Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 59(1): 171-93, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26681070

RESUMO

We recently reported the bioinspired synthesis of a highly potent nonpeptidic xanthone, 2c (AM-0016), with potent antibacterial activity against MRSA. Herein, we report a thorough structure-activity relationship (SAR) analysis of a series of nonpeptidic amphiphilic xanthone derivatives in an attempt to identify more potent compounds with lower hemolytic activity and greater membrane selectivity. Forty-six amphiphilic xanthone derivatives were analyzed in this study and structurally classified into four groups based on spacer length, cationic moieties, lipophilic chains, and triarm functionalization. We evaluated and explored the effects of the structures on their membrane-targeting properties. The SAR analysis successfully identified 3a with potent MICs (1.56-3.125 µ/mL) and lower hemolytic activity (80.2 µg/mL for 3a versus 19.7 µg/mL for 2c). Compound 3a displayed a membrane selectivity of 25.7-50.4. Thus, 3a with improved HC50 value and promising selectivity could be used as a lead compound for further structural optimization for the treatment of MRSA infection.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Membranas/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Xantonas/síntese química , Xantonas/farmacologia , Trifosfato de Adenosina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Córnea/citologia , Córnea/efeitos dos fármacos , Desenho de Fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Hemólise/efeitos dos fármacos , Humanos , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade
2.
J Med Chem ; 58(16): 6533-48, 2015 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-26214729

RESUMO

Treating infections caused by multidrug-resistant Gram-negative pathogens is challenging, and there is concern regarding the toxicity of the most effective antimicrobials for Gram-negative pathogens. We hypothesized that conjugating a fatty acid moiety onto a peptide dimer could maximize the interaction with lipopolysaccharide (LPS) and facilitate the permeabilization of the LPS barrier, thereby improving potency against Gram-negative pathogens. We systematically designed a series of N-lipidated peptide dimers that are active against Gram-negative bacteria, including carbapenem-resistant Enterobacteriaceae (CRE). The optimized lipid length was 6-10 carbons. At these lipid lengths, the N-lipidated peptide dimers exhibited strong LPS permeabilization. Compound 23 exhibited synergy with select antibiotics in most of the combinations tested. 23 and 32 also displayed rapid bactericidal activity. Importantly, 23 and 32 were nonhemolytic at 10 mg/mL, with no cellular or in vivo toxicity. These characteristics suggest that these compounds can overcome the limitations of current Gram-negative-targeted antimicrobials such as polymyxin B.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Lipopeptídeos/síntese química , Lipopeptídeos/farmacologia , Lipopolissacarídeos/metabolismo , Animais , Antibacterianos/toxicidade , Carbapenêmicos/farmacologia , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular , Farmacorresistência Bacteriana , Enterobacteriaceae/efeitos dos fármacos , Ácidos Graxos/química , Feminino , Fibroblastos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Técnicas In Vitro , L-Lactato Desidrogenase/metabolismo , Lipopeptídeos/toxicidade , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Permeabilidade , Coelhos
3.
J Med Chem ; 58(2): 739-52, 2015 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-25474410

RESUMO

Antibiotic resistance is a critical global health care crisis requiring urgent action to develop more effective antibiotics. Utilizing the hydrophobic scaffold of xanthone, we identified three components that mimicked the action of an antimicrobial cationic peptide to produce membrane-targeting antimicrobials. Compounds 5c and 6, which contain a hydrophobic xanthone core, lipophilic chains, and cationic amino acids, displayed very promising antimicrobial activity against multidrug-resistant Gram-positive bacteria, including MRSA and VRE, rapid time-kill, avoidance of antibiotic resistance, and low toxicity. The bacterial membrane selectivity of these molecules was comparable to that of several membrane-targeting antibiotics in clinical trials. 5c and 6 were effective in a mouse model of corneal infection by S. aureus and MRSA. Evidence is presented indicating that 5c and 6 target the negatively charged bacterial membrane via a combination of electrostatic and hydrophobic interactions. These results suggest that 5c and 6 have significant promise for combating life-threatening infections.


Assuntos
Antibacterianos/síntese química , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Xantonas/síntese química , Aminoácidos/farmacologia , Animais , Antibacterianos/farmacologia , Membrana Celular/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Espectroscopia de Ressonância Magnética , Camundongos , Testes de Sensibilidade Microbiana , Coelhos , Relação Estrutura-Atividade , Lipossomas Unilamelares , Xantonas/farmacologia
4.
J Med Chem ; 56(6): 2359-73, 2013 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-23441632

RESUMO

This work describes how to tune the amphiphilic conformation of α-mangostin, a natural compound that contains a hydrophobic xanthone scaffold, to improve its antimicrobial activity and selectivity for Gram-positive bacteria. A series of xanthone derivatives was obtained by cationic modification of the free C3 and C6 hydroxyl groups of α-mangostin with amine groups of different pKa values. Modified structures using moieties with high pKa values, such as AM-0016 (3b), exhibited potent antimicrobial properties against Gram-positive bacteria. Compound 3b also killed bacteria rapidly without inducing drug resistance and was nontoxic when applied topically. Biophysical studies and molecular dynamics simulations revealed that 3b targets the bacterial inner membrane, forming an amphiphilic conformation at the hydrophobic-water interface. In contrast, moieties with low pKa values reduced the antimicrobial activity of the parent compound when conjugated to the xanthone scaffold. This strategy provides a new way to improve "hits" for the development of membrane-active antibiotics that target drug-resistant pathogens.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Membrana Celular/efeitos dos fármacos , Desenho de Fármacos , Interações Hidrofóbicas e Hidrofílicas , Xantonas/química , Xantonas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , Bactérias/efeitos dos fármacos , Membrana Celular/metabolismo , Técnicas de Química Sintética , Testes de Sensibilidade Microbiana , Conformação Molecular , Simulação de Dinâmica Molecular , Coelhos , Especificidade por Substrato , Xantonas/síntese química , Xantonas/toxicidade
6.
Artigo em Chinês | MEDLINE | ID: mdl-18761792

RESUMO

OBJECTIVE: To investigate the use of dendritic cells derived from mice bone marrow to evaluate the cutaneous allergic reaction induced by chemical sensitizers. METHODS: Dendritic cells derived from mice bone marrow were cultured and administrated with 2, 4-dinitrochlorobenzene (DNCB), nickel sulfate (NiSO4), sodium dodecyl sulfate (SDS) and hexyl cinnamic aldehyde (HCA), respectively. Cell membrane molecule CD86 and extracellular IL-1 beta, IL-6 and IL-12 were detected after 0, 1, 6, 12, 24, 36, 48 hour's administration, respectively. RESULTS: CD86 expression reached the highest level after exposure to DNCB for 48 h, and increased by about 279% compared with the control (P < 0.05), while it was lower than that of control after administrated with NiSO4 and HCA for 1 h and 6 h, and SDS for 36 h, respectively (P < 0.05). Extracellular IL-1 beta increased greatly after exposure to NiSO4 just for 1 h, with the maximum at 48 h (298 pg/ml, P < 0.05), and after exposure to HCA for 6 h, with maximum at 48 h (84 pg/ml, P < 0.05). However, it didn't fluctuate significantly after administrated with DNCB and SDS respectively, compared with the control. Extracellular IL-6 increased significantly after exposure to NiSO4 for 1 h, with the maximum at 24 h (2152 pg/ml, P < 0.05). After exposure to HCA, extracellular IL-6 reached the maximum at 1 h (1403 pg/ml), and then it was decreased quickly, but still higher than the control (P < 0.05), while it didn't change significantly after treatment with DNCB and SDS, compared with the control (P > 0.05). Extracellular IL-12 was not detected out among all the groups. CONCLUSION: Chemical sensitizer DNCB could induce the high expression of CD86 on DC membrane, and NiSO4 and HCA could induce DC to release IL-1 beta and IL-6. However, the irritant SDS had no such effect.


Assuntos
Células Dendríticas/efeitos dos fármacos , Dinitroclorobenzeno/farmacologia , Níquel/farmacologia , Dodecilsulfato de Sódio/farmacologia , Animais , Antígeno B7-2/metabolismo , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interleucina-12/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
7.
J Nanosci Nanotechnol ; 8(6): 3040-9, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18681044

RESUMO

In this paper, a series of organic-inorganic hybrid materials consisting of epoxy resin frameworks and dispersed nanoparticles of amino-modified silica (AMS) were successfully prepared. First of all, the AMS nanoparticles were synthesized by carrying out the conventional acid-catalyzed sol-gel reactions of tetraethyl orthosilicate (TEOS) in the presence of (3-aminopropyl)-trimethoxysilane (APTES) molecules. The as-prepared AMS nanoparticles were then characterized by FTIR, 13C-NMR and 29Si-NMR spectroscopy. Subsequently, a series of hybrid materials were prepared by performing in-situ thermal ring-opening polymerization reactions of epoxy resin in the presence of as-prepared AMS nanoparticles and raw silica (RS) particles. The as-prepared epoxy-silica hybrid materials with AMS nanoparticles were found to show better dispersion capability than that of RS particles existed in hybrid materials based on the morphological observation of transmission electron microscopy (TEM). The hybrid materials containing AMS nanoparticles in the form of coating on cold-rolled steel (CRS) were found to be much superior in corrosion protection over those of hybrid materials with RS particles when tested by a series of electrochemical measurements of potentiodynamic and impedance spectroscopy in 5 wt% aqueous NaCI electrolyte. The increase of corrosion protection effect of hybrid coatings may have probably resulted from the enhancement of the adhesion strength of the hybrid coatings on CRS coupons, which may be attributed to the formation of Fe-O-Si covalent bond at the interface of coating/CRS system based on the FTIR-RAS (reflection absorption spectroscopy) studies. The better dispersion capability of AMS nanoparticles in hybrid materials were found to lead more effectively enhanced molecular barrier property, mechanical strength, surface hydrophobicity and optical clarity as compared to that of RS particles, in the form of coating and membrane, based on the measurements of molecular permeability analysis, dynamic mechanical analysis, contact angle measurements and ultraviolet-visible transmission spectra, respectively.

8.
Biochemistry ; 45(23): 7092-9, 2006 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-16752899

RESUMO

Allophycocyanin (APC) is one of the phycobiliproteins expressed in cyanobacteria. Phycobiliproteins contain a covalently bound chromophore, and thus, they are valuable as fluorescent probes. Biosynthesis of a functional phycobiliprotein is achieved by a bilin attachment process between the chromophore and apoprotein. Chromophore lyases are necessary to catalyze the chromophorylation of cyanobacterial phycobiliproteins, such as C-phycocyanin, and phycoerythrocyanin. To identify the lyase that catalyzes the chromophorylation of the APC alpha-subunit (ApcA), we searched the entire genomes of two cyanobacteria, Synechocystis sp. PCC6803 and Anabaena sp. PCC 7120; however, these genomes do not appear to encode an APC-specific chromophore lyase. In this study, chromophorylated ApcA (chromo-ApcA) was obtained via a spontaneous bilin attachment reaction. The absorption and fluorescence characteristics of chromo-ApcA were similar to those of the native APC alpha-subunit. The extent of chromophore attachment to apo-ApcA was comparable to that of the lyase-catalyzed reactions for other phycobiliproteins. These results indicate that ApcA has autocatalytic bilin:biliprotein lyase activity.


Assuntos
Pigmentos Biliares/metabolismo , Ficocianina/biossíntese , Synechocystis/metabolismo , Sequência de Bases , Catálise , Dicroísmo Circular , Primers do DNA , Eletroforese em Gel de Poliacrilamida , Fluorescência , Plasmídeos , Espectrometria de Massas por Ionização por Electrospray
9.
Int J Dermatol ; 43(11): 801-7, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15533060

RESUMO

Asiaticoside, isolated from Centella asiatica, promotes fibroblast proliferation and extracullar matrix synthesis in wound healing. The precise mechanism, however, in molecular and gene expression levels still remains partially understood. Using cDNA microarray technology, the alternation of genes expression profiles was determined in a human dermal fibroblast in vitro in the presence of asiaticoside (30 microg/ml). Fifty-four genes, with known functions for cell proliferation, cell-cycle progression and synthesis of the extracellular matrix, were significantly up-regulated in our "whole-genes nest" expression profile at various timepoints. Furthermore, mRNA levels and protein productions of certain genes responsible for extracellular matrix (ECM) synthesis (e.g. encoding type I and type III collagen proteins) were evaluated by Northern blot and radioimmunoassay, respectively. As a result, there is a close correlation among the gene profile, mRNA and protein production in the cells response to asiaticoside stimulation. This information could be used for exploring the target genes in response to asiaticoside in fibroblasts.


Assuntos
Ciclo Celular/efeitos dos fármacos , Ciclo Celular/fisiologia , Colágeno/biossíntese , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Triterpenos/farmacologia , Ciclo Celular/genética , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Fibroblastos/citologia , Regulação da Expressão Gênica , Humanos , Pele/citologia
10.
Aquat Toxicol ; 69(3): 215-27, 2004 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-15276328

RESUMO

Metallothionein (Mt) has been considered as a molecular marker of metal pollution in aquatic ecosystems. Less is known about the expression of mt gene during embryogenesis. Here, we report the cloning, sequencing, and the expression pattern of mt gene during developmental stages in zebrafish. The zebrafish embryogenesis when takes place in a medium containing a dosage of 1000 microM zinc resulted in high mortality, indicating the deleterious effect of zinc on development. The zebrafish mt gene consists of three exons encoding 60 amino acids with 20 conserved cysteine residues. RT-PCR result indicates the maternal contribution of Mt transcripts. Using digoxigenin (DIG)-labeled anti-sense RNA probe, whole-mount in situ hybridization was performed to observe the expression pattern of zebrafish mt gene during embryonic and early larval stages. Stronger as well as ubiquitous expression of mt gene during early embryonic stages narrowed to specific expression after hatching. The mt promoter region contains seven copies of putative metal-responsive elements (MREs), which are shown to be important for the high level activity by deletion analysis. The expression of mt gene during embryogenesis implies its significant role on development.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Metalotioneína/metabolismo , Peixe-Zebra/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Primers do DNA , Biblioteca Genômica , Hibridização In Situ , Metalotioneína/genética , Dados de Sequência Molecular , Plasmídeos/genética , Regiões Promotoras Genéticas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Peixe-Zebra/embriologia , Peixe-Zebra/crescimento & desenvolvimento , Zinco
11.
Wei Sheng Yan Jiu ; 31(1): 24-7, 2002 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-12561566

RESUMO

In order to study whether Jingtian compound extracted from herbs could delay the process of skin aging, the skin on the back of Guinea pigs (6 and 15 months old) were shaved topically and applied with and without 0.5% Jingtian compound for 30 days by self-control design. The possible alterations caused by Jingtian compound were observed by histological and biochemical techniques. Results showed that the number and the activity of fibroblast in dermis was increased prominently compared with the control. The activities of superoxide dismutase, glutathion peroxidase and the hydroxyproline level of acid soluble collagen in dermis were enhanced, and the malondialdehyde content was inhibited concomitantly. It is suggested that Jingtian compound might play a protective role on skin aging.


Assuntos
Crassulaceae/química , Medicamentos de Ervas Chinesas/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Pele/química , Animais , Colágeno/metabolismo , Cosméticos , Medicamentos de Ervas Chinesas/isolamento & purificação , Feminino , Cobaias , Superóxido Dismutase/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA