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1.
Bioorg Med Chem Lett ; 22(17): 5503-7, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22835871

RESUMO

There are numerous potential applications for melanin-binding compounds, and new methods are of interest to identify melanin-binding agents. A portion of the polymerization to eumelanin, the black to brown pigment in humans, is thought to be supramolecular aggregation of nanoparticles derived from dihydroxyindoles. Starting with chloroquine, a known eumelanin-binding compound, the ability of small molecules to influence aggregation in synthetic eumelanin polymerizations was investigated. Twenty-eight compounds were tested, including pharmaceuticals, dyes, aromatics, and amines. Compounds that either accelerate or delay the appearance of macroscopic particles in synthetic eumelanin polymerizations were uncovered.


Assuntos
Melaninas/metabolismo , Polimerização/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Cloroquina/química , Cloroquina/farmacologia , Vermelho Congo/química , Vermelho Congo/farmacologia , Humanos , Melaninas/química
2.
Bioinorg Chem Appl ; 2012: 361803, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22611345

RESUMO

Interactions between metal ions and different forms of melanin play significant roles in melanin biochemistry. The binding properties of natural melanin and related synthetic materials can be exploited for nonbiological applications, potentially including water purification. A method for investigating metal ion-melanin interactions on solid support is described, with lead as the initial target. 2.5 cm discs of the hydrophobic polymer PVDF were coated with synthetic eumelanin from the tyrosinase-catalyzed polymerization of L-dopa, and with melanin extracted from human hair. Lead (Pb(2+)) binding was quantified by atomic absorption spectroscopy (flame mode), and the data was well fit by the Langmuir model. Langmuir affinities ranged from 3.4 · 10(3) to 2.2 · 10(4) M(-1). At the maximum capacity observed, the synthetic eumelanin coating bound ~9% of its mass in lead. Binding of copper (Cu(2+)), zinc (Zn(2+)), and cadmium (Cd(2+)) to the synthetic-eumelanin-coated discs was also investigated. Under the conditions tested, the Langmuir affinities for Zn(2+), Cd(2+), and Cu(2+) were 35%, 53%, and 77%, respectively, of the Langmuir affinity for Pb(2+). The synthetic-eumelanin-coated discs have a slightly higher capacity for Cu(2+) on a per mole basis than for Pb(2+), and lower capacities for Cd(2+) and Zn(2+). The system described can be used to address biological questions and potentially be applied toward melanin-based water purification.

3.
Bioorg Med Chem Lett ; 20(15): 4475-8, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20594849

RESUMO

Inhibitors of melanin formation are sought after for a range of applications. Boronophenylalanine is known to inhibit melanogenesis via boronic acid-catechol interactions. A spectroscopic assay was developed to study the polymerization of l-dopa to synthetic melanin in the presence of para-substituted aryl boronic acids. The best inhibition was observed for aryl boronic acids with electron-withdrawing substituents. The IC(50) values exhibit a correlation with the Hammett sigma(p) parameter (rho=0.97, r(2)=0.92).


Assuntos
Ácidos Borônicos/química , Melaninas/metabolismo , Ácidos Borônicos/farmacologia , Catecóis/química , Levodopa/química , Melaninas/antagonistas & inibidores , Relação Estrutura-Atividade
4.
RSC Adv ; 9(48): 27754, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-35532451

RESUMO

[This corrects the article DOI: 10.1039/C8RA06148C.].

5.
Chem Biol ; 14(10): 1140-51, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17961826

RESUMO

Supramolecular chemistry has been employed to develop flexible and adaptable multivalent neoglycoconjugates for binding galectin-1 (Gal-1). Gal-1, a dimeric lectin with two galactoside-binding sites, regulates cancer progression and immune responses. Self-assembled pseudopolyrotaxanes consisting of lactoside-displaying cyclodextrin (LCD) "beads" threaded onto polyviologen "strings" display mobile ligands as a result of cyclodextrin rotation about, and limited translation along, the polymer chain. The pseudopolyrotaxanes rapidly and efficiently precipitate Gal-1 and provide valency-corrected enhancements of up to 30-fold compared to native lactose and 20-fold over free LCD in a T-cell agglutination assay. A supramolecular statistical effect was observed, wherein the efficacy of Gal-1 inhibition correlates with the number of ligands connected to each other solely through mechanical and noncovalent interactions. Such flexible and adaptable self-assembled pseudopolyrotaxanes show promise for the study of multivalent interactions and targeting of therapeutically relevant lectins.


Assuntos
Ciclodextrinas/metabolismo , Galectina 1/metabolismo , Poloxâmero/metabolismo , Rotaxanos/metabolismo , Testes de Aglutinação , Sítios de Ligação , Configuração de Carboidratos , Sequência de Carboidratos , Precipitação Química , Ciclodextrinas/química , Dimerização , Galectina 1/química , Glicosídeos/química , Humanos , Ligantes , Substâncias Macromoleculares/química , Substâncias Macromoleculares/farmacologia , Dados de Sequência Molecular , Poloxâmero/química , Rotaxanos/química , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos
6.
RSC Adv ; 8(50): 28323-28328, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-35542496

RESUMO

Dihydroxyindoles such as 5,6-dihydroxyindole-2-carboxylic acid (DHICA) are the main monomer units of eumelanin, the black to brown pigment in humans, and have emerging biological roles beyond melanin. Elaboration of commercially available 5,6-dimethoxy-2-carboxylate ethyl ester provides ready access to DHICA-inspired small molecules, including 3-(hetero)aryl-indoles and 4,7-di-(hetero)aryl-indoles.

