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1.
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 Drogas , Larva/efeitos dos fármacos , Dose Letal Mediana , Estrutura Molecular , Oxazóis/síntese química , Relação Estrutura-Atividade , Ácidos Sulfônicos/química , Tetranychidae/efeitos dos fármacos
2.
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
3.
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 Drogas , 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
4.
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
5.
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
6.
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
7.
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
8.
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
9.
Chem Commun (Camb) ; 55(42): 5902-5905, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31045188

RESUMO

Multifunctional isoquinoline-oxazolines (MIQOXs) were conceived and synthesized from commercially available chiral amino acids. The multifunctional role of MIQOXs was demonstrated by Pd-catalyzed highly enantioselective addition of arylboronic acids to nitrostyrenes, and by the discovery of novel antifungal candidates.


Assuntos
Isoquinolinas/química , Oxazóis/química , Catálise , Ligantes , Estereoisomerismo
10.
J Agric Food Chem ; 67(24): 6708-6715, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31140799

RESUMO

This is the first systemic assessment of the stereoselectivity of etoxazole enantiomers. Etoxazole's stereoselective bioactivity was assessed against target organisms ( Tetranychus urticae eggs and Tetranychus cinnabarinus eggs), and its acute toxicity was assessed toward nontarget aquatic organisms ( Daphnia magna and Danio rerio). Additionally, stereoselective elimination was investigated in three species of fruits (grape and strawberry grown in a greenhouse and apple grown in an open field) and in field soil. The ovicidal activity of (+)-( S)-etoxazole against Tetranychus urticae and Tetranychus cinnabarinus eggs was about 16 and 24 times higher, respectively, than that of (-)-( R)-etoxazole. Inconsistent order of etoxazole isomer toxicity was found toward different aquatic organisms: (+)-( S)-etoxazole showed nearly 8.7 times higher acute toxicity than (-)-( R)-etoxazole toward Daphnia magna, whereas (-)-( R)-etoxazole was ∼4.5 times more toxic to Danio rerio than (+)-( S)-etoxazole. Stereoselective degradation of etoxazole enantiomers showed significant variation in various fruits and field soil. The (+)-( S)-etoxazole was preferentially dissipated in grape and strawberry fruits grown under greenhouse condition, whereas (-)-( R)-etoxazole degraded faster than its antipode in apple fruits and soils under open-field condition. Overall, the stereoselectivity of etoxazole enantiomers should be fully considered in comprehensive environmental health risk in future work.


Assuntos
Acaricidas/química , Acaricidas/toxicidade , Frutas/química , Oxazóis/química , Oxazóis/toxicidade , Poluentes do Solo/química , Poluentes do Solo/toxicidade , Animais , Fragaria/química , Fragaria/crescimento & desenvolvimento , Frutas/crescimento & desenvolvimento , Malus/química , Malus/crescimento & desenvolvimento , Solo/química , Estereoisomerismo , Tetranychidae/efeitos dos fármacos , Vitis/química , Vitis/crescimento & desenvolvimento
11.
Eur J Pharm Sci ; 136: 104941, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136788

RESUMO

SN-38 is the active metabolite of irinotecan, an FDA-approved chemotherapeutic agent indicated for colorectal carcinoma, which would not be clinically applicable due to its very poorly soluble and hydrolytic degradation properties. To overcome these limitations, it was proposed to conjugate SN38 to residing carboxylic acid residues in poly (2-ethyl 2-oxazoline) block poly (L-glutamic acid), inducing nano-assembly in aqueous medium. Following a series of reactions including poly (2-ethyl oxazoline) macro-initiated ring opening polymerization of N-carboxyanhydride, deprotection of benzyl group and chemical conjugation of SN38 via biodegradable ester linkage, the as-synthesized product was characterized by dynamic light scattering, ζ potential and transmission electron microscopy. The resulting particles presented about 90% loading efficiency with a mean size of 90 nm. Upon incubation with colorectal carcinoma CT26 cell line, higher association of SN-38 fluorescence and significantly more specific cytotoxicity was noticed for the SN38 conjugated particles than free drug. Therapeutic applicability of the as-synthesized product was evaluated in CT26 allograft tumor model in BALB/c mice, showing superior efficiency of the SN38 conjugated particles particularly in tumors with sizes larger than 200 mm3 than parent irinotecan and reduced mortality rate by 2.5 times. Conclusively, the poly (2-ethyl 2-oxazoline) decorated nano-conjugates of poly (L-glutamic acid) and SN38 can be regarded as a novel and potentially efficient drug delivery system for advanced colorectal carcinoma.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Ácido Glutâmico/química , Irinotecano/administração & dosagem , Irinotecano/química , Nanopartículas/química , Oxazóis/química , Polímeros/química , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Feminino , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Endogâmicos BALB C
12.
Eur J Med Chem ; 176: 326-342, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31112893

