síntese química , Pirrolidinas/síntese química , Stevia/química , Aminoácidos/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Glicina/química , Glicosídeos/metabolismo , Hidroxiprolina/química , Imino Açúcares/química , Piperidinas/síntese química , alfa-Galactosidase/antagonistas & inibidores , beta-Alanina/química , beta-Galactosidase/antagonistas & inibidores
16.
Org Biomol Chem ; 17(22): 5595-5600, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31115426

RESUMO

2-(Methylthio)aniline (MTA) directed C(sp3)-H functionalisations are efficient and straightforward protocols for the selective ß-modification of N-methylated amino acids. The decreased reactivity of MTA in comparison with the 8-aminoquinoline (AQ) directing group allows for selective monoarylations in high yields without the formation of side products. The protocol is also suitable for the introduction of highly functionalised side chains onto the C-terminal alanines of dipeptides. The MTA directing group can easily be removed, providing free carboxylic acids as valuable building blocks.


Assuntos
Aminoácidos/síntese química , Compostos de Anilina/química , Peptídeos/síntese química , Aminoácidos/química , Metilação , Conformação Molecular , Peptídeos/química
17.
Chemphyschem ; 20(11): 1475-1487, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-30950574

RESUMO

Specific spin labeling allows the site-selective investigation of biomolecules by EPR and DNP enhanced NMR spectroscopy. A novel spin labeling strategy for commercially available Fmoc-amino acids is developed. In this approach, the PROXYL spin label is covalently attached to the hydroxyl side chain of three amino acids hydroxyproline (Hyp), serine (Ser) and tyrosine (Tyr) by a simple three-step synthesis route. The obtained PROXYL containing building-blocks are N-terminally protected by the Fmoc-protection group, which makes them applicable for the use in solid-phase peptide synthesis (SPPS). This approach allows the insertion of the spin label at any desired position during SPPS, which makes it more versatile than the widely used post synthetic spin labeling strategies. For the final building-blocks, the radical activity is proven by EPR. DNP enhanced solid-state NMR experiments employing these building-blocks in a TCE solution show enhancement factors of up to 26 for 1 H and 13 C (1 H→13 C cross-polarization). To proof the viability of the presented building-blocks for insertion of the spin label during SPPS the penta-peptide Acetyl-Gly-Ser(PROXYL)-Gly-Gly-Gly was synthesized employing the spin labeled Ser building-block. This peptide could successfully be isolated and the spin label activity proved by EPR and DNP NMR measurements, showing enhancement factors of 12.1±0.1 for 1 H and 13.9±0.5 for 13 C (direct polarization).


Assuntos
Aminoácidos/síntese química , Fluorenos/síntese química , Oligopeptídeos/síntese química , Pirrolidinas/síntese química , Técnicas de Síntese em Fase Sólida/métodos , Marcadores de Spin/síntese química , Espectroscopia de Ressonância de Spin Eletrônica , Hidroxiprolina/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Serina/síntese química , Tirosina/síntese química
18.
World J Microbiol Biotechnol ; 35(4): 67, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30963257

RESUMO

Unnatural amino acids (UAAs) are valuable building blocks in the manufacture of a wide range of pharmaceuticals. UAAs exhibit biological activity as free acids and they can be incorporated into linear or cyclic peptides with biological activity. However, the scope of biotechnological application of UAAs goes beyond this, as they can be used to investigate the structure and dynamics of proteins, to study protein interactions, or to modulate the activity of proteins in living cells. The means to expand nature's repertoire of amino acids include chemical and biological routes. An UAA can be made through chemical modifications of natural amino acids, or related compounds. These modifications typically rely on utilisation of ligands and palladium catalysts. Employing biocatalysts in the synthesis of UAAs can also afford novel molecules with different physical and chemical properties. A number of transaminases for example have been identified and employed in the production of UAAs. This review will compare the chemical and biological routes for the synthesis of UAAs and provide an overview of their applications.


Assuntos
Aminoácidos/biossíntese , Aminoácidos/síntese química , Biotecnologia/métodos , Aminoácidos/química , Biocatálise , Enzimas/metabolismo , Engenharia Metabólica , Engenharia de Proteínas/métodos
19.
Org Biomol Chem ; 17(10): 2753-2758, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30785174

RESUMO

A system for the directed hydrogenation of nitrogen heterocycles is described in which hydrogen is delivered cis to a hydroxymethyl group by a rhodium catalyst with a simple phosphine ligand. The chemistry is applied to the synthesis of the hygric acid moiety of lincomycin and the pipecolic acid moiety of Argatroban. A series of control experiments indicate that the stereoselectivity is a result of a combination of both coordination and hydrogen bonding.


Assuntos
Aminoácidos/química , Aminoácidos/síntese química , Catálise , Técnicas de Química Sintética , Ligações de Hidrogênio , Hidrogenação , Ligantes , Lincomicina/química , Estereoisomerismo
20.
Bioorg Med Chem ; 27(5): 729-747, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30692024

RESUMO

Fosmidomycin is a natural antibiotic with promising IspC (DXR, 1-deoxy-d-xylulose-5-phosphate reductoisomerase) inhibitory activity. This enzyme catalyzes the first committed step of the non-mevalonate isoprenoid biosynthesis pathway, which is essential in Plasmodium falciparum and Mycobacterium tuberculosis. Mainly as a result of its high polarity, fosmidomycin displays suboptimal pharmacokinetic properties. Furthermore, fosmidomycin is inactive against M. tuberculosis as a result of its inability to penetrate the bacterial cell wall. Temporarily masking the phosphonate moiety as a prodrug has the potential to solve both issues. We report the application of two amino acid based prodrug approaches on a fosmidomycin surrogate. Conversion of the phosphonate moiety into tyrosine-derived esters increases the in vitro activity against asexual blood stages of P. falciparum, while phosphonodiamidate prodrugs display promising antitubercular activities. Selected prodrugs were tested in vivo in a P. berghei malaria mouse model. These results indicate good in vivo antiplasmodial potential.


Assuntos
Aminoácidos/farmacologia , Antimaláricos/farmacologia , Antituberculosos/farmacologia , Fosfomicina/análogos & derivados , Pró-Fármacos/farmacologia , Aminoácidos/síntese química , Aminoácidos/toxicidade , Animais , Antimaláricos/síntese química , Antimaláricos/toxicidade , Antituberculosos/síntese química , Antituberculosos/toxicidade , Linhagem Celular , Feminino , Fosfomicina/síntese química , Fosfomicina/farmacologia , Fosfomicina/toxicidade , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Pró-Fármacos/síntese química , Pró-Fármacos/toxicidade
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