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1.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443608

RESUMO

In order to develop novel bioactive substances with potent activities, some new valine-derived compounds incorporating a 4-(phenylsulfonyl)phenyl fragment, namely, acyclic precursors from N-acyl-α-amino acids and N-acyl-α-amino ketones classes, and heterocycles from the large family of 1,3-oxazole-based compounds, were synthesized. The structures of the new compounds were established using elemental analysis and spectral (UV-Vis, FT-IR, MS, NMR) data, and their purity was checked by reversed-phase HPLC. The newly synthesized compounds were evaluated for their antimicrobial and antibiofilm activities, for toxicity on D. magna, and by in silico studies regarding their potential mechanism of action and toxicity. The 2-aza-3-isopropyl-1-[4-(phenylsulfonyl)phenyl]-1,4-butanedione 4b bearing a p-tolyl group in 4-position exhibited the best antibacterial activity against the planktonic growth of both Gram-positive and Gram-negative strains, while the N-acyl-α-amino acid 2 and 1,3-oxazol-5(4H)-one 3 inhibited the Enterococcus faecium biofilms. Despite not all newly synthesized compounds showing significant biological activity, the general scaffold allows several future optimizations for obtaining better novel antimicrobial agents by the introduction of various substituents on the phenyl moiety at position 5 of the 1,3-oxazole nucleus.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Cetonas/síntese química , Cetonas/farmacologia , Oxazóis/síntese química , Oxazóis/farmacologia , Anti-Infecciosos/química , Biofilmes/efeitos dos fármacos , Técnicas de Química Sintética , Cetonas/química , Oxazóis/química , Relação Estrutura-Atividade
2.
Chem Commun (Camb) ; 57(59): 7236-7239, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34263271

RESUMO

The extent of thermodynamic stabilization of telomeric G-quadruplex (G4) by isomers of G4 ligand L2H2-6OTD, a telomestatin analog, is inversely correlated with susceptibility to S1 nuclease. L2H2-6OTD facilitated the S1 nuclease activities through the base flipping in G4, unlike the conventional role of G4 ligands which inhibit the protein binding to DNA/RNA upon ligand interactions.


Assuntos
Quadruplex G , Endonucleases Específicas para DNA e RNA de Cadeia Simples/metabolismo , Isomerismo , Ligantes , Conformação de Ácido Nucleico , Oxazóis/química , Telômero/química , Termodinâmica
3.
Eur J Med Chem ; 222: 113583, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34119832

RESUMO

Herein we disclosed the novel nucleophilic addition reactions of the thiophenols and oxazolinium (DCZ0358) to produce N-2'-aryletheryl-1'-alkoxy-ethyl substituted arylisoquinolones. After evaluating the anti-inflammatory activity in vitro, 2d was found having significant anti-TNFα activity. Through the amplified synthesis of 2d, four monomers (3a-b and 4a-d) were obtained by chiral separation of the product. The reaction mechanism was proposed and explored by the control experiments. However, only the R-stereoisomers 3b and 4b have significant anti-TNFα activity in vitro (IC50 = 56 and 14 nM, respectively). Moreover, 4b exerts potent therapeutic effects on ulcerative colitis in vivo (30 mg/kg bw, qd, i. g.). The subsequent bio-target exploration of compound 4bvia molecular docking and the experimental validation disclosed that 4b has 3-fold selectivity of binding activity on estrogen receptor (ER) beta (ß) (Ki = 760.86 nM) vs. alpha (α) (Ki = 2320.58 nM). Thus, it provides a novel type of non-steroidal leads for developing anti-inflammatory drugs.


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa/tratamento farmacológico , Descoberta de Drogas , Oxazóis/farmacologia , Fenóis/farmacologia , Quinolonas/farmacologia , Compostos de Sulfidrila/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Sulfato de Dextrana , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxazóis/química , Fenóis/química , Quinolonas/síntese química , Quinolonas/química , Células RAW 264.7 , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
4.
Molecules ; 26(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069470

RESUMO

The intermolecular interactions in a series of nine similar 4,5-phenyl-oxazoles were studied on the basis of crystal structures determined by X-ray diffraction. The crystal architectures were analyzed for the importance and hierarchies of different, weak intermolecular interactions using three approaches: the geometrical characteristics, topological analysis (for the model based on the transfer of multipolar parameters), and energetics of the molecule-molecule interactions. The geometries of the molecules were quite similar and close to the typical values. The results of the analysis of the interactions suggest that the number of nonspecific interactions is more important than the apparent strength of the specific interactions. The interactions involving covalently bound bromine and divalent sulfur atoms were classified as secondary, they certainly did not define the crystal packing, and they played a minor role in the overall crystal cohesion energies. Incidentally, another method for confirming the degree of isostructurality, according to the topologies of the interactions, is described.