RESUMO

Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular disease, obesity, and diabetes. These receptors show a high degree of stereoselectivity towards several classes of drugs. This review covers the most relevant findings that have been made in the last decade and takes into consideration only those compounds in which stereochemistry led to unexpected results or peculiar interactions with the receptors. These cases are reviewed and discussed with the aim to show how enantiomeric recognition originates at the molecular level. The structural characterization by crystallographic methods and docking experiments of complexes formed by PPARs with their ligands turns out to be an essential tool to explain receptor stereoselectivity.


Assuntos
Derivados de Benzeno/química , Derivados de Benzeno/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Acetatos/química , Acetatos/metabolismo , Animais , Sítios de Ligação , Cristalografia por Raios X , Humanos , Indóis/química , Indóis/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Oxazóis/química , Oxazóis/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/antagonistas & inibidores , Receptores Ativados por Proliferador de Peroxissomo/química , Fenilpropionatos/química , Fenilpropionatos/metabolismo , Ligação Proteica , Estereoisomerismo , Relação Estrutura-Atividade , Tirosina/análogos & derivados , Tirosina/metabolismo
13.
Molecules ; 24(8)2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31010019

RESUMO

We performed single molecule studies to investigate the impact of several prominent small molecules (the oxazole telomestatin derivative L2H2-6OTD, pyridostatin, and Phen-DC3) on intermolecular G-quadruplex (i-GQ) formation between two guanine-rich DNA strands that had 3-GGG repeats in one strand and 1-GGG repeat in the other (3+1 GGG), or 2-GGG repeats in each strand (2+2 GGG). Such structures are not only physiologically significant but have recently found use in various biotechnology applications, ranging from DNA-based wires to chemical sensors. Understanding the extent of stability imparted by small molecules on i-GQ structures, has implications for these applications. The small molecules resulted in different levels of enhancement in i-GQ formation, depending on the small molecule and arrangement of GGG repeats. The largest enhancement we observed was in the 3+1 GGG arrangement, where i-GQ formation increased by an order of magnitude, in the presence of L2H2-6OTD. On the other hand, the enhancement was limited to three-fold with Pyridostatin (PDS) or less for the other small molecules in the 2+2 GGG repeat case. By demonstrating detection of i-GQ formation at the single molecule level, our studies illustrate the feasibility to develop more sensitive sensors that could operate with limited quantities of materials.


Assuntos
Quadruplex G/efeitos dos fármacos , Descoberta de Drogas , Estrutura Molecular , Conformação de Ácido Nucleico/efeitos dos fármacos , Oxazóis/química , Oxazóis/farmacologia , Repetições de Trinucleotídeos
14.
Carbohydr Res ; 477: 11-19, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30933786

RESUMO

Enzymatic degradation of locust bean gum provides a Manß(1 → 4)Man disaccharide, which may be converted into the core Manß(1 → 4)GlcNAc disaccharide unit of all N-glycans via conversion to a 2-iodo-glycosyl azide, and Lafont rearrangement. The Manß(1 → 4)GlcNAc disaccharide may be used as a key intermediate for elaboration into more complex N-glycan structures providing a route to N-glycan oxazolines as donor substrates for ENGase enzymes that is considerably shorter than those reported previously.


Assuntos
Galactanos/metabolismo , Mananas/metabolismo , Oxazóis/metabolismo , Gomas Vegetais/metabolismo , Poligalacturonase/metabolismo , Polissacarídeos/metabolismo , Configuração de Carboidratos , Galactanos/química , Mananas/química , Oxazóis/química , Gomas Vegetais/química , Polissacarídeos/química
15.
Org Biomol Chem ; 17(14): 3635-3639, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30916700

RESUMO

Oxazoles are an important class of biologically active metabolites from nature, and exhibit broad biological activities as the lead for drug discovery. Hinduchelins are a class of unusual natural products with an oxazole unit, isolated from Streptoalloteichus hindustanus, and with a potential iron-chelating ability. These compounds are the first identified naturally occurring unusual oxazole derivatives to possess a catechol unit. However, some of these compounds are not abundant in nature, and thus, the efficient syntheses of these compounds are advantageous in exploring their potential applications. This paper reports the efficient synthesis and bio-evaluation of hinduchelins A-D and their derivatives with convenient procedures and high yields.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Inseticidas/farmacologia , Oxazóis/farmacologia , Actinomycetales/química , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Afídeos/efeitos dos fármacos , Produtos Biológicos/síntese química , Produtos Biológicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Inseticidas/síntese química , Inseticidas/química , Testes de Sensibilidade Microbiana , Mariposas , Oxazóis/síntese química , Oxazóis/química
16.
ACS Chem Biol ; 14(4): 751-757, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30840432

RESUMO

Colloidal drug aggregates have been a nuisance in drug screening, yet, because they inherently comprise drug-rich particles, they may be useful in vivo if issues of stability can be addressed. As the first step toward answering this question, we optimized colloidal drug aggregate formulations using a fluorescence-based assay to study fulvestrant colloidal formation and stability in high (90%) serum conditions in vitro. We show, for the first time, that the critical aggregation concentration of fulvestrant depends on media composition and increases with serum concentration. Excipients, such as polysorbate 80, stabilize fulvestrant colloids in 90% serum in vitro for over 48 h. Using fulvestrant and an investigational pro-drug, pentyloxycarbonyl-( p-aminobenzyl) doxazolidinylcarbamate (PPD), as proof-of-concept colloidal formulations, we demonstrate that the in vivo plasma half-life for stabilized colloids is greater than their respective monomeric forms. These studies demonstrate the potential of turning the nuisance of colloidal drug aggregation into an opportunity for drug-rich formulations.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacocinética , Carbamatos/química , Carbamatos/farmacocinética , Doxorrubicina/análogos & derivados , Oxazóis/química , Oxazóis/farmacocinética , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Animais , Antineoplásicos/sangue , Carbamatos/sangue , Coloides , Doxorrubicina/sangue , Doxorrubicina/química , Doxorrubicina/farmacocinética , Estabilidade de Medicamentos , Excipientes , Feminino , Fulvestranto/química , Humanos , Células MCF-7 , Camundongos , Transplante de Neoplasias , Oxazóis/sangue , Polissorbatos/química , Estudo de Prova de Conceito , Soro
17.
Molecules ; 24(5)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30866506

RESUMO

A series of novel 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-diones were designed and synthesized by using 4-aminophenol and α-glycolic acid or lactic acid as starting materials in three or four steps. The key step is the metal-catalyzed oxidative cyclization of the amide to 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-diones (10a and 10b), the reaction conditions of which are investigated and optimized. The anticancer activity of 17 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione derivatives was evaluated. Preliminary results showed that 15 compounds have moderate to potent activity against human lung cancer A549, human breast cancer MDA-MB-231, and human cervical cancer HeLa cancer cell lines. Among them, compounds 11b and 11h were the most potent against A549 cell line with 0.18 and 0.19 µM of IC50, respectively; compounds 11d, 11h, and 11k showed the most potent cytotoxicity against MDA-MB-231 cell line with 0.08, 0.08, and 0.09 µM of IC50, respectively, while the activities of 11h, 11k, and 12c against HeLa cell line were the most potent with 0.15, 0.14, and 0.14 µM of IC50, respectively. Compound 11h is a promising candidate for further development, which emerged as the most effective compound overall against the three tested cancer cell lines.


Assuntos
Antineoplásicos/síntese química , Oxazóis/síntese química , Células A549 , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Oxazóis/química , Oxazóis/farmacologia , Relação Estrutura-Atividade
18.
Mar Drugs ; 17(2)2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30736491

