Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.046
Filtrar
1.
Proc Natl Acad Sci U S A ; 117(24): 13267-13274, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32487725

RESUMO

Continuous reaction networks, which do not rely on purification or timely additions of reagents, serve as models for chemical evolution and have been demonstrated for compounds thought to have played important roles for the origins of life such as amino acids, hydroxy acids, and sugars. Step-by-step chemical protocols for ribonucleotide synthesis are known, but demonstrating their synthesis in the context of continuous reaction networks remains a major challenge. Herein, compounds proposed to be important for prebiotic RNA synthesis, including glycolaldehyde, cyanamide, 2-aminooxazole, and 2-aminoimidazole, are generated from a continuous reaction network, starting from an aqueous mixture of NaCl, NH4Cl, phosphate, and HCN as the only carbon source. No well-timed addition of any other reagents is required. The reaction network is driven by a combination of γ radiolysis and dry-down. γ Radiolysis results in a complex mixture of organics, including the glycolaldehyde-derived glyceronitrile and cyanamide. This mixture is then dried down, generating free glycolaldehyde that then reacts with cyanamide/NH3 to furnish a combination of 2-aminooxazole and 2-aminoimidazole. This continuous reaction network models how precursors for generating RNA and other classes of compounds may arise spontaneously from a complex mixture that originates from simple reagents.


Assuntos
Evolução Química , Modelos Químicos , RNA/química , RNA/síntese química , Acetaldeído/análogos & derivados , Acetaldeído/síntese química , Acetaldeído/química , Cianamida/síntese química , Cianamida/química , Raios gama , Imidazóis/síntese química , Imidazóis/química , Origem da Vida , Oxazóis/síntese química , Oxazóis/química , Fotoquímica , Água/química
2.
Int J Nanomedicine ; 15: 1771-1786, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214810

RESUMO

Purpose: In this study, pH-sensitive poly(2-ethyl-2-oxazoline)-poly(lactic acid)-poly(ß-amino ester) (PEOz-PLA-PBAE) triblock copolymers were synthesized and were conjugated with an antimalaria drug artesunate (ART), for inhibition of a colon cancer xenograft model. Methods: The as-prepared polymer prodrugs are tended to self-assemble into polymeric micelles in aqueous milieu, with PEOz segment as hydrophilic shell and PLA-PBAE segment as hydrophobic core. Results: The pH sensitivity of the as-prepared copolymers was confirmed by acid-base titration with pKb values around 6.5. The drug-conjugated polymer micelles showed high stability for at least 96 h in PBS and 37°C, respectively. The as-prepared copolymer prodrugs showed high drug loading content, with 9.57%±1.24% of drug loading for PEOz-PLA-PBAE-ART4. The conjugated ART could be released in a sustained and pH-dependent manner, with 92% of released drug at pH 6.0 and 57% of drug released at pH 7.4, respectively. In addition, in vitro experiments showed higher inhibitory effect of the prodrugs on rodent CT-26 cells than that of free ART. Animal studies also demonstrated the enhanced inhibitory efficacy of PEOz-PLA-PBAE-ART2 micelles on the growth of rodent xenograft tumor. Conclusion: The pH-responsive artesunate polymer prodrugs are promising candidates for colon cancer adjuvant therapy.


Assuntos
Artesunato/farmacocinética , Neoplasias do Colo/tratamento farmacológico , Polímeros/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Animais , Artesunato/química , Neoplasias do Colo/patologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Camundongos Endogâmicos BALB C , Micelas , Oxazóis/química , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Ecotoxicol Environ Saf ; 192: 110287, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32036102