Assuntos
Oxazóis/química , Bromo/química , Cristalografia por Raios X , Ligação de Hidrogênio , Estrutura Molecular , Enxofre/química , Termodinâmica
5.
Sensors (Basel) ; 21(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062922

RESUMO

Interactions between proteins and carbohydrates with larger biomacromolecules, e.g., lectins, are usually examined using self-assembled monolayers on target gold surfaces as a simplified model measuring setup. However, most of those measuring setups are either limited to a single substrate or do not allow for control over ligand distance and spacing. Here, we develop a synthetic strategy, consisting of a cascade of a thioesterification, native chemical ligation (NCL) and thiol-ene reaction, in order to create three-component polymer conjugates with a defined double bioactivation at the chain end. The target architecture is the vicinal attachment of two biomolecule residues to the α telechelic end point of a polymer and a thioether group at the ω chain end for fixating the conjugate to a gold sensor chip surface. As proof-of-principle studies for affinity measurements, we demonstrate the interaction between covalently bound mannose and ConA in surface acoustic wave (SAW) and surface plasmon resonance (SPR) experiments.


Assuntos
Ouro , Oxazóis/química , Ressonância de Plasmônio de Superfície , Concanavalina A , Lectinas , Manose
6.
Methods Mol Biol ; 2306: 105-121, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33954943

RESUMO

Fatty acids are an essential structural and energy storage component of cells and hence there is much interest in their metabolism, requiring identification and quantification with readily available instrumentation, such as GC-MS. Fatty acid methyl esters (FAMEs) can be generated and extracted directly from biological tissue, in a one-pot process, and following high resolution GC, their respective chain length, degrees of unsaturation, and other functionalities can be readily identified using EI-MS. Defining the positions of the double bonds in the alkyl chain requires conversion of the FAMEs into their respective dimethyloxazoline (DMOX) derivatives. Following EI, this derivative allows charge retention on the heterocycle, and concomitant charge remote fragmentation of the alkyl chain to yield key double bond position identifying ions. The protocols described herein have been applied to the identification and quantification of fatty acids harvested from microalgae grown to produce biofuels and to the screening of salt tolerant Arabidopsis mutants.


Assuntos
Arabidopsis/química , Ácidos Graxos/isolamento & purificação , Lipidômica/métodos , Microalgas/química , Biologia Computacional , Esterificação , Ácidos Graxos/química , Cromatografia Gasosa-Espectrometria de Massas , Estrutura Molecular , Oxazóis/química , Folhas de Planta/química , Raízes de Plantas/química , Caules de Planta/química , Software
7.
ACS Chem Biol ; 16(5): 820-828, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33843189

RESUMO

Actin is the most abundant protein in eukaryotic cells and is key to many cellular functions. The filamentous form of actin (F-actin) can be studied with help of natural products that specifically recognize it, as for example fluorophore-labeled probes of the bicyclic peptide phalloidin, but no synthetic probes exist for the monomeric form of actin (G-actin). Herein, we have panned a phage display library consisting of more than 10 billion bicyclic peptides against G-actin and isolated binders with low nanomolar affinity and greater than 1000-fold selectivity over F-actin. Sequence analysis revealed a strong similarity to a region of thymosin-ß4, a protein that weakly binds G-actin, and competition binding experiments confirmed a common binding region at the cleft between actin subdomains 1 and 3. Together with F-actin-specific peptides that we also isolated, we evaluated the G-actin peptides as probes in pull-down, imaging, and competition binding experiments. While the F-actin peptides were applied successfully for capturing actin in cell lysates and for imaging, the G-actin peptides did not bind in the cellular context, most likely due to competition with thymosin-ß4 or related endogenous proteins for the same binding site.


Assuntos
Actinas/química , Proteínas dos Microfilamentos/química , Peptídeos Cíclicos/química , Timosina/química , Citoesqueleto de Actina/química , Sítios de Ligação , Ligação Competitiva , Células HeLa , Humanos , Técnicas In Vitro , Toxinas Marinhas/química , Oxazóis/química , Biblioteca de Peptídeos , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade
8.
J Mater Chem B ; 9(19): 4031-4038, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-33908590

RESUMO

Valvular heart disease is an important disease that endangers human health and heart valve replacement has become one of the main treatments for patients with severe valvular heart disease. However, the traditional surgical valve replacement (SVR) suffers several drawbacks such as high risk, great trauma and long recovery time, and more than 30% of patients are intolerant to SVR, especially elderly patients. In recent years, with the development of minimally invasive technology, transcatheter heart valve replacement (THVR) as a method of implantation without thoracotomy has become an optimal treatment for severe valvular heart disease due to its advantages of minimal trauma, low risk and fast recovery. Meanwhile, the usage of bioprosthetic heart valves (BHVs) has been enlarged greatly with the rapid development of THVR and the aging population. Most BHVs in clinics are crosslinked by glutaraldehyde (Glut), which shows great mechanical properties and chemical stability. However, some problems such as poor biocompatibility, calcification, coagulation and endothelialization difficulty also need to be solved urgently for Glut-treated BHVs. In this work, a non-Glut treated BHV from 7a-ethyltetrahydro-oxazolo[3,4-c]oxazole (OX-Et) crosslinked porcine pericardium (PP) has been developed. Compared with glutaraldehyde-crosslinked porcine pericardium (Glut-PP), good physical and chemical properties similar to Glut-PP are shown for OX-Et treated porcine pericardium (OX-Et-PP). It is noteworthy that better biocompatibility, endothelialization performance, and anti-coagulant effect as well as the improved anti-calcification property can also be observed for OX-Et-PP in the in vitro and in vivo study, potentially making OX-Et-PP a good candidate in the application of BHVs.


Assuntos
Anticoagulantes/química , Materiais Biocompatíveis/química , Reagentes para Ligações Cruzadas/química , Oxazóis/química , Animais , Anticoagulantes/farmacologia , Materiais Biocompatíveis/farmacologia , Calcificação Fisiológica/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Glutaral/química , Hemólise/efeitos dos fármacos , Pericárdio/química , Pericárdio/patologia , Agregação Plaquetária/efeitos dos fármacos , Próteses e Implantes , Ratos , Suínos
9.
Eur J Med Chem ; 219: 113455, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33894528

RESUMO

Proteasomes contribute to maintaining protein homeostasis and their inhibition is beneficial in certain types of cancer and in autoimmune diseases. However, the inhibition of the proteasomes in healthy cells leads to unwanted side-effects and significant effort has been made to identify inhibitors specific for the immunoproteasome, especially to treat diseases which manifest increased levels and activity of this proteasome isoform. Here, we report our efforts to discover fragment-sized inhibitors of the human immunoproteasome. The screening of an in-house library of structurally diverse fragments resulted in the identification of benzo[d]oxazole-2(3H)-thiones, benzo[d]thiazole-2(3H)-thiones, benzo[d]imidazole-2(3H)-thiones, and 1-methylbenzo[d]imidazole-2(3H)-thiones (with a general term benzoXazole-2(3H)-thiones) as inhibitors of the chymotrypsin-like (ß5i) subunit of the immunoproteasome. A subsequent structure-activity relationship study provided us with an insight regarding growing vectors. Binding to the ß5i subunit was shown and selectivity against the ß5 subunit of the constitutive proteasome was determined. Thorough characterization of these compounds suggested that they inhibit the immunoproteasome by forming a disulfide bond with the Cys48 available specifically in the ß5i active site. To obtain fragments with biologically more tractable covalent interactions, we performed a warhead scan, which yielded benzoXazole-2-carbonitriles as promising starting points for the development of selective immunoproteasome inhibitors with non-peptidic scaffolds.


Assuntos
Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/química , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Oxazóis/química , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/metabolismo , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/metabolismo , Relação Estrutura-Atividade , Tiazóis/química , Tionas/química
10.
Eur J Med Chem ; 218: 113406, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33823395

RESUMO

The cyanobacterial oligopeptides are recognized for being highly selective, efficacious and relatively safer compounds with diverse bioactivities. Azoline-based natural compounds consist of heterocycles which are reduced analogues of five-membered heterocyclic azoles. Among other varieties of azoline-based natural compounds, the heteropeptides bearing oxazoline or thiazoline heterocycles possess intrinsic structural properties with captivating pharmacological profiles, representing excellent templates for the design of novel therapeutics. The specificity of heteropeptides has been translated into prominent safety, tolerability, and efficacy profiles in humans. These peptidic congeners serve as ideal intermediary between small molecules and biopharmaceuticals based on their typically low production complexity compared to the protein-based biopharmaceuticals. The distinct bioproperties and unique structures render these heteropeptides one of the most promising lead compounds for drug discovery. The high degree of chemical diversity in cyanobacterial secondary metabolites may constitute a prolific source of new entities leading to the development of new pharmaceuticals. This review focuses on the azoline-based natural oligopeptides with emphasis on distinctive structural features, stereochemical aspects, biological activities, structure activity relationship, synthetic and biosynthetic aspects as well as mode of action of cyanobacteria-derived peptides.


Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Cianobactérias/química , Oligopeptídeos/farmacologia , Oxazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Proliferação de Células/efeitos dos fármacos , Células HeLa , Humanos , Oligopeptídeos/síntese química , Oligopeptídeos/química , Oxazóis/síntese química , Oxazóis/química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo
11.
J Med Chem ; 64(8): 4709-4729, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33797924

RESUMO

We describe the discovery of histone deacetylase (HDACs) 1, 2, and 3 inhibitors with ethyl ketone as the zinc-binding group. These HDACs 1, 2, and 3 inhibitors have good enzymatic and cellular activity. Their serum shift in cellular potency has been minimized, and selectivity against hERG has been improved. They are also highly selective over HDACs 6 and 8. These inhibitors contain a variety of substituted heterocycles on the imidazole or oxazole scaffold. Compounds 31 and 48 stand out due to their good potency, high selectivity over HDACs 6 and 8, reduced hERG activity, optimized serum shift in cellular potency, and good rat and dog PK profiles.


Assuntos
Canal de Potássio ERG1/metabolismo , HIV-1/fisiologia , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Cetonas/química , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/antagonistas & inibidores , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/química , Humanos , Imidazóis/química , Oxazóis/química , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Ratos , Relação Estrutura-Atividade , Ativação Viral/efeitos dos fármacos
12.
Int J Nanomedicine ; 16: 2735-2749, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33859475

RESUMO

Purpose: Nanocarriers, with a high drug loading content and good safety, to achieve desirable therapeutic effect are always the goals for industry and research. Methods and Results: In the present study, we developed a docetaxel loaded poly-2-oxazoline polymer micellar system which employed poly-2-butyl-2 oxazoline and poly-2-methyl-2 oxazoline as the hydrophobic chain and hydrophilic chain, respectively. This micellar system achieves a high load up to 25% against the docetaxel, and further demonstrates an IC50 as low as 40% of the commercialized docetaxel injection in vitro and a double maximum tolerated dose in MCF-7 cells in vivo. Conclusion: The high drug loading content, superior safety, and considerable anti-cancer activity make this newly developed docetaxel loaded poly(2-oxazoline) micelle go further in future clinical research.


Assuntos
Antineoplásicos/uso terapêutico , Docetaxel/uso terapêutico , Micelas , Neoplasias/tratamento farmacológico , Oxazóis/química , Células A549 , Animais , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Docetaxel/farmacologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Masculino , Dose Máxima Tolerável , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/patologia , Tamanho da Partícula , Tensoativos/química , Distribuição Tecidual
13.
Biomed Pharmacother ; 138: 111495, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33765586

RESUMO

Thiazole and oxazole are compounds with a heterocyclic nucleus that have attracted the attention of medicinal chemistry due to the great variety of biological activities that they enable. In recent years, their study has increased, finding a wide range of biological activities, including antifungal, antiparasitic, anti-inflammatory, and anticancer activities. This systematic review provides evidence from the literature on the antiproliferative and antitumor activities of thiazole and oxazole and their derivatives from 2014 to April 2020. Three bibliographical databases were consulted (PubMed, Web of Science, and Scopus), and a total of 32 studies were included in this paper based on our eligibility criteria. The analysis of the activity-structure relationship allows us to conclude that most of the promising compounds identified contained thiazole nuclei or derivatives.


Assuntos
Proliferação de Células/efeitos dos fármacos , Oxazóis/química , Oxazóis/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Células A549 , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Proliferação de Células/fisiologia , Células HeLa , Células Hep G2 , Humanos , Relação Estrutura-Atividade
14.
Molecules ; 26(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668340

RESUMO

Sigma-1 (σ-1) receptor agonists are considered as potential treatment for stroke. TS-157 is an alkoxyisoxazole-based σ-1 receptor agonist previously discovered in our group. The present study describes TS-157 profile in a battery of tests for cerebral ischemia. Initial evaluation demonstrated the compound's safety profile and blood-brain barrier permeability, as well as its ability to induce neurite outgrowth in vitro. The neurite outgrowth was shown to be mediated via σ-1 receptor agonism and involves upregulation of ERK phosphorylation (pERK). In particular, TS-157 also significantly accelerated the recovery of motor function in rats with transient middle cerebral artery occlusion (tMCAO). Overall, the results herein support the notion that σ-1 receptor agonists are potential therapeutics for stroke and further animal efficacy studies are warranted.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Oxazóis/farmacologia , Receptores sigma/agonistas , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/química , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
15.
Int J Mol Sci ; 22(4)2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33672348

RESUMO

In this work, we sought to examine whether the presence of alkyl substituents randomly distributed within the main chain of a 2-isopropyl-2-oxazoline-based copolymer will decrease its ability to crystallize when compared to its homopolymer. At the same time, we aimed to ensure an appropriate hydrophilic/lipophilic balance in the copolymer and maintain the phase transition in the vicinity of the human body temperature. For this reason, copolymers of 2-ethyl-4-methyl-2-oxazoline and 2-isopropyl-2-oxazoline were synthesized. The thermoresponsive behavior of the copolymers in water, the influence of salt on the cloud point, the presence of hysteresis of the phase transition and the crystallization ability in a water solution under long-term heating conditions were studied by turbidimetry. The ability of the copolymers to crystallize in the solid state, and their thermal properties, were analyzed by differential scanning calorimetry and X-ray diffractometry. A cytotoxicity assay was used to estimate the viability of human fibroblasts in the presence of the obtained polymers. The results allowed us to demonstrate a nontoxic alternative to poly(2-isopropyl-2-oxazoline) (PiPrOx) with a physiological phase transition temperature (LCST) and a greatly reduced tendency to crystallize. The synthesis of 2-oxazoline polymers with such well-defined properties is important for future biomedical applications.


Assuntos
Oxazóis/química , Polímeros/química , Cristalização , Fibroblastos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Transição de Fase , Polímeros/farmacologia , Polímeros/toxicidade , Soluções , Temperatura , Testes de Toxicidade , Água/química
16.
ACS Chem Biol ; 16(3): 501-509, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33595276

RESUMO

Cell-to-cell communication via chemical signals is an essential mechanism that pathogenic bacteria use to coordinate group behaviors and promote virulence. The Pseudomonas virulence factor (pvf) gene cluster is distributed in more than 500 strains of proteobacteria including both plant and human pathogens. The pvf cluster has been implicated in the production of signaling molecules important for virulence; however, the regulatory impact of these signaling molecules on virulence had not been elucidated. Using the insect pathogen Pseudomonas entomophila L48 as a model, we demonstrated that pvf-encoded biosynthetic enzymes produce PVF autoinducers that regulate the expression of pvf genes and a gene encoding the toxin monalysin via quorum sensing. In addition, PVF autoinducers regulate the expression of nearly 200 secreted and membrane proteins, including toxins, motility proteins, and components of the type VI secretion system, which play key roles in bacterial virulence, colonization, and competition with other microbes. Deletion of pvf also altered the secondary metabolome. Six major compounds upregulated by PVF autoinducers were isolated and structurally characterized, including three insecticidal 3-indolyl oxazoles, the labradorins, and three antimicrobial pyrrolizidine alkaloids, the pyreudiones. The signaling properties of PVF autoinducers and their wide-ranging regulatory effects indicate multifaceted roles of PVF in controlling cell physiology and promoting virulence. The broad genome distribution of pvf suggests that PVF-mediated signaling is relevant to many bacteria of agricultural and biomedical significance.


Assuntos
Proteínas de Bactérias/metabolismo , Pseudomonas/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Virulência/metabolismo , Proteínas de Bactérias/genética , Extratos Celulares/química , Regulação Bacteriana da Expressão Gênica , Oxazóis/química , Pseudomonas/genética , Percepção de Quorum , Metabolismo Secundário , Transdução de Sinais , Virulência , Fatores de Virulência/genética
17.
Org Biomol Chem ; 19(13): 2891-2894, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33570069

RESUMO

The selective alkylation of nucleic acids is important for a medicinal approach and biological study. We now report a novel selective alkylation of the parallel G-quadruplex structure using the conjugate of the macrocyclic hexaoxazole L2G2-6OTD-1M1PA and vinyl-quinazolinone-S(O)Me (6OTD-VQ-S(O)Me).


Assuntos
DNA/síntese química , Compostos Macrocíclicos/química , Oxazóis/química , Quinazolinonas/química , Compostos de Vinila/química , Alquilação , DNA/química , Quadruplex G , Estrutura Molecular
18.
Molecules ; 26(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525514

RESUMO

Spirocyclic nitroxyl radicals (SNRs) are stable paramagnetics bearing spiro-junction at a-, b-, or g-carbon atom of the nitroxide fragment, which is part of the heterocyclic system. Despite the fact that the first representatives of SNRs were obtained about 50 years ago, the methodology of their synthesis and their usage in chemistry and biochemical applications have begun to develop rapidly only in the last two decades. Due to the presence of spiro-function in the SNRs molecules, the latter have increased stability to various reducing agents (including biogenic ones), while the structures of the biradicals (SNBRs) comprises a rigid spiro-fused core that fixes mutual position and orientation of nitroxide moieties that favors their use in dynamic nuclear polarization (DNP) experiments. This first review on SNRs will give a glance at various strategies for the synthesis of spiro-substituted, mono-, and bis-nitroxides on the base of six-membered (piperidine, 1,2,3,4-tetrahydroquinoline, 9,9'(10H,10H')-spirobiacridine, piperazine, and morpholine) or five-membered (2,5-dihydro-1H-pyrrole, pyrrolidine, 2,5-dihydro-1H-imidazole, 4,5-dihydro-1H-imidazole, imidazolidine, and oxazolidine) heterocyclic cores.


Assuntos
Disciplinas das Ciências Naturais/métodos , Óxidos de Nitrogênio/química , Imidazóis/química , Imidazolidinas/química , Morfolinas/química , Oxazóis/química , Piperidinas/química , Pirrolidinas/química , Substâncias Redutoras/química
19.
Molecules ; 26(4)2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33562033

RESUMO

Chiral 2-oxazolines are valuable building blocks and famous ligands for asymmetric catalysis. The most common synthesis involves the reaction of an amino alcohol with a carboxylic acid. In this paper, an efficient synthesis of 2-oxazolines has been achieved via the stereospecific isomerization of 3-amido-2-phenyl azetidines. The reactions were studied in the presence of both Brønsted and Lewis acids, and Cu(OTf)2 was found to be the most effective.


Assuntos
Azetidinas/química , Oxazóis/química , Oxazóis/síntese química , Técnicas de Química Sintética , Modelos Moleculares , Conformação Molecular , Estereoisomerismo
20.
AAPS PharmSciTech ; 22(2): 62, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33528714

RESUMO

Nowadays, the incidence of acute bacterial skin and skin structure infection (ABSSSI) is increasing. The increased bioavailability and reduced drug resistance of antibiotics are crucial to obtain a more effective treatment response in these infections. These favorable properties could be achieved by different drug delivery systems such as liposomes. In this study, nanosized, radiolabeled tedizolid phosphate liposomal formulations were prepared and evaluated with their in vitro cellular binding capacity and biocompatible profile for topical treatment of ABSSSI. Liposomes were characterized by evaluation of their visual inspection, particle size (about 190-270 nm), zeta potential value (around 0), and encapsulation efficiency (nearly 10%). The release rate of tedizolid phosphate from liposomes was also studied using dialysis membranes and evaluated kinetically. The stability of formulations was observed at three different temperatures and humidity conditions for 28 days. Afterward, liposomes were labeled with 99mTc, and the optimal amount of reducing agent (stannous chloride) was determined as 500 µg in this direct labeling procedure. All liposome formulations were successfully radiolabeled with high efficiency and exhibited high radiochemical purity (> 80%) during 6 h in different media. Furthermore, the cellular bindings of liposomal formulations were evaluated in human skin fibroblast cells by measuring the radioactivity. Higher radioactivity values were obtained in CCD-1070Sk cells incubated by liposome formulations compared to sodium pertechnetate. This finding suggested that liposomal formulation increased the cellular binding of radioactivity. By the result of our study, nanosized, tedizolid phosphate encapsulated liposome formulation was found to be a favorable carrier system in the treatment of ABSSSI.


Assuntos
Antibacterianos/administração & dosagem , Organofosfatos/administração & dosagem , Organofosfatos/farmacocinética , Oxazóis/administração & dosagem , Oxazóis/farmacocinética , Dermatopatias Bacterianas/tratamento farmacológico , Tecnécio/farmacocinética , Administração Tópica , Animais , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Lipossomos/administração & dosagem , Lipossomos/farmacocinética , Organofosfatos/química , Oxazóis/química
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