RESUMO

Bengazoles A⁻G from the marine sponge Jaspis sp. exhibit potent in vitro antifungal activity against Candida spp. and other pathogenic fungi. The mechanism of action (MOA) of bengazole A was explored in Candida albicans under both liquid culture and surface culture on Mueller-Hinton agar. Pronounced dose-dependent synergistic antifungal activity was observed with bengazole A in the presence of bengamide A, which is also a natural product from Jaspis sp. The MOA of bengazole A was further explored by monitoring the sterol composition of C. albicans in the presence of sub-lethal concentrations of bengazole A. The GCMS of solvent extracts prepared from liquid cultures of C. albicans in the presence of clotrimazole-a clinically approved azole antifungal drug that suppresses ergosterol biosynthesis by the inhibition of 14α-demethylase-showed reduced cellular ergosterol content and increased concentrations of lanosterol and 24-methylenedihydrolanosterol (a shunt metabolite of ergosterol biosynthesis). No change in relative sterol composition was observed when C. albicans was cultured with bengazole A. These results eliminate an azole-like MOA for the bengazoles, and suggest that another as-yet unidentified mechanism is operative.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Oxazóis/farmacologia , Poríferos/química , Animais , Antifúngicos/isolamento & purificação , Azóis/química , Azóis/isolamento & purificação , Azóis/farmacologia , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Sinergismo Farmacológico , Ergosterol/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazóis/química , Oxazóis/isolamento & purificação
19.
ACS Chem Biol ; 14(4): 674-687, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30785725

RESUMO

Environmental and pathogenic microbes produce siderophores as small iron-binding molecules to scavenge iron from natural environments. It is common for microbes to produce multiple siderophores to gain a competitive edge in mixed microbial environments. Strains of human pathogenic Acinetobacter baumannii produce up to three siderophores: acinetobactin, baumannoferrin, and fimsbactin. Production of acinetobactin and baumannoferrin is highly conserved among clinical isolates while fimsbactin production appears to be less common. Fimsbactin is structurally related to acinetobactin through the presence of catecholate and phenolate oxazoline metal-binding motifs, and both are derived from nonribosomal peptide assembly lines with similar catalytic domain orientations and identities. Here we report on the chemical, biochemical, and microbiological investigation of fimsbactin and acinetobactin alone and in combination. We show that fimsbactin forms a 1:1 complex with iron(III) that is thermodynamically more stable than the 2:1 acinetobactin ferric complex. Alone, both acinetobactin and fimsbactin stimulate A. baumannii growth, but in combination the two siderophores appear to compete and collectively inhibit bacterial growth. We show that fimsbactin directly competes with acinetobactin for binding the periplasmic siderophore-binding protein BauB suggesting a possible biochemical mechanism for the phenomenon where the buildup of apo-siderophores in the periplasm leads to iron starvation. We propose an updated model for siderophore utilization and competition in A. baumannii that frames the molecular, biochemical, and cellular interplay of multiple iron acquisition systems in a multidrug resistant Gram-negative human pathogen.


Assuntos
Acinetobacter baumannii/metabolismo , Proteínas de Bactérias/metabolismo , Complexos de Coordenação/metabolismo , Imidazóis/metabolismo , Ferro/metabolismo , Oxazóis/metabolismo , Periplasma/metabolismo , Sideróforos/metabolismo , Acinetobacter baumannii/efeitos dos fármacos , Proteínas de Bactérias/química , Complexos de Coordenação/química , Humanos , Imidazóis/química , Imidazóis/farmacologia , Ferro/química , Estrutura Molecular , Oxazóis/química , Oxazóis/farmacologia , Ligação Proteica , Sideróforos/farmacologia
20.
Food Chem ; 275: 154-160, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30724182

RESUMO

Magnetic nanoparticles were modified by plasma polymerization, using allylamine, acrylic acid and 2-methyl-2-oxazoline as precursor to produce amine, carboxyl and oxazoline functional group rich surfaces. The nanoparticles were characterized by Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and zeta potential measurements. The capacity of nanoparticles carrying different surface properties to remove haze-forming proteins from Sémillon and Sauvignon Blanc unfined wines was examined by high-performance liquid chromatography (HPLC). The protein capture efficiency of the modified surfaces decreases in the following order: COOH > POx > NH2. This study will help optimising the design of this new technology for the selective removal of haze proteins from white wines.


Assuntos
Manipulação de Alimentos/métodos , Nanopartículas/química , Proteínas de Plantas/isolamento & purificação , Vinho , Acrilatos/química , Alilamina/química , Magnetismo , Oxazóis/química , Espectroscopia Fotoeletrônica , Proteínas de Plantas/metabolismo , Polimerização , Espectroscopia de Infravermelho com Transformada de Fourier , Propriedades de Superfície , Vinho/análise , Difração de Raios X
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