RESUMO

An environmentally-friendly and fast analytical method for the stereoselective determination of etoxazole was developed and then applied to estimate stereoselective bioaccumulation and elimination in zebrafish using SFC-MS/MS. Optimal enantioseparation conditions were determined using a Chiralpak IG-3 column and CO2/MeOH mobile phase (80/20, v/v), at 3.0 mL/min within 1 min, 30°Me and 18 MPa. A modified QuEChERS method was developed for zebrafish sample pretreatment, and mean recoveries were 88.43-110.12% with relative standard deviations ranging from 0.32 to 5.34%. The enantioselectives of etoxazole enantiomers in zebrafish during uptake and depuration phases were evaluated. Significant enantioselective bioaccumulation was observed, with preferential accumulation of (-)-R-etoxazole compared to its antipode, during uptake at both low and high exposure concentrations. The toxic effects of etoxazole on zebrafish were further explored, and activities of antioxidant enzymes were determined in liver of zebrafish. Significant changes were observed in the SOD and GST activities and in the MDA levels, which indicated the occurrence of oxidative stress in liver of zebrafish. The toxic effects exhibited time- and dose-dependent properties. These results can facilitate the accurate risk evaluation of etoxazole and provide basic knowledge for further study of biotoxicity mechanisms.


Assuntos
Cromatografia com Fluido Supercrítico/métodos , Oxazóis/química , Oxazóis/toxicidade , Estresse Oxidativo , Espectrometria de Massas em Tandem/métodos , Poluentes Químicos da Água/química , Animais , Antioxidantes/metabolismo , Bioacumulação , Fígado/efeitos dos fármacos , Fígado/enzimologia , Oxazóis/análise , Oxazóis/farmacocinética , Estereoisomerismo , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo
4.
Yakugaku Zasshi ; 140(2): 273-287, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32009047

RESUMO

Our investigations of various aspects of organic chemistry over the past 43 years are reviewed in this paper. The following subjects are discussed: 1) the diastereoselective addition reaction to chiral imines and oxazolidines of organometallic reagents and its applications and 2) the reaction and synthesis of fluorine-containing compounds.


Assuntos
Química Orgânica/tendências , Compostos de Flúor/síntese química , Iminas/química , Compostos Organometálicos/química , Oxazóis/química , Estereoisomerismo , Fatores de Tempo
5.
J Enzyme Inhib Med Chem ; 35(1): 460-467, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31899981

RESUMO

The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are primary targets in attenuating the symptoms of neurodegenerative diseases. Their inhibition results in elevated concentrations of the neurotransmitter acetylcholine which supports communication among nerve cells. It was previously shown for trans-4/5-arylethenyloxazole compounds to have moderate AChE and BChE inhibitory properties. A preliminary docking study showed that elongating oxazole molecules and adding a new NH group could make them more prone to bind to the active site of both enzymes. Therefore, new trans-amino-4-/5-arylethenyl-oxazoles were designed and synthesised by the Buchwald-Hartwig amination of a previously synthesised trans-chloro-arylethenyloxazole derivative. Additionally, naphthoxazole benzylamine photoproducts were obtained by efficient photochemical electrocyclization reaction. Novel compounds were tested as inhibitors of both AChE and BChE. All of the compounds exhibited binding preference for BChE over AChE, especially for trans-amino-4-/5-arylethenyl-oxazole derivatives which inhibited BChE potently (IC50 in µM range) and AChE poorly (IC50≫100 µM). Therefore, due to the selectivity of all of the tested compounds for binding to BChE, these compounds could be applied for further development of cholinesterase selective inhibitors.HIGHLIGHTSSeries of oxazole benzylamines were designed and synthesisedThe tested compounds showed binding selectivity for BChENaphthoxazoles were more potent AChE inhibitors.


Assuntos
Benzilaminas/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Oxazóis/química , Acetilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Técnicas Eletroquímicas , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Processos Fotoquímicos , Relação Estrutura-Atividade
6.
Chem Rev ; 120(4): 1981-2048, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-31967451

RESUMO

In this contribution, we provide a comprehensive overview of C-H activation methods promoted by NHC-transition metal complexes, covering the literature since 2002 (the year of the first report on metal-NHC-catalyzed C-H activation) through June 2019, focusing on both NHC ligands and C-H activation methods. This review covers C-H activation reactions catalyzed by group 8 to 11 NHC-metal complexes. Through discussing the role of NHC ligands in promoting challenging C-H activation methods, the reader is provided with an overview of this important area and its crucial role in forging carbon-carbon and carbon-heteroatom bonds by directly engaging ubiquitous C-H bonds.