7.
Tetrahedron ; 63(27): 6146-6151, 2007 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-18596841

RESUMO

Hairpin pyrrole-imidazole (Py-Im) polyamides are programmable oligomers that bind the DNA minor groove in a sequence-specific manner with affinities comparable to those of natural DNA-binding proteins. These cell-permeable small molecules have been shown to enter the nuclei of live cells and downregulate endogenous gene expression. We complete here a library of 27 hairpin Py-Im polyamides which bind 7-base-pair sequences of the general form 5'-WWGNNNW-3' (where W = A or T, N = W, G, or C). Their equilibrium association constants (K(a)) range from K(a) = 1×10(8) M(-1) to 4×10(10) M(-1) with good sequence specificity. A table of binding affinities and sequence contexts for this completed 27-member library has been assembled for the benefit of the chemical biology community interested in molecular control of transcription.

8.
J Mol Biol ; 321(2): 249-63, 2002 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-12144782

RESUMO

Pyrrole-imidazole (Py-Im) polyamides are synthetic ligands that bind in the minor groove of DNA. Previous studies have established that sites on nucleosomal DNA facing away from the histone octamer, or even partially facing the histone octamer, are fully accessible for molecular recognition by Py-Im polyamides, and that nucleosomes remain fully folded upon ligand binding. Two polyamides that bind within the sea urchin 5S gene nucleosome positioning sequence inhibit both heat-induced nucleosome sliding and transcription by bacteriophage T7 RNA polymerase from the nucleosomal template, but not from histone-free DNA. These polyamides prevent repositioning of the histone octamer by RNA polymerase, and thereby inhibit passage of the elongating polymerase through nucleosomal DNA. These results establish unambiguously the requirement for octamer mobility for transcription of nucleosomal templates by T7 RNA polymerase.


Assuntos
RNA Polimerases Dirigidas por DNA/metabolismo , DNA/metabolismo , Nucleossomos/genética , Nucleossomos/metabolismo , Nylons/síntese química , Nylons/metabolismo , Transcrição Gênica , Animais , Sequência de Bases , Sítios de Ligação , DNA/genética , Pegada de DNA , Desoxirribonuclease I , Regulação da Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Temperatura Alta , Radical Hidroxila , Ligantes , Dados de Sequência Molecular , Nucleossomos/química , Nylons/farmacologia , RNA Ribossômico 5S/genética , Ouriços-do-Mar/genética , Moldes Genéticos , Transcrição Gênica/efeitos dos fármacos , Proteínas Virais
9.
Chem Biol ; 10(9): 859-67, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14522056

RESUMO

Pyrrole-imidazole polyamides bind DNA with affinities comparable to those of transcriptional regulatory proteins and inhibit the DNA binding activities of components of the transcription apparatus. If polyamides are to be useful for the regulation of gene expression in cell culture experiments, one pivotal issue is accessibility of specific sites in nuclear chromatin. We first determined the kinetics of uptake and subcellular distribution of polyamides in lymphoid and myeloid cells using fluorescent polyamide-bodipy conjugates and deconvolution microscopy. Then cells were incubated with a polyamide-chlorambucil conjugate, and the sites of specific DNA cleavage in the nuclear chromatin were assayed by ligation-mediated PCR. In addition, DNA microarray analysis revealed that two different polyamides generated distinct transcription profiles. Remarkably, the polyamides affected only a limited number of genes.


Assuntos
Cromatina/química , Nylons/farmacologia , Transcrição Gênica/efeitos dos fármacos , Alquilação , Apoptose/efeitos dos fármacos , Sítios de Ligação , Divisão Celular/efeitos dos fármacos , Linhagem Celular , DNA/química , Perfilação da Expressão Gênica , Humanos , Linfócitos/citologia , Linfócitos/metabolismo , Microscopia de Fluorescência , Células Mieloides/citologia , Células Mieloides/metabolismo , Nylons/química , Nylons/farmacocinética , Análise de Sequência com Séries de Oligonucleotídeos
10.
Org Biomol Chem ; 4(2): 250-6, 2006 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-16391767

RESUMO

Self-assembled multivalent pseudopolyrotaxanes, composed of lactoside-bearing cyclodextrin (CD) rings threaded on linear polyviologen polymers, have been introduced recently as flexible and dynamic neoglycoconjugates. In the course of this research, it was found that polyviologens are responsive to the Bradford assay, which is traditionally highly selective for proteins. The response of the pseudopolyrotaxanes to the Bradford assay was dependant on, and thus indicative of, the degree of threading of the CD rings onto the polyelectrolyte. The assay was then used to report on the threading and dethreading of native and lactoside-bearing alpha-CD rings onto and off of polyviologen chains, a phenomenon which demonstrates the utility of biochemical assays to address problems unique to supramolecular chemistry.


Assuntos
Ciclodextrinas/análise , Poloxâmero/análise , Polímeros/análise , Rotaxanos/análise , Viologênios/análise , Ciclodextrinas/química , Glicosídeos , Substâncias Macromoleculares/análise , Substâncias Macromoleculares/química , Métodos , Polímeros/química , Viologênios/química
11.
Biochemistry ; 42(20): 6249-58, 2003 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-12755629

RESUMO

The retroviral integrase (IN) carries out the integration of the viral DNA into the host genome. Both IN and the DNA sequences at the viral long-terminal repeat (LTR) are required for the integration function. In this report, a series of minor groove binding hairpin polyamides targeting sequences within terminal inverted repeats of the Moloney murine leukemia virus (M-MuLV) LTR were synthesized, and their effects on integration were analyzed. Using cell-free in vitro integration assays, polyamides targeting the conserved CA dinucleotide with cognate sites closest to the terminal base pairs were effective at blocking 3' processing but not strand transfer. Polyamides which efficiently inhibited 3' processing and strand transfer targeted the LTR sequences through position 9. Polyamides that inhibited integration were effective at nanomolar concentrations and showed subnanomolar affinity for their cognate LTR sites. These studies highlight the role of minor groove interactions within the LTR termini for retroviral integration.


Assuntos
Vírus da Leucemia Murina de Moloney/efeitos dos fármacos , Vírus da Leucemia Murina de Moloney/genética , Nylons/farmacologia , Sequências Repetidas Terminais/efeitos dos fármacos , Integração Viral/efeitos dos fármacos , Integração Viral/genética , Animais , Sequência de Bases , Sítios de Ligação/genética , DNA Viral/efeitos dos fármacos , DNA Viral/genética , Desenho de Fármacos , Técnicas In Vitro , Cinética , Camundongos , Vírus da Leucemia Murina de Moloney/fisiologia , Nylons/química , Nylons/metabolismo
12.
J Am Chem Soc ; 126(38): 11914-22, 2004 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-15382926

RESUMO

A self-assembled pseudopolyrotaxane consisting of lactoside-displaying cyclodextrin (CD) "beads" threaded onto a linear polyviologen "string" was investigated for its ability to inhibit galectin-1-mediated T-cell agglutination. The CDs of the pseudopolyrotaxane are able to spin around the axis of the polymer chain as well as to move back and forth along its backbone to alter the presentation of its ligand. This supramolecular superstructure incorporates all the advantages of polymeric structures, such as the ability to span large distances, along with a distinctively dynamic presentation of its lactoside ligands to afford a neoglycoconjugate that can adjust to the relative stereochemistries of the lectin's binding sites. The pseudopolyrotaxane exhibited a valency-corrected 10-fold enhancement over native lactose in the agglutination assay, which was greater than the enhancements observed for lactoside-bearing trivalent glycoclusters and a lactoside-bearing chitosan polymer tested using the same assay. The experimental results indicate that supramolecular architectures, such as the pseudopolyrotaxane, provide tools for investigating protein-carbohydrate interactions.


Assuntos
Galectina 1/análogos & derivados , Galectina 1/química , Rotaxanos/química , Testes de Aglutinação , Sequência de Carboidratos , Linhagem Celular Tumoral , Quitosana/análogos & derivados , Quitosana/síntese química , Quitosana/química , Quitosana/farmacologia , Galectina 1/antagonistas & inibidores , Galectina 1/farmacologia , Glicosídeos/síntese química , Glicosídeos/química , Glicosídeos/farmacologia , Humanos , Leucemia de Células T , Dados de Sequência Molecular , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacologia , Rotaxanos/síntese química , Rotaxanos/farmacologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Viologênios/síntese química , Viologênios/química , alfa-Ciclodextrinas/química , alfa-Ciclodextrinas/farmacologia
13.
Bioorg Med Chem ; 10(10): 3313-8, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12150878

RESUMO

The cellular uptake and localization properties of DNA binding N-methylpyrrole/N-methylimidazole polyamide-dye conjugates in a variety of living cells have been examined by confocal laser scanning microscopy. With the exception of certain T-cell lines, polyamide-dye conjugates localize mainly in the cytoplasm and not in the nucleus. Reagents such as methanol typically used to fix cells for microscopy significantly alter the cellular localization of these DNA-binding ligands.


Assuntos
Corantes Fluorescentes/farmacocinética , Imidazóis/farmacocinética , Nylons/farmacocinética , Pirróis/farmacocinética , Compostos de Boro/farmacocinética , Compartimento Celular , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Humanos , Microscopia Confocal , Linfócitos T/citologia , Linfócitos T/metabolismo , Linfócitos T/ultraestrutura , Células Tumorais Cultivadas
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