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1.
Amino Acids ; 51(9): 1247-1257, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31350614

RESUMO

Somatostatin (SST) is an endogenous cyclic tetradecapeptide hormone that exerts multiple biological activities via a family of five receptors. BIM-23052 (DC-23-99) D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2 is a linear SST analog with established in vitro GH-inhibitory activity and high affinity to sstr5, sstr3 and sstr2. The different SSTR subtypes are expressed in different tissues and in some tumor cells. Based on this finding, a series of new analogs of BIM-23052 with expected antitumor activity have been synthesized. The Thr at position 6 in BIM-23052 was replaced by the conformationally hindered Tle, Aib, Ac5c and Ac6c of the new analogs. The peptides were synthesized by standard solid-phase peptide chemistry methods, Fmoc strategy. The cytotoxic effects of the compounds were tested in vitro against a panel of tumor cell lines: HT-29, MDA-MB-23, Hep-G2, HeLa and the normal human diploid cell line Lep-3. All five somatostatin receptor subtypes were modeled and docking was performed to determine the binding affinity of the analogs. The new peptides exhibited different concentration-dependent antiproliferative effect on the tumor cell lines after 24 h of treatment. The compound 3B (Aib6) demonstrated the most pronounced antiproliferative effects on HepG-2 cells with the IC50 = 0.01349 nM. Docking confirmed that all compounds bind well to SST receptors with preference to sstr3 and sstr5, which is most probably the reason for the observed biological effects.


Assuntos
Aminoácidos/química , Antineoplásicos/química , Somatostatina/análogos & derivados , Aminoácidos Cíclicos/química , Ácidos Aminoisobutíricos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Sintética , Ácidos Cicloexanocarboxílicos/química , Cicloleucina/química , Células HT29 , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Peptídeos/síntese química , Peptídeos/farmacologia , Receptores de Somatostatina/química , Somatostatina/química , Somatostatina/farmacologia , Relação Estrutura-Atividade
2.
Chirality ; 31(8): 547-560, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31241803

RESUMO

Peptide models built from cis- and trans-2-aminocyclobutane-1-carboxylic acids (ACBCs) are studied in the solid phase by combining Fourier-transform infrared spectroscopy (FTIR) absorption spectroscopy, vibrational circular dichroism (VCD), and quantum chemical calculations using density functional theory (DFT). The studied systems are N-tert-butyloxycarbonyl (Boc) derivatives of 2-aminocyclobutanecarboxylic acid (ACBC) benzylamides, namely Boc-(cis-ACBC)-NH-Bn and Boc-(trans-ACBC)-NH-Bn. These two diastereomers show very different VCD signatures and intensities, which of the trans-ACBC derivative being one order of magnitude larger in the region of the ν (CO) stretch. The spectral signature of the cis-ACBC derivative is satisfactorily reproduced by that of the monomer extracted from the solid-state geometry of related ACBC derivatives, which shows that no long-range effects are implicated for this system. In terms of hydrogen bonds, the geometry of this monomer is intermediate between the C6 and C8 structures (exhibiting a 6- or 8-membered cyclic NH⋯O hydrogen bond) previously evidenced in the gas phase. The benzyl group must be in an extended geometry to reproduce satisfactorily the shape of the VCD spectrum in the ν (CO) range, which qualifies VCD as a potential probe of dispersion interaction. In contrast, reproducing the IR and VCD spectrum of the trans-ACBC derivative requires clusters larger than four units, exhibiting strong intermolecular H-bonding patterns. A qualitative agreement is obtained for a tetramer, although the intensity enhancement is not reproduced. These results underline the sensitivity of VCD to the long-range organisation in the crystal.


Assuntos
Aminoácidos Cíclicos/química , Amidas/química , Aminoácidos Cíclicos/síntese química , Dicroísmo Circular , Cristalografia por Raios X , Teoria da Densidade Funcional , Gases/química , Ligações de Hidrogênio , Espectroscopia de Infravermelho com Transformada de Fourier , Estereoisomerismo
3.
Mol Biotechnol ; 61(9): 650-662, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31201604

RESUMO

1-Aminocyclopropane carboxylic acid oxidase (ACCO) catalyzes the last step of ethylene biosynthesis in plants. Although some sets of structures have been described, there are remaining questions on the active conformation of ACCO and in particular, on the conformation and potential flexibility of the C-terminal part of the enzyme. Several techniques based on the introduction of a probe through chemical modification of amino acid residues have been developed for determining the conformation and dynamics of proteins. Cysteine residues are recognized as convenient targets for selective chemical modification of proteins, thanks to their relatively low abundance in protein sequences and to their well-mastered chemical reactivity. ACCOs have generally 3 or 4 cysteine residues in their sequences. By a combination of approaches including directed mutagenesis, activity screening on cell extracts, biophysical and biochemical characterization of purified enzymes, we evaluated the effect of native cysteine replacement and that of insertion of cysteines on the C-terminal part in tomato ACCO. Moreover, we have chosen to use paramagnetic labels targeting cysteine residues to monitor potential conformational changes by electron paramagnetic resonance (EPR). Given the level of conservation of the cysteines in ACCO from different plants, this work provides an essential basis for the use of cysteine as probe-anchoring residues.


Assuntos
Aminoácido Oxirredutases/química , Aminoácidos Cíclicos/química , Cisteína/química , Etilenos/química , Lycopersicon esculentum/enzimologia , Óxidos de Nitrogênio/química , Proteínas de Plantas/química , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Substituição de Aminoácidos , Aminoácidos Cíclicos/metabolismo , Sítios de Ligação , Clonagem Molecular , Cisteína/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Escherichia coli/genética , Escherichia coli/metabolismo , Etilenos/biossíntese , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Cinética , Lycopersicon esculentum/química , Modelos Moleculares , Mutagênese Sítio-Dirigida , Óxidos de Nitrogênio/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Marcadores de Spin , Especificidade por Substrato
4.
Amino Acids ; 51(4): 669-678, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30758725

RESUMO

The synthesis of α/ß-chimeras comprises peptide bond formation from α- to ß-, from ß- to ß-, and from ß- to α-amino acid residues. The fine-tuned solid phase synthesis of -GXXG- chimera peptides containing the simplest achiral α-amino acid glycine and two cyclic SAAs of different ring size [X denoting cyclic ß-Sugar Amino Acids (ß-SAA)] is reported, variants containing Fmoc-RibAFU(ip)-OH a furanoid-, and Fmoc-GlcAPU(Me)-OH a pyranoid-type structural "Lego-element". Systematic search for the best coupling strategy with both H-ß-SAA-OHs is described, including the comparison of the different coupling reagents and conditions. Selecting the optimal reagent (from commonly used PyBOP, HATU and HOBt) was assisted by time-resolved 1H-NMR: formation and stability of the Fmoc protected active esters were compared. We found that PyBOP is the best choice for successfully coupling both H-ß-SAA-OH prototypes. The present comparative results open a reasonable route for building efficiently various -ß-SAA- containing homo- and heterooligomers.


Assuntos
Aminoácidos Cíclicos/química , Amino Açúcares/química , Biossíntese Peptídica , Fragmentos de Peptídeos/síntese química , Técnicas de Síntese em Fase Sólida
5.
Bioorg Med Chem Lett ; 29(2): 297-301, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30470494

RESUMO

Analogs based on the 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate scaffold showed high potency and selectivity as both group II mGlu receptors orthosteric agonists and antagonists. This scaffold was initially designed to mimic the fully extended glutamate backbone conformation that was hypothesized to be the active conformation for the group II mGlu receptors. With the availability of crystal structures of l-Glu-bound amino terminal domain proteins from multiple mGlu receptor subtypes spanning all three subgroups, a new steric hindrance hypothesis was proposed to account for the scaffold's unique group II selectivity that explores the subtle distance differences between the α-carbon of l-Glu and the center of the tyrosine phenyl ring from the bottom lobe (e.g. Y216 of mGlu2).


Assuntos
Aminoácidos Cíclicos/farmacologia , Ácidos Dicarboxílicos/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Aminoácidos Cíclicos/química , Animais , Ácidos Dicarboxílicos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-Atividade
6.
Biomed Res Int ; 2018: 1470305, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30519568

RESUMO

Endophytic actinomycetes are a promising source of novel metabolites with diverse biological activities. Tea plants (Camellia sinensis) produce arsenals of phytochemicals, which are linked to a number of medicinal and nutritional properties. However, a systematic investigation into the abundance and diversity of cultivated actinomycetes residing in tea plants has not been performed. In this study, a total of 46 actinobacteria were recovered from leaf, stem, and root samples of 15 tea cultivars collected in Fujian province, China. Their abundance and diversity were shown to be influenced by both the genotypes and tissue types of tea plants. Based on 16S RNA sequence analysis, these isolates were taxonomically grouped into 11 families and 13 genera, including Streptomyces, Actinomadura, Kribbella, Nocardia, Kytococcus, Leifsonia, Microbacterium, Micromonospora, Mobilicoccus, Mycobacterium, Nocardiopsis, Piscicoccus, and Pseudonocardia. The genus Streptomyces was most prevalent whereas rare genera, Mobilicoccus and Piscicoccus, were reported for the first time to occur as plant endophytes. PCR screening of polyketide synthase genes (PKS-I and PKS-II) and nonribosomal peptide synthetase genes (NRPS), along with antimicrobial assays against a set of bacterial and fungal pathogens, showed that endophytic actinomycetes associated with tea plants have a high potential for producing antimicrobial metabolites. Furthermore, indole acetic acid (IAA) production and 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase activities were recorded in 93.5% and 21.7% of all isolates, respectively. Overall, these results indicate that endophytic actinomycetes from tea plants represent a valuable source of bioactive metabolites with antibacterial, antifungal, and plant-growth-promoting properties.


Assuntos
Actinobacteria/isolamento & purificação , Antibacterianos/isolamento & purificação , Endófitos/isolamento & purificação , Chá/microbiologia , Actinobacteria/química , Actinobacteria/classificação , Actinobacteria/genética , Aminoácidos Cíclicos/química , Antibacterianos/química , Antibacterianos/farmacologia , China , Endófitos/química , Ácidos Indolacéticos/química , Filogenia , Desenvolvimento Vegetal/efeitos dos fármacos , RNA Ribossômico 16S/genética
7.
Molecules ; 23(5)2018 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-29734782

RESUMO

Lysine-specific demethylase 1 (LSD1) mainly removes methyl groups of mono- or di-methylated lysine residues at the fourth position of histone H3 to epigenetically regulate the expression of genes associated with several diseases, such as cancer. Therefore, LSD1 inactivators are expected to be used as therapeutic agents. In this study, to identify novel peptide-based LSD1 inactivators, we focused on the X-ray structure of LSD1 complexed with a H3 peptide-based suicide substrate. It has been proposed that a methylated histone substrate forms three consecutive γ-turn structures in the active pocket of LSD1. Based on this, we designed and synthesized novel histone H3 peptide-based LSD1 inactivators 2a⁻c by incorporating various α,α-disubstituted amino acids with γ-turn-inducing structures. Among synthetic peptides 2a⁻c, peptide 2b incorporating two 1-aminocyclohexanecarboxylic acids at both sides of a lysine residue bearing a trans-2-phenylcyclopropylamine (PCPA) moiety, which is a pharmacophore for LSD1 inactivation, was the most potent and selective LSD1 inactivator. These findings are useful for the further development of histone H3 peptide-based LSD1 inactivators.


Assuntos
Aminoácidos/síntese química , Inibidores Enzimáticos/síntese química , Histona Desmetilases/antagonistas & inibidores , Histonas/química , Lisina/química , Peptídeos/síntese química , Aminoácidos Cíclicos/química , Domínio Catalítico , Ácidos Cicloexanocarboxílicos/química , Desenho de Drogas , Ensaios Enzimáticos , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/química , Histona Desmetilases/metabolismo , Histonas/metabolismo , Humanos , Hidrólise , Isoenzimas/química , Isoenzimas/metabolismo , Lisina/metabolismo , Metilação , Simulação de Acoplamento Molecular , Monoaminoxidase/química , Monoaminoxidase/metabolismo , Peptídeos/farmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Relação Estrutura-Atividade , Tranilcipromina/química
8.
J Chromatogr A ; 1535: 72-79, 2018 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-29307528

RESUMO

In the present work the effects of N-methylation and N-amidination of ampholytic cyclic ß-amino acids on their retention and enantioseparation characteristics on Cinchona alkaloid- and sulfonic acid-based zwitterionic chiral selectors, namely Chiralpak ZWIX(+)™ and ZWIX(-)™ columns are described. In a polar-ionic mobile phase, a double ion-pairing interaction mechanism takes place between the charged sites of the chiral analytes (the selectands) and the chiral selector moieties. As a support to correlate the chromatographic results with the structural details of the analytes, pKa values and van der Waals volumes of the substituted amino groups were calculated. In order to ensure better understanding of the mechanistic details of the chromatographic system the composition of the bulk solvent, the role of acid base additives, the concentration of the counter-ions, temperature and the structures of the ampholytic analytes have been investigated. Applying N-Fmoc protection, the ampholytic character of the analytes diminished, leading to a marked loss of retention. In the temperature range studied (5-40 °C) thermodynamic parameters, such as the difference in the standard enthalpy change Δ(ΔH°), entropy Δ(ΔS) and Gibbs energy Δ(ΔG°) were calculated from linear van't Hoff plots derived from the ln α vs. 1/T curves. The values of the thermodynamic parameters depended on the structures of the chiral selectors applied and the analytes studied.


Assuntos
Aminoácidos Cíclicos/química , Cromatografia Líquida/métodos , Alcaloides de Cinchona/química , Ácidos Sulfônicos/química , Amidas/química , Metilação , Estereoisomerismo , Temperatura Ambiente , Termodinâmica
9.
Bioorg Med Chem ; 25(24): 6554-6562, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29097029

RESUMO

Ascidiacyclamide [ASC, cyclo(-Ile-oxazoline-d-Val-thiazole-)2] is a cyclic octapeptide isolated from tunicates. We designed ASC analogues [cyclo(-Ile-Xxx-d-Val-thiazole-)2] in which Pro or a homologue was substituted for oxazoline: [Pro]ASC (Xxx: proline), [Aze]ASC (Xxx: (S)-Azetidine-2-carboxylic acid), [Pip]ASC (Xxx: (S)-Piperidine-2-carboxylic acid) and [ΔPro]ASC (Xxx: (S)-3-pyrroline-2-carboxylic acid) to explore their potential to serve as substitutes for the oxazoline ring. The conformations of these analogues were examined using X-ray diffraction, 1H NMR and CD spectroscopy. In both the crystal and solution states, the conformations of [Pro]ASC, [Aze]ASC and [ΔPro]ASC were novel square structures having two trans imide bonds and stabilized by two intramolecular hydrogen bonds. The crystal structure of [Pip]ASC was a folded conformation with cis and trans imide bonds. Three isomers (cc, ct and tt) were present in a solution of [Pip]ASC. From crystal structures, the degree of puckering in the side chains of Pro and its homologues was estimated to be in the order Pip > Pro > Aze > ΔPro. [Pro]ASC and [Pip]ASC showed strong cytotoxicity, but [Aze]ASC and [ΔPro]ASC showed no cytotoxicity. Among the four analogues, there is consistency between the prolyl ring puckering and cytotoxicity, but not between the peptide backbone structure and cytotoxicity.


Assuntos
Aminoácidos Cíclicos/química , Oxazóis/química , Peptídeos Cíclicos/química , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células HL-60 , Humanos , Modelos Moleculares , Conformação Molecular , Peptídeos Cíclicos/síntese química , Relação Estrutura-Atividade
10.
Amino Acids ; 49(9): 1441-1455, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28634827

RESUMO

Peptide-based drug research has received high attention in the field of medicinal chemistry over the past decade. For drug design, to improve proteolytic stability, it is desirable to include unnatural building blocks, such as conformationally restricted ß-amino acid moieties, into the peptide sequence. Accordingly, the synthesis and incorporation of such conformationally rigid systems into novel type of peptides has gained large interest. Our research group has designed highly efficient methods for the construction of potential antimicrobial peptides. Moreover, a number of synthetic approaches have been developed for the synthesis of various pharmacologically interesting cyclic ß-amino acid derivatives as monomers with multiple stereogenic centers.


Assuntos
Aminoácidos Cíclicos/química , Peptídeos Catiônicos Antimicrobianos/síntese química , Desenho de Drogas , Peptídeos/síntese química , Peptidomiméticos/síntese química , Sequência de Aminoácidos , Química Farmacêutica , Técnicas de Química Combinatória , Humanos , Estrutura Secundária de Proteína
11.
Cancer Biother Radiopharm ; 31(8): 295-301, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27754748

RESUMO

Improving the in vivo pharmacokinetics (PK) of positron emission tomography (PET) radiotracers is of critical importance to tumor diagnosis and therapy. In the case of peptide-based radiotracers, the modification and addition of a linker or spacer functional group often offer faster in vivo pharmacokinetic behavior. In this study, the authors introduced two new PEGlyated dimeric c(RGD-ACH-K) conjugates, in which an aminocyclohexane carboxylic acid (ACH) is inserted into the ring chain of the cyclic RGD peptides, with a common bifunctional chelator (DOTA or NOTA) used for labeling with radiometals (including 68Ga and 64Cu). The addition of polyethylene glycol (PEG) and dimerization of c(RGD-ACH-K) affected the PK of the renal system and the tumor-targeting ability, relative to unmodified molecule. As a result, both 64Cu-DOTA-E[c(RGD-ACH-K)]2 (complex 1) and 64Cu-NOTA-E[c(RGD-ACH-K)]2 (complex 2) exhibited specific tumor-targeting properties relative to tumor-blocking control group, most likely resulting from improved in vivo tumor imaging. The in vivo tumor-to-blood ratio of the 64Cu(NOTA) complex shows better PET imaging than that of the 64Cu(DOTA) complex, which should lead to improved dosimetry and increased suitability for noninvasive monitoring of tumor growth or tumor-targeted radionuclide therapy.


Assuntos
Aminoácidos Cíclicos/química , Neoplasias Encefálicas/diagnóstico por imagem , Ácidos Cicloexanocarboxílicos/química , Glioma/diagnóstico por imagem , Oligopeptídeos/química , Polietilenoglicóis/química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Aminoácidos Cíclicos/farmacocinética , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Radioisótopos de Cobre/química , Ácidos Cicloexanocarboxílicos/farmacocinética , Dimerização , Feminino , Glioma/metabolismo , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Oligopeptídeos/farmacocinética , Compostos Radiofarmacêuticos/química
12.
PLoS One ; 11(10): e0164785, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27764176

RESUMO

Insulin secretagogues are used for treatment of type 2 diabetes. We attempted to discover novel small molecules to stimulate insulin secretion by using in silico similarity search using sulfonylureas as query, followed by measurement of insulin secretion. Among 38 compounds selected by in silico similarity search, we found three diphenylsemicarbazides and one quinolone that stimulate insulin secretion. We focused on compound 8 (C8), which had the strongest insulin-secreting effect. Based on the structure-activity relationship of C8-derivatives, we identified diphenylthiosemicarbazide (DSC) 108 as the most potent secretagogue. DSC108 increased the intracellular Ca2+ level in MIN6-K8 cells. Competitive inhibition experiment and electrophysiological analysis revealed sulfonylurea receptor 1 (SUR1) to be the target of DSC108 and that this diphenylthiosemicarbazide directly inhibits ATP-sensitive K+ (KATP) channels. Pharmacokinetic analysis showed that DSC108 has a short half-life in vivo. Oral administration of DSC108 significantly suppressed the rises in blood glucose levels after glucose load in wild-type mice and improved glucose tolerance in the Goto-Kakizaki (GK) rat, a model of type 2 diabetes with impaired insulin secretion. Our data indicate that DSC108 is a novel insulin secretagogue, and is a lead compound for development of a new anti-diabetic agent.


Assuntos
Aminoácidos Cíclicos/farmacologia , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Semicarbazidas/farmacologia , Tiossemicarbazonas/farmacologia , Administração Oral , Aminoácidos Cíclicos/química , Aminoácidos Cíclicos/metabolismo , Aminoácidos Cíclicos/uso terapêutico , Animais , Glicemia/análise , Cálcio/metabolismo , Linhagem Celular , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Teste de Tolerância a Glucose , Glibureto/farmacologia , Glibureto/uso terapêutico , Meia-Vida , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Hipoglicemiantes/uso terapêutico , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Canais KATP/antagonistas & inibidores , Canais KATP/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Ratos , Semicarbazidas/sangue , Semicarbazidas/química , Semicarbazidas/metabolismo , Relação Estrutura-Atividade , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/metabolismo , Compostos de Sulfonilureia/farmacologia , Receptores Sulfonilureia/antagonistas & inibidores , Receptores Sulfonilureia/metabolismo , Tiossemicarbazonas/química , Tiossemicarbazonas/metabolismo , Tiossemicarbazonas/uso terapêutico
13.
Acta Biomater ; 40: 31-37, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27090589

RESUMO

UNLABELLED: For surface-based diagnostic devices to achieve reliable biomarker detection in complex media such as blood, preventing nonspecific protein adsorption and incorporating high loading of biorecognition elements are paramount. In this work, a novel method to produce nonfouling zwitterionic hydrogel coatings was developed to achieve these goals. Poly(carboxybetaine acrylamide) (pCBAA) hydrogel thin films (CBHTFs) prepared with a carboxybetaine diacrylamide crosslinker (CBAAX) were coated on gold and silicon dioxide surfaces via a simple spin coating process. The thickness of CBHTFs could be precisely controlled between 15 and 150nm by varying the crosslinker concentration, and the films demonstrated excellent long-term stability. Protein adsorption from undiluted human blood serum onto the CBHTFs was measured with surface plasmon resonance (SPR). Hydrogel thin films greater than 20nm exhibited ultra-low fouling (<5ng/cm(2)). In addition, the CBHTFs were capable of high antibody functionalization for specific biomarker detection without compromising their nonfouling performance. This strategy provides a facile method to modify SPR biosensor chips with an advanced nonfouling material, and can be potentially expanded to a variety of implantable medical devices and diagnostic biosensors. STATEMENT OF SIGNIFICANCE: In this work, we developed an approach to realize ultra-low fouling and high ligand loading with a highly-crosslinked, purely zwitterionic, carboxybetaine thin film hydrogel (CBHTF) coating platform. The CBHTF on a hydrophilic surface demonstrated long-term stability. By varying the crosslinker content in the spin-coated hydrogel solution, the thickness of CBHTFs could be precisely controlled. Optimized CBHTFs exhibited ultra-low nonspecific protein adsorption below 5ng/cm(2) measured by a surface plasmon resonance (SPR) sensor, and their 3D architecture allowed antibody loading to reach 693ng/cm(2). This strategy provides a facile method to modify SPR biosensor chips with an advanced nonfouling material, and can be potentially expanded to a variety of implantable medical devices and diagnostic biosensors.


Assuntos
Aminoácidos Cíclicos/química , Anticorpos/química , Técnicas Biossensoriais/métodos , Materiais Revestidos Biocompatíveis/química , Ciclobutanos/química , Hidrogéis/química , Membranas Artificiais , Humanos
14.
Eur J Med Chem ; 117: 1-7, 2016 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-27081742

RESUMO

In this paper a straightforward synthesis of a novel pyrazole derivative is reported. Prominent feature of this synthetic process is a 1,3-Dipolar Cycloaddition of a suitable nitrile imine with an activated α,ß-unsaturated lactam to afford directly and regioselectively the corresponding ring-fused pyrazole. Having obtained the central core of the synthetic target, a double stepwise functionalization with a "side chain" characterized by a terminal cyclic aliphatic amine was carried out. This molecular structure was designed to interact strongly with typical biological residues, and indeed it showed potent anticancer capability: in vitro cytotoxicity test on five different cancer cell lines showed interesting IC50 values in the range of 15-60 µM for exposure time of 24-72 h, thus resulting comparable with commercially available and nowadays therapeutically exploited anticancer compounds, such as 5-FU and NVP-BEZ235.


Assuntos
Antineoplásicos/síntese química , Pirazóis/síntese química , Aminoácidos Cíclicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Reação de Cicloadição , Desenho de Drogas , Humanos , Iminas/química , Lactamas/química , Nitrilos/química , Pirazóis/farmacologia
15.
Molecules ; 21(3): 350, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26999079

RESUMO

A solid-phase procedure is used to synthesize racemic peptidomimetics based on the fundamental peptide unit. The peptidomimetics are constructed around proline or proline homologues variably substituted at the amine and carbonyl sites. The procedure expands the diversity of substituted peptidomimetic molecules available to the Distributed Drug Discovery (D3) project. Using a BAL-based solid-phase synthetic sequence the proline or proline homologue subunit is both constructed and incorporated into the peptidomimetic by an α-alkylation, hydrolysis and intramolecular cyclization sequence. Further transformations on solid-phase provide access to a variety of piperazine derivatives representing a class of molecules known to exhibit central nervous system activity. The procedure works well with proline cores, but with larger six- and seven-membered ring homologues the nature of the carboxylic acid acylating the cyclic amine can lead to side reactions and result in poor overall yields.


Assuntos
Aminas/química , Ácidos Carboxílicos/química , Prolina/síntese química , Técnicas de Síntese em Fase Sólida , Aminoácidos Cíclicos/química , Prolina/química
16.
J Biomol Struct Dyn ; 34(1): 184-200, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25723403

RESUMO

There were 1765 contacts identified between DNA nucleobases or deoxyribose and cyclic (W, H, F, Y) or acyclic (R, E, D) amino acids in 672 X-ray structures of DNA-protein complexes. In this first study to compare π-interactions between the cyclic and acyclic amino acids, visual inspection was used to categorize amino acid interactions as nucleobase π-π (according to biological edge) or deoxyribose sugar-π (according to sugar edge). Overall, 54% of contacts are nucleobase π-π interactions, which involve all amino acids, but are more common for Y, F, and R, and involve all DNA nucleobases with similar frequencies. Among binding arrangements, cyclic amino acids prefer more planar (stacked) π-systems than the acyclic counterparts. Although sugar-π interactions were only previously identified with the cyclic amino acids and were found to be less common (38%) than nucleobase-cyclic amino acid contacts, sugar-π interactions are more common than nucleobase π-π contacts for the acyclic series (61% of contacts). Similar to DNA-protein π-π interactions, sugar-π contacts most frequently involve Y and R, although all amino acids adopt many binding orientations relative to deoxyribose. These DNA-protein π-interactions stabilize biological systems, by up to approximately -40 kJ mol(-1) for neutral nucleobase or sugar-amino acid interactions, but up to approximately -95 kJ mol(-1) for positively or negatively charged contacts. The high frequency and strength, despite variation in structure and composition, of these π-interactions point to an important function in biological systems.


Assuntos
Aminoácidos Cíclicos/química , Proteínas de Ligação a DNA/química , DNA/química , Desoxirribose/química , Ácidos Acíclicos/química , Carboidratos/química , Histidina/química , Modelos Moleculares , Ligação Proteica , Termodinâmica
17.
Biopolymers ; 106(4): 555-62, 2016 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-26566886

RESUMO

Chiral five-membered carbocyclic ring amino acids bearing various diol acetal moieties were synthesized starting from l-malic acid, and homo-chiral homopeptides composed of cyclic amino acid (S)-Ac5 c(3EG) bearing an ethylene glycol acetal, up to an octapeptide, were prepared. A conformational analysis revealed that (S)-Ac5 c(3EG) homopeptides formed helical structures. (S)-Ac5 c(3EG) homopeptides, up to hexapeptides, formed helical structures without controlling the helical screw direction, while (S)-Ac5 c(3EG) hepta- and octapeptides formed helical structures with a preference for the left-handed (M) helical-screw direction. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 555-562, 2016.


Assuntos
Aminoácidos Cíclicos , Peptídeos , Aminoácidos Cíclicos/síntese química , Aminoácidos Cíclicos/química , Etilenoglicol/química , Peptídeos/síntese química , Peptídeos/química , Estrutura Secundária de Proteína
18.
Angew Chem Int Ed Engl ; 54(33): 9564-7, 2015 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-26148838

RESUMO

A one pot synthesis of 1H-benzo[g]indoles, tetrahydrobenzo[h]quinolines, and naphtho[1,2-b]azepines from 2-alkynyl benzaldehydes and cyclic amino acids is reported. The salient feature of the strategy involves formation of three new bonds (one C-N and two C-C bonds) by a metal-free decarboxylation/cyclization/one-carbon ring expansion sequence in one pot.


Assuntos
Aminoácidos Cíclicos/química , Azepinas/síntese química , Benzaldeídos/química , Derivados de Benzeno/síntese química , Indóis/síntese química , Quinolinas/síntese química , Alquinos/síntese química , Alquinos/química , Aminoácidos Cíclicos/síntese química , Azepinas/química , Benzaldeídos/síntese química , Derivados de Benzeno/química , Catálise , Técnicas de Química Combinatória , Ciclização , Indóis/química , Quinolinas/química
19.
PLoS One ; 10(7): e0133548, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26193112

RESUMO

Partial agonists at the NMDA receptor co-agonist binding site may have potential therapeutic efficacy in a number of cognitive and neurological conditions. The entorhinal cortex is a key brain area in spatial memory and cognitive processing. At synapses in the entorhinal cortex, NMDA receptors not only mediate postsynaptic excitation but are expressed in presynaptic terminals where they tonically facilitate glutamate release. In a previous study we showed that the co-agonist binding site of the presynaptic NMDA receptor is endogenously and tonically activated by D-serine released from astrocytes. In this study we determined the effects of two co-agonist site partial agonists on both presynaptic and postsynaptic NMDA receptors in layer II of the entorhinal cortex. The high efficacy partial agonist, D-cycloserine, decreased the decay time of postsynaptic NMDA receptor mediated currents evoked by electrical stimulation, but had no effect on amplitude or other kinetic parameters. In contrast, a lower efficacy partial agonist, 1-aminocyclobutane-1-carboxylic acid, decreased decay time to a greater extent than D-cycloserine, and also reduced the peak amplitude of the evoked NMDA receptor mediated postsynaptic responses. Presynaptic NMDA receptors, (monitored indirectly by effects on the frequency of AMPA receptor mediated spontaneous excitatory currents) were unaffected by D-cycloserine, but were reduced in effectiveness by 1-aminocyclobutane-1-carboxylic acid. We discuss these results in the context of the effect of endogenous regulation of the NMDA receptor co-agonist site on receptor gating and the potential therapeutic implications for cognitive disorders.


Assuntos
Aminoácidos Cíclicos/química , Ciclosserina/química , Córtex Entorrinal/efeitos dos fármacos , Córtex Entorrinal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Algoritmos , Animais , Astrócitos/metabolismo , Bicuculina/análogos & derivados , Bicuculina/química , Sítios de Ligação , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Ácido Glutâmico/química , Hipocampo/metabolismo , Masculino , Neurônios/metabolismo , Técnicas de Patch-Clamp , Picrotoxina/química , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Wistar , Receptores de GABA-A/metabolismo , Estricnina/química
20.
Org Lett ; 17(13): 3342-5, 2015 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-26102233

RESUMO

1-Amino-2,2-difluorocyclopropane-1-carboxylic acid (DFACC) is of interest in the study of 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase due to the increased reactivity of its cyclopropyl functionality. It is shown that DFACC is unstable under near-physiological conditions where it primarily decomposes via specific-base catalysis to 3-fluoro-2-oxobut-3-enoic acid with a rate constant of 0.18 ± 0.01 min(-1). Upon incubation with ACC deaminase, DFACC is found to be a slow-dissociating inhibitor of ACC deaminase with submicromolar affinity.


Assuntos
Aminoácidos Cíclicos/química , Carbono-Carbono Liases/antagonistas & inibidores , Ácidos Carboxílicos/química , Catálise , Estrutura Molecular
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