Assuntos
Técnicas de Química Sintética/métodos , Compostos Heterocíclicos/química , Metano/análogos & derivados , Compostos Organometálicos/química , Paládio/química , Compostos Heterocíclicos/síntese química , Imidazóis/química , Metano/química , Oxazóis/química , Tiazóis/química
7.
Chemistry ; 26(12): 2749-2753, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-31826315

RESUMO

Poly(2-oxazoline)s (POx) bottle-brush brushes have excellent biocompatible and lubricious properties, which are promising for the functionalization of surfaces for biomedical devices. Herein, a facile synthesis of POx is reported which is based bottle-brush brushes (BBBs) on solid substrates. Initially, backbone brushes of poly(2-isopropenyl-2-oxazoline) (PIPOx) were fabricated via surface initiated Cu0 plate-mediated controlled radical polymerization (SI-Cu0 CRP). Poly(2-methyl-2-oxazoline) (PMeOx) side chains were subsequently grafted from the PIPOx backbone via living cationic ring opening polymerization (LCROP), which result in ≈100 % increase in brush thickness (from 58 to 110 nm). The resultant BBBs shows tunable thickness up to 300 nm and high grafting density (σ) with 0.42 chains nm-2 . The synthetic procedure of POx BBBs can be further simplified by using SI-Cu0 CRP with POx molecular brush as macromonomer (Mn =536 g mol-1 , PDI=1.10), which results in BBBs surface up to 60 nm with well-defined molecular structure. Both procedures are significantly superior to the state-of-art approaches for the synthesis of POx BBBs, which are promising to design bio-functional surfaces.


Assuntos
Materiais Biocompatíveis/síntese química , Oxazóis/síntese química , Cobre/química , Estrutura Molecular , Oxazóis/química , Poliaminas/química , Polimerização , Polipropilenos/química
8.
Biochim Biophys Acta Gen Subj ; 1864(1): 129440, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31536751

RESUMO

BACKGROUND: Half of human cancers harbour TP53 mutations that render p53 inactive as a tumor suppressor. As such, reactivation of mutant (mut)p53 through restoration of wild-type (wt)-like function represents one of the most promising therapeutic strategies in cancer treatment. Recently, we have reported the (S)-tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a new reactivator of wt and mutp53 R280K with in vitro and in vivo p53-dependent antitumor activity. The present work aimed a mechanistic elucidation of mutp53 reactivation by SLMP53-1. METHODS AND RESULTS: By cellular thermal shift assay (CETSA), it is shown that SLMP53-1 induces wt and mutp53 R280K thermal stabilization, which is indicative of intermolecular interactions with these proteins. Accordingly, in silico studies of wt and mutp53 R280K DNA-binding domain with SLMP53-1 unveiled that the compound binds at the interface of the p53 homodimer with the DNA minor groove. Additionally, using yeast and p53-null tumor cells ectopically expressing distinct highly prevalent mutp53, the ability of SLMP53-1 to reactivate multiple mutp53 is evidenced. CONCLUSIONS: SLMP53-1 is a p53-activating agent with the ability to directly target wt and a set of hotspot mutp53. GENERAL SIGNIFICANCE: This work reinforces the encouraging application of SLMP53-1 in the personalized treatment of cancer patients harboring distinct p53 status.


Assuntos
Proteínas de Ligação a DNA/genética , Isoindóis/farmacologia , Neoplasias/tratamento farmacológico , Oxazóis/farmacologia , Proteína Supressora de Tumor p53/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Isoindóis/química , Mutação/efeitos dos fármacos , Neoplasias/genética , Neoplasias/patologia , Oxazóis/química , Domínios Proteicos/efeitos dos fármacos , Proteína Supressora de Tumor p53/antagonistas & inibidores
9.
Appl Radiat Isot ; 155: 108915, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31590101

RESUMO

To develop PET radiotracers for imaging of Alzheimer's disease, a new carbon-11 labeled potent and selective γ-secretase modulator (GSM) has been synthesized. The reference standard tetrahydrobenzisoxazole derivative 8 and its desmethylated precursor 9 were synthesized from cyclohex-2-en-1-one and 3-hydroxy-4-nitrobenzaldehyde in eight and nine steps with 11% and 5% overall chemical yield, respectively. The radiotracer [11C]8 was prepared from its corresponding precursor 9 with [11C]CH3OTf through O-11C-methylation and isolated by RP-HPLC combined with SPE in 45-50% radiochemical yield, based on [11C]CO2 and decay corrected to EOB. The radiochemical purity was >99%, and the molar activity (Am) at EOB was 555-740 GBq/µmol.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Secretases da Proteína Precursora do Amiloide/metabolismo , Radioisótopos de Carbono/química , Oxazóis/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Doença de Alzheimer/enzimologia , Cromatografia de Fase Reversa , Humanos , Extração em Fase Sólida
10.
J Agric Food Chem ; 67(49): 13544-13549, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31725276

RESUMO

With the ultimate goal of addressing pest-related constraints on global agricultural production, we used combination principles to design and synthesize 2,4-diphenyl-1,3-oxazolines containing a sulfonate moiety at the para-position of the 4-phenyl group. The target compounds, which have strong affinity for lipids and can be expected to traverse cell membranes, were characterized by 1H and 13C NMR spectroscopy and high-resolution mass spectrometry. Their activities against the larvae and eggs of carmine spider mites (Tetranychus cinnabarinus) were determined by a leaf-dipping method and compared with the activity of the commercial acaricide etoxazole. Most of the test compounds displayed good ovicidal and larvicidal activities. In particular, a tert-butylphenyl-substituent compound possessed better larvicidal activity (LC50 = 0.022 ± 0.009 mg/L) and ovicidal activity (0.044 ± 0.020 mg/L) than etoxazole (0.091 ± 0.051 and 0.095 ± 0.059 mg/L, respectively). Given its outstanding bioactivities, this compound deserves further attention as a pesticide candidate.


Assuntos
Acaricidas/química , Acaricidas/farmacologia , Oxazóis/química , Oxazóis/farmacologia , Acaricidas/síntese química , Animais , Desenho de Fármacos , Larva/efeitos dos fármacos , Dose Letal Mediana , Estrutura Molecular , Oxazóis/síntese química , Relação Estrutura-Atividade , Ácidos Sulfônicos/química , Tetranychidae/efeitos dos fármacos
11.
Eur J Med Chem ; 182: 111613, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31437780

RESUMO

Alzheimer's disease (AD) is associated with multifactorial neuropathological conditions, which include cholinergic deficit, amyloid-beta plaques formation, loss of neuronal plasticity and neuronal death. Treating such multifactorial conditions with a single target directed approach is considered to be inadequate. Accordingly, multi-target directed ligand (MTDL) strategy has been evolved as an auspicious approach for the treatment of AD. In light of that, a library of 2-substituted benzo[d]oxazol-5-amine derivatives (29-39; 86-107) was designed using the scaffold hopping guided MTDLs strategy, synthesized and evaluated through various in-vitro and in-vivo biological studies. The optimal compound 92 exhibited potent inhibitory activities against AChE (IC50 = 0.052 ±â€¯0.010 µM), BuChE (IC50 = 1.085 ±â€¯0.035 µM), and significant amyloid-beta aggregation (20 µM) inhibition. The compound possessed better blood-brain barrier permeability (Pe = 10.80 ±â€¯0.055 × 10-6 cm s-1) in PAMPA assay and neuro protective properties (40 µM) on SH-SY5Y neuroblastoma cell lines. Furthermore, in-vivo behavioural studies were performed on Y-maze test (scopolamine-induced amnesia model) and Morris water maze test (Aß1-42 induced ICV rat model). The compound 92, at a dose of 10 mg/kg oral administration, demonstrated a substantial improvement of the cognitive and special memory impairment. In summary, both in-vitro and in-vivo investigations evidenced that compound 92 was a potential lead for the discovery of safe and effective disease-modifying agents for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminas/farmacologia , Inibidores da Colinesterase/farmacologia , Descoberta de Drogas , Fármacos Neuroprotetores/farmacologia , Oxazóis/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Aminas/síntese química , Aminas/química , Amnésia/induzido quimicamente , Amnésia/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Enguias , Feminino , Cavalos , Humanos , Ligantes , Masculino , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Oxazóis/síntese química , Oxazóis/química , Ratos , Ratos Wistar , Escopolamina , Relação Estrutura-Atividade
12.
Molecules ; 24(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443550

RESUMO

Herbicide safeners selectively protect crops from herbicide injury while maintaining the herbicidal effect on the target weed. To some extent, the detoxification of herbicides is related to the effect of herbicide safeners on the level and activity of herbicide target enzymes. In this work, the expression of the detoxifying enzyme glutathione S-transferase (GST) and antioxidant enzyme activities in maize seedlings were studied in the presence of three potential herbicide safeners: 3-dichloroacetyl oxazolidine and its two optical isomers. Further, the protective effect of chiral herbicide safeners on detoxifying chlorsulfuron in maize was evaluated. All safeners increased the expression levels of herbicide detoxifying enzymes, including GST, catalase (CAT), and peroxidase (POD) to reduce sulfonylurea herbicide phytotoxicity in maize seedlings. Our results indicate that the R-isomer of 3-(dichloroacetyl)-2,2,5-trimethyl-1,3-oxazolidine can induce glutathione (GSH) production, GST activity, and the ability of GST to react with the substrate 1-chloro-2,4-dinitrobenzene (CDNB) in maize, meaning that the R-isomer can protect maize from damage by chlorsulfuron. Information about antioxidative enzyme activity was obtained to determine the role of chiral safeners in overcoming the oxidative stress in maize attributed to herbicides. The interaction of safeners and active target sites of acetolactate synthase (ALS) was demonstrated by molecular docking modeling, which indicated that both isomers could form a good interaction with ALS. Our findings suggest that the detoxification mechanism of chiral safeners might involve the induction of the activity of herbicide detoxifying enzymes as well as the completion of the target active site between the safener and chlorsulfuron.


Assuntos
Inativação Metabólica/efeitos dos fármacos , Oxazóis/química , Oxazóis/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Zea mays/efeitos dos fármacos , Zea mays/metabolismo , Acetolactato Sintase/química , Acetolactato Sintase/metabolismo , Sítios de Ligação , Catalase/metabolismo , Domínio Catalítico , Glutationa/metabolismo , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peroxidase/metabolismo , Ligação Proteica , Relação Estrutura-Atividade , Zea mays/química
13.
ACS Appl Mater Interfaces ; 11(34): 31356-31366, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31381296

RESUMO

Plasma polymerization is gaining popularity as a technique for coating surfaces due to the low cost, ease of operation, and substrate-independent nature. Recently, the plasma polymerization (or deposition) of 2-oxazoline monomers was reported resulting in coatings that have potential applications in regenerative medicine. Despite the structural versatility of 2-oxazolines, only a few monomers have been subjected to plasma polymerization. Within this study, however, we explore the near atmospheric pressure plasma polymerization of a range of 2-oxazoline monomers, focusing on the influence of the aliphatic side-chain length (methyl to butyl) on the plasma polymerization process conditions as well as the properties of the obtained coatings. While side-chain length had only a minor influence on the chemical composition, clear effects on the plasma polymerization conditions were observed, thus gaining valuable insights in the plasma polymerization process as a function of monomer structure. Additionally, cytocompatibility and cell attachment on the coatings obtained by 2-oxazoline plasma polymerization was assessed. The coatings displayed strong cell interactive properties, whereby cytocompatibility increased with increasing aliphatic side-chain length of the monomer, reaching up to 93% cell viability after 1 day of cell culture compared to tissue culture plates. As this is in stark contrast to the antifouling behavior of the parent polymers, we compared the properties and composition of the plasma-polymerized coatings to the parent polymers revealing that a significantly different coating structure was obtained by plasma polymerization.


Assuntos
Pressão Atmosférica , Materiais Revestidos Biocompatíveis , Fibroblastos/metabolismo , Teste de Materiais , Gases em Plasma , Polimerização , Sobrevivência Celular , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Fibroblastos/citologia , Humanos , Oxazóis/química , Oxazóis/farmacologia
14.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370144

RESUMO

Normally ubiquitin C-terminal hydrolase L1 (UCH-L1) is expressed in the central nervous and reproductive systems of adults, but its de novo expression has been detected in many human cancers. There is a growing body of evidence that UCH-L1 de-ubiquitinating (DUB) activity plays a major pro-metastatic role in certain carcinomas. Here we tested anti-metastatic effects of the small-molecule inhibitor of UCH-L1 DUB activity, LDN-57444, in cell lines from advanced oral squamous cell carcinoma (OSCC) as well as invasive nasopharyngeal (NP) cell lines expressing the major pro-metastatic gene product of Epstein-Barr virus (EBV) tumor virus, LMP1. To overcome the limited aqueous solubility of LDN-57444 we developed a nanoparticle formulation of LDN-57444 by incorporation of the compound in polyoxazoline micellear nanoparticles (LDN-POx). LDN-POx nanoparticles were equal in effects as the native compound in vitro. Our results demonstrate that inhibition of UCH-L1 DUB activity with LDN or LDN-POx inhibits secretion of exosomes and reduces levels of the pro-metastatic factor in exosomal fractions. Both forms of UCH-L1 DUB inhibitor suppress motility of metastatic squamous carcinoma cells as well as nasopharyngeal cells expressing EBV pro-metastatic Latent membrane protein 1 (LMP1) in physiological assays. Moreover, treatment with LDN and LDN-POx resulted in reduced levels of pro-metastatic markers, a decrease of carcinoma cell adhesion, as well as inhibition of extra-cellular vesicle (ECV)-mediated transfer of viral invasive factor LMP1. We suggest that soluble inhibitors of UCH-L1 such as LDN-POx offer potential forms of treatment for invasive carcinomas including EBV-positive malignancies.


Assuntos
Antineoplásicos/farmacologia , Portadores de Fármacos , Células Epiteliais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Indóis/farmacologia , Oximas/farmacologia , Ubiquitina Tiolesterase/genética , Proteínas da Matriz Viral/genética , Antineoplásicos/química , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Humanos , Indóis/química , Micelas , Boca/metabolismo , Boca/patologia , Nanopartículas/química , Nanopartículas/ultraestrutura , Nasofaringe/metabolismo , Nasofaringe/patologia , Oxazóis/química , Oximas/química , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/metabolismo , Proteínas da Matriz Viral/metabolismo
15.
ACS Appl Mater Interfaces ; 11(36): 32697-32705, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31411033

RESUMO

Bioorthogonal chemistry together with biomarker-installing techniques is very promising in the amplification of the tumor targeting efficiency of nanomedicine. In this work, we newly synthesized an amphiphilic block copolymer polyoxazoline-block-polycaprolactone (POX-PCL) in which a certain number of amino groups were dangled in the side chain of the POX block and then functionalized into triarylphosphine groups for active tumor targeting via Staudinger ligation. By using the block copolymer self-assembly, the Staudinger ligation reagent-containing and drug-loaded reactive micelles were prepared with a hydrodynamic diameter of ∼74 nm. Such drug-loaded reactive POX-PCL micelles exhibited significant tumor target ability through the Staudinger ligation between the micelles and the tumors metabolically labeled with azide group, as demonstrated by a series of in vitro and in vivo evaluations. In this work, a novel method was proposed for the application of Staudinger ligation in the nanomedicine for amplifying the tumor targeting ability and antitumor activity of nanodrugs.


Assuntos
Sistemas de Liberação de Medicamentos , Micelas , Polímeros/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Masculino , Camundongos Endogâmicos ICR , Nanomedicina , Oxazóis/química , Poliésteres/química , Distribuição Tecidual/efeitos dos fármacos
16.
J Agric Food Chem ; 67(36): 10018-10031, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31448918

RESUMO

Plant diseases seriously endanger plant health, and it is very difficult to control them. A series of nortopsentin analogues were designed, synthesized, and evaluated for their antiviral activities and fungicidal activities. Most of these compounds displayed higher antiviral activities than ribavirin. Compounds 1d, 1e, and 12a, with excellent antiviral activities, emerged as novel antiviral lead compounds, among which 1e was selected for further antiviral mechanism research. The mechanism research results indicated that these compounds may play an antiviral role by aggregating viral particles to prevent their movement in plants. Further fungicidal activity tests revealed that nortopsentin analogues displayed broad-spectrum fungicidal activities. Compounds 2p and 2f displayed higher antifungal activities against Alternaria solani than the commercial fungicides carbendazim and chlorothalonil. Current research has laid a foundation for the application of nortopsentin analogues in plant protection.


Assuntos
Antivirais/farmacologia , Fungicidas Industriais/farmacologia , Oxazóis/farmacologia , Tiazóis/farmacologia , Alternaria/efeitos dos fármacos , Alternaria/crescimento & desenvolvimento , Antivirais/síntese química , Antivirais/química , Desenho de Fármacos , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Oxazóis/química , Relação Estrutura-Atividade , Tiazóis/química , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Vírus do Mosaico do Tabaco/crescimento & desenvolvimento
17.
J Phys Chem A ; 123(34): 7470-7485, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31361130

RESUMO

Advances in the utilization of porphyrinoids for photomedicine, catalysis, and artificial photosynthesis require a fundamental understanding of the relationships between their molecular connectivity and resulting electronic structures. Herein, we analyze how the replacement of two pyrrolic Cß═Cß bonds of a porphyrin by two lactone (O═C-O) moieties modulates the ground-state thermodynamic stability and electronic structure of the resulting five possible pyrrole-modified porphyrin isomers. We made these determinations based on density functional theory (DFT) and time-dependent DFT computations of the optical spectra of all regioisomers. We also analyzed the computed magnetically induced currents of their aromatic π-systems. All regioisomers adopt the tautomeric state that maximizes aromaticity, whether or not transannular steric strains are incurred. In all isomers, the O═Cß-Oß bonds were found to support a macrocycle diatropic ring current. We attributed this to the delocalization of nonbonding electrons from the ring oxa- and oxo-atoms into the macrocycle. As a consequence of this delocalization, the dilactone regioisomers are as-or even more-aromatic than their hydroporphyrin congeners. The electronic structures follow different trends for the bacteriochlorin- and isobacteriochlorin-type isomers. The presence of either oxo- or oxa-oxygens conjugated with the macrocyclic π-system was found to be the minimal structural requirement for the regioisomers to exhibit distinct electronic properties. Our computational methods and mechanistic insights provide a basis for the systematic exploration of the physicochemical properties of porphyrinoids as a function of the number, relative orientation, and degree of macrocycle-π-conjugation of ß-substituents, in general, and for dilactone-based porphyrinic chromophores, in particular.


Assuntos
Lactonas/química , Porfirinas/química , Teoria da Densidade Funcional , Isomerismo , Modelos Químicos , Conformação Molecular , Oxazóis/química , Termodinâmica
18.
Orig Life Evol Biosph ; 49(3): 163-185, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31327111

RESUMO

In line with the postulated intermediacy of aminoxazoles derived from small sugars toward the direct assembly of nucleoside precursors, we show here a potential prebiotic scenario where aminoxazolines might have also played further roles as complexing and/or sequestering agents of other primeval blocks, namely amino acids. To this end, a bis-aminoxazoline derivative, generated from dihydroxyacetone and cyanamide, gives rise to stable co-crystal forms with dicarboxylic amino acids (Asp and Glu), while ionic interactions owing to proton transfer are inferred from spectroscopic data in aqueous solution. The structure of a 1:2 aminoxazoline: aspartic acid complex, discussed in detail, was elucidated by X-ray diffractometry. Optimized geometries of such ionic structures with bulk aqueous solvation were assessed by DFT calculations, which disclose preferential arrangements that validate the experimental data. Peripherally, we were able to detect in a few cases amino acid dimerization (i.e. dipeptide formation) after prolonged incubation with the bis-aminoxazole derivative. A mechanistic simulation aided by computation provides some predictive conclusions for future explorations and catalytic design.


Assuntos
Aminoácidos/química , Origem da Vida , Oxazóis/química , Biologia Computacional , Química Computacional
19.
Pestic Biochem Physiol ; 157: 60-68, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31153478

RESUMO

A series of novel substituted oxazole isoxazole carboxamides derivatives were designed on the basis of active subunit combination. Forty-four novel compounds were synthesized by an efficient one-pot procedure under microwave irradiation. The bioactivity was evaluated as herbicide safener against the injury of chlorsulfuron. It was found that most of the synthesized compounds displayed remarkable protection against chlorsulfuron via enhanced glutathione content and glutathione S transferase activity. Especially compound I-11 exhibited better bioactivity than the safeners isoxadifen-ethyl and R-28725. Molecular docking simulations suggested that the target compounds could compete with chlorsulfuron in the active site of acetolactate synthase, which could explain the protective effects of safeners. The present work demonstrates that the target compounds containing oxazole isoxazole groups could be considered as potential candidates for developing novel safeners in the future.


Assuntos
Herbicidas/química , Herbicidas/farmacologia , Isoxazóis/química , Oxazóis/química , Sulfonamidas/farmacologia , Triazinas/farmacologia , Acetolactato Sintase/genética , Acetolactato Sintase/metabolismo , Ativação Enzimática/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Relação Estrutura-Atividade , Zea mays/enzimologia
20.
Biochem Pharmacol ; 166: 163-173, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31085160

RESUMO

Despite the steadily increased numbers of formyl peptide receptor (FPR) ligands identified over the years, few have been characterized in studies using animal disease models and even less have entered clinical trials in human subjects. A small-molecule compound, Act-389949, was however recently tested in a phase I clinical trial and found to be safe and well tolerated in healthy human subjects. The desired anti-inflammatory property of Act-389949 was proposed to be mediated through FPR2, one of the FPRs expressed in neutrophils, but no basic characterization was included in the study. To gain more insights into FPR2 recognition of this first-in-class compound for future utility of the agonist, we have in this study determined the receptor preference and down-stream signaling characteristics induced by Act-389949 in human blood neutrophils isolated from healthy donors. Our data demonstrate that Act-389949 is an agonist for FPR2 that triggers functional/signaling repertoires comparable to what has been earlier described for other FPR2 agonists, including neutrophil chemotaxis, granule mobilization and activation of the NADPH-oxidase. In fact, Act-389949 was found to be as potent as the prototype FPR2 peptide agonist WKYMVM and had the advantage of being resistant to oxidation by MPO-H2O2-halide derived oxidants, as compared to the sensitive WKYMVM. The down-stream signals generated by Act-389949 include an FPR2-dependent and Gαq-independent transient rise in intracellular Ca2+ and recruitment of ß-arrestin. In summary, our data show that Act-389949 serves as an excellent tool-compound for further dissection of FPR2-regulated activities in vitro and in vivo. Potent and stable FPR ligands such as Act-389949 may therefore be used to develop the next generation of FPR signaling regulating anti-inflammatory therapeutics.


Assuntos
Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Oxazóis/farmacologia , Receptores de Formil Peptídeo/agonistas , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/agonistas , Receptores de Lipoxinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triazóis/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Oxazóis/química , Transdução de Sinais/fisiologia , Triazóis/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA