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Low Micromolar Range (low + micromolar_range)
Selected AbstractsSynthetic dsDNA-Binding Peptides Using Natural Compounds as ModelHELVETICA CHIMICA ACTA, Issue 6 2006Filip Borgions Abstract We have developed a series of short DNA-binding peptides containing newly synthesized, unnatural as well as natural amino acid building blocks. By a combinatorial-library approach, oligopeptides were developed with moderate dsDNA-binding affinities. Two strategies were used to further enhance the binding affinity of the lead peptides: Ac-Arg-Ual-Sar-Chi-Chi-Chi-Arg-NH2 and Ac-Arg-Cbg-Cha-Chi-Chi-Tal-Arg-NH2. Site-selective amino acid substitutions increased the binding affinities up to 2,×,10,5,M. Further enhancement of the binding affinities could be achieved by coupling of an acridine intercalating unit, using linker arms of different length and flexibility. With the introduction of a new lysine-based acridine unit, different types of oligopeptide,acridine conjugates were designed using known dsDNA-binding ligands as model compounds. The binding capacities of these new oligopeptide,acridine conjugates have been investigated by a fluorescent intercalator (ethidium bromide) displacement (FID) assay. With the synthesis of the dipeptide,acridine conjugates, binding affinities in the low micromolar range were obtained (6.4,×,10,6,M), which is similar to the binding strength of the well-known DNA binder Hoechst 33258. [source] High-resolution real-time recording with microelectrode biosensors reveals novel aspects of adenosine release during hypoxia in rat hippocampal slicesJOURNAL OF NEUROCHEMISTRY, Issue 6 2003B. G. Frenguelli Abstract We have used improved miniaturized adenosine biosensors to measure adenosine release during hypoxia from within the CA1 region of rat hippocampal slices. These microelectrode biosensors record from the extracellular space in the vicinity of active synapses as they detect the synaptic field potentials evoked in area CA1 by stimulation of the afferent Schaffer collateral-commissural fibre pathway. Our new measurements demonstrate the rapid