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1.
Carbohydr Res ; 486: 107841, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31655420

RESUMO

In order to investigate the possibilities of Fischer glycosylation towards the synthesis of bromoalkylglycosides we performed a variety of different reactions resulting in a small library of 16 different glycosides. Using standardized reaction conditions we could gain a broad range of results from small to higher yields. Finally we randomly selected three reactions and performed them with higher amounts of bromoalcohol resulting in significantly better yields, showing the optimization potential of these basic research work.


Assuntos
Bromo/química , Glicosídeos/química , Glicosídeos/síntese química , Técnicas de Química Sintética , Glicosilação
2.
Cell Chem Biol ; 26(11): 1535-1543.e5, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31492597

RESUMO

Diadenosine polyphosphates (ApnAs) such as diadenosine tri- and tetraphosphates are formed in prokaryotic as well as eukaryotic cells. Since upon stress intracellular ApnA concentrations increase, it was postulated that ApnAs are alarmones triggering stress-adaptive processes. The major synthesis pathway of ApnAs is assumed to be a side reaction of amino acid activation. How this process is linked to stress adaptation remains enigmatic. The first step of one of the most prominent eukaryotic post-translational modification systems-the conjugation of ubiquitin (Ub) and ubiquitin-like proteins (Ubl) to target proteins-involves the formation of an adenylate as intermediate. Like ApnA formation, Ub and Ubl conjugation is significantly enhanced during stress conditions. Here, we demonstrate that diadenosine tri- and tetraphosphates are indeed synthesized during activation of Ub and Ubls. This links one of the most prevalent eukaryotic protein-modification systems to ApnA formation for the first time.

3.
Org Biomol Chem ; 16(46): 8904-8907, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30203829

RESUMO

Poly(ADP-ribose) polymerase-1 (PARP-1) is an important target in cancer therapy. We present the synthesis of novel disaccharide nucleoside analogues that resemble the central motif of poly(ADP-ribose) and test their inhibitory effects on human PARP-1. Some compounds show inhibition of enzymatic activity in vitro and thus might be interesting for further investigations.


Assuntos
Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli Adenosina Difosfato Ribose/análogos & derivados , Poli Adenosina Difosfato Ribose/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Técnicas de Química Sintética , Dissacarídeos/síntese química , Dissacarídeos/química , Dissacarídeos/farmacologia , Descoberta de Drogas , Humanos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli Adenosina Difosfato Ribose/síntese química , Poli Adenosina Difosfato Ribose/química , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química
4.
ACS Chem Biol ; 12(10): 2682-2689, 2017 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-28892605

RESUMO

The intracellular concentration of diadenosine tetraphospate (Ap4A) increases upon exposure to stress conditions. Despite being discovered over 50 years ago, the cellular functions of Ap4A are still enigmatic. If and how the varied Ap4A is a signal and involved in the signaling pathways leading to an appropriate cellular response remain to be discovered. Because the turnover of Ap4A by Ap4A cleaving enzymes is rapid, small molecule inhibitors for these enzymes would provide tools for the more detailed study of the role of Ap4A. Here, we describe the development of a high-throughput screening assay based on a fluorogenic Ap4A substrate for the identification and optimization of small molecule inhibitors for Ap4A cleaving enzymes. As proof-of-concept we screened a library of over 42 000 compounds toward their inhibitory activity against the Ap4A phosphorylase (Rv2613c) of Mycobacterium tuberculosis (Mtb). A sulfanylacrylonitril derivative with an IC50 of 260 ± 50 nM in vitro was identified. Multiple derivatives were synthesized to further optimize their properties with respect to their in vitro IC50 values and their cytotoxicity against human cells (HeLa). In addition, we selected two hits to study their antimycobacterial activity against virulent Mtb to show that they might be candidates for further development of antimycobacterial agents against multidrug-resistant Mtb.


Assuntos
Fosfatos de Dinucleosídeos/metabolismo , Inibidores Enzimáticos/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Nucleotidiltransferases/metabolismo , Sobrevivência Celular , Fosfatos de Dinucleosídeos/química , Inibidores Enzimáticos/química , Células HeLa , Ensaios de Triagem em Larga Escala , Humanos , Concentração Inibidora 50 , Nucleotidiltransferases/genética , Ligação Proteica
5.
Carbohydr Res ; 425: 28-34, 2016 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-27015143

RESUMO

Three different building blocks have been synthesised and used for the synthesis of linear triazole linked pseudo oligosaccharides with copper(I)-catalysed cycloaddition (CuAAC). Ethynylferrocene has been used as analytical probe to improve the UV/Vis properties and HPLC methods have been used and optimised for the analysis of the pseudo oligosaccharides. The smallest ones have been isolated and characterised by analytical HPLC, NMR, ESI-MS and elemental analysis.


Assuntos
Compostos Ferrosos/química , Sondas Moleculares/química , Oligossacarídeos/análise , Oligossacarídeos/síntese química , Triazóis/química , Conformação Molecular , Oligossacarídeos/química
6.
Dalton Trans ; 44(37): 16475-85, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-26325575

RESUMO

A series of novel sulfonamide substituted heteroleptic salan titanium(IV)-bis-chelates complexed to 2,6-pyridinedicarboxylic acid were synthesized, structurally characterized and evaluated for their anticancer activity against two human carcinoma cell lines. All cytotoxic complexes showed complete inhibition of cell growth at active concentration, two complexes based on pyrrolidine and azepane substituted sulfonamides displayed IC50 values below 1.7 µM and are more cytotoxic than cisplatin in both tested cell lines. The azepane substituted complex [L3Ti(dipic)] exhibited excellent activity with an IC50 value of 0.5 ± 0.1 µM in Hela S3 and 1.0 ± 0.1 µM in Hep G2.


Assuntos
Antineoplásicos/síntese química , Quelantes/química , Complexos de Coordenação/síntese química , Sulfonamidas/química , Titânio/química , Antineoplásicos/química , Antineoplásicos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Cristalografia por Raios X , Células HeLa , Células Hep G2 , Humanos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Ácidos Picolínicos , Piridinas/química
7.
Biotechnol Lett ; 35(4): 585-90, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23242497

RESUMO

Alcohol oxidase from Pichia pastoris was immobilized on nanoporous aluminium oxide membranes by silanization and activation by carbonyldiimidazole to create a flow-through enzyme reactor. Kinetic analysis of the hydrogen peroxide generation was carried out for a number of alcohols using a subsequent reaction with horseradish peroxidase and ABTS. The activity data for the immobilized enzyme showed a general similarity with literature data in solution, and the reactor could generate 80 mmol H2O2/h per litre reactor volume. Horseradish peroxidase was immobilized by the same technique to construct bienzymatic modular reactors. These were used in both single pass mode and circulating mode. Pulsed injections of methanol resulted in a linear relation between response and concentration, allowing quantitative concentration measurement. The immobilized alcohol oxidase retained 58 % of initial activity after 3 weeks of storage and repeated use.


Assuntos
Oxirredutases do Álcool/metabolismo , Óxido de Alumínio , Enzimas Imobilizadas/metabolismo , Peróxido de Hidrogênio/metabolismo , Pichia/enzimologia , Álcoois/metabolismo , Reatores Biológicos , Cinética
8.
J Comput Chem ; 31(14): 2568-76, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20740555

RESUMO

The charge density and its Laplacian at the Li-C and C-H bond critical points and other features of the electron density distribution of the methyl lithium crystal have been compared by density functional methods for (i) the isolated (LiCH(3))(4) tetramer or larger clusters, (ii) for quantum mechanically treated clusters in polarizable continuum model (PCM) surroundings, (iii) for clusters augmented by the periodic electrostatic embedded cluster model (PEECM), and for (iv) the periodic crystal. Comparisons with identical functional and basis sets indicate that both PCM and PEECM embedding of only a tetramer did not fully account for the environmental effect. In contrast, embedding of a full unit cell gave results that were essentially converged to the periodic crystal data. Effects of basis set and exchange correlation functional on the QTAIM bond descriptors are of a comparable order of magnitude as the crystal environmental effects. In this context, embedded cluster computations provide distinct advantages over explicit solid-state calculations with respect to their freedom of the choice of computational and theoretical level. This is demonstrated by embedded MP2 calculations.


Assuntos
Lítio/química , Modelos Químicos , Simulação de Dinâmica Molecular , Compostos Organometálicos/química , Cristalografia por Raios X , Modelos Moleculares , Teoria Quântica
9.
Chemistry ; 16(22): 6582-9, 2010 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-20432419

RESUMO

The neutral hexacoordinate silicon(IV) complex 6 (SiO(2)N(4) skeleton) and the neutral pentacoordinate silicon(IV) complexes 7-11 (SiO(2)N(2)C skeletons) were synthesized from Si(NCO)(4) and RSi(NCO)(3) (R = Me, Ph), respectively. The compounds were structurally characterized by solid-state NMR spectroscopy (6-11), solution NMR spectroscopy (6 and 10), and single-crystal X-ray diffraction (8 and 11 were studied as the solvates 8 x CH(3)CN and 11 x C(5)H(12) x 0.5 CH(3)CN, respectively). The silicon(IV) complexes 6 (octahedral Si-coordination polyhedron) and 7-11 (trigonal-bipyramidal Si-coordination polyhedra) each contain two bidentate ligands derived from an alpha-amino acid: (S)-alanine, (S)-phenylalanine, or (S)-tert-leucine. The deprotonated amino acids act as monoanionic (6) or as mono- and dianionic ligands (7-11). The experimental investigations were complemented by computational studies of the stereoisomers of 6 and 7.


Assuntos
Alanina/química , Aminoácidos/química , Leucina/química , Fenilalanina/química , Compostos de Silício/química , Cristalografia por Raios X , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estereoisomerismo , Relação Estrutura-Atividade
10.
J Am Chem Soc ; 131(30): 10763-74, 2009 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-19569685

RESUMO

A series of P-phospholyl-substituted N-heterocyclic phosphines was prepared and characterized by single-crystal X-ray diffraction and solution and solid-state (31)P NMR spectroscopy. The molecular structures are distinguished by the presence of P-P bonds of exceptionally variable lengths (2.35-2.70 A) that are all well beyond the standard distance of 2.21 A. The unique flexibility is best illustrated by a specimen 4f where minor conformational changes of remote substituents induce a deviation in P-P bond lengths of some 5 pm between crystallographically independent molecules in the same unit cell. Computational studies suggest to rationalize the bond elasticity as the consequence of a very flat potential energy basin that allows even weak forces to have large impact on bond lengths. Solid-state (31)P NMR studies show that the bond distance variation coincides with substantial changes in the magnitude and sign of (1)J(PP), which is explained in the context of a dominant Fermi contact contribution. A relation between increasing internuclear distance and decreasing magnitude of (1)J(PP) was experimentally proven by determination of effective dipolar coupling constants by the double-quantum dephasing experiment (DoDe) for the crystallographically independent conformers of 4f and further supported by comparison with calculated coupling tensors with inclusion of the anisotropic J-coupling. NMR studies revealed large discrepancies in the values of (1)J(PP) measured in solution and the solid state and a substantial temperature dependence of the former. Interpretation of this behavior was feasible by taking into account that the value of (1)J(PP) in solution is affected by both temperature-dependent equilibria between trans and gauche conformers and additional bond length relaxation that accompanies the dissolution process. Consideration of experimental observations and population analysis of computed electron densities suggested to classify the P-P bonds in the molecules under study as "dative" rather than "normal" covalent bonds and to address the compounds 4 as hybrids between covalent diphosphines and phosphenium-phospholide contact ion pairs.

11.
ChemMedChem ; 4(7): 1143-52, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19496083

RESUMO

C/Si switch: Twofold sila-substitution (C/Si exchange) in the RXR-selective retinoids 4 a (SR11237) and 5 a leads to 4 b (disila-SR11237) and 5 b, respectively. Chemistry and biology of the C/Si pairs are reported.SR11237 (BMS649, 4 a) is a pan-RXR-selective retinoid agonist. Its silicon analogue, disila-SR11237 (4 b; twofold C/Si exchange), was prepared in a multistep synthesis by starting from 1,2-bis(ethynyldimethylsilyl)ethane. In addition, the related C/Si analogues 5 a and 5 b, with an indane (disila-indane) instead of a tetraline (disila-tetraline) skeleton, were synthesized. The C/Si pairs 4 a/4 b and 5 a/5 b were studied for their interaction with retinoid receptors and were demonstrated to be highly potent RXR-selective ("rexinoid") agonists. Interestingly, twofold C/Si exchange in the indane moiety of 5 a resulted in a 10-fold increase in biological activity of the corresponding silicon-containing rexinoid 5 b, possibly resulting from an increased receptor affinity or a divergent allosteric effect on co-regulator-binding surfaces. The crystal structures of the ternary complexes formed by 5 a and 5 b, respectively, with the ligand-binding domain of hRXRalpha and a peptide of the co-activator TIF2/GRIP1 revealed additional interactions of the disila analogue 5 b with the H7 and H11 residues, supporting the first option of increased binding affinity. This is the first demonstration of an increase in binding affinity of a ligand to a nuclear receptor by C/Si replacement, thereby adding this C/Si switch strategy to the repertoire of nuclear receptor ligand design.


Assuntos
Benzoatos/farmacologia , Receptores X Retinoide/agonistas , Retinoides/farmacologia , Silício/química , Benzoatos/química , Sítios de Ligação , Linhagem Celular Tumoral , Simulação por Computador , Cristalografia por Raios X , Células HeLa , Humanos , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/metabolismo , Receptores X Retinoide/metabolismo , Retinoides/química , Silício/farmacologia , Eletricidade Estática
12.
Chemistry ; 15(29): 7150-5, 2009 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-19544503

RESUMO

Herein we report for the first time full details on the synthesis and structural characterization of novel homodinuclear bridging cobalt and nickel borylene complexes containing bridging carbonyl ligands, an unusual coordination motif rarely before observed for homodinuclear borylene complexes. Furthermore, the homodinuclear nickel complex represents the first instance of a nickel borylene complex. Quantum chemical analyses of charge-density topology, electron localization function (ELF) and natural charges indicate the absence of direct metal-metal bonds in both the cobalt and nickel systems, in contradiction with electron counting. The topology of the Laplacian of the electron density and of the ELF around the bridging boron atom is consistent with a bis-metallo-substituted borane situation for the dicobalt system, but with a three-center-bonding borylene for the dinickel complex.

13.
Chemistry ; 15(3): 623-32, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19040224

RESUMO

Bonding in borylene-, carbene-, and vinylidene-bridged dinuclear manganese complexes [MnCp(CO)(2)](2)X (X = B-tBu, B = NMe(2), CH(2), C=CH(2)) has been compared by analyses based on quantum theory of atoms in molecules (QTAIM), on the electron-localization function (ELF), and by natural-population analyses. All of the density functional theory based analyses agree on the absence of a significant direct Mn-Mn bond in these complexes and confirm a dominance of delocalized bonding via the bridging ligand. Interestingly, however, the topology of both charge density and ELF related to the Mn-bridge-Mn bonding depend qualitatively on the chosen density functional (except for the methylene-bridged complex, which exhibits only one three-center-bonding attractor both in -nabla(2)rho and in ELF). While gradient-corrected functionals provide a picture with localized two-center X-Mn bonding, increasing exact-exchange admixture in hybrid functionals concentrates charge below the bridging atom and suggests a three-center bonding situation. For example, the bridging boron ligands may be described either as substituted boranes (e.g., at BLYP or BP86 levels) or as true bridging borylenes (e.g., at BHLYP level). This dependence on the theoretical level appears to derive from a bifurcation between two different bonding situations and is discussed in terms of charge transfer between X and Mn, and in the context of self-interaction errors exhibited by popular functionals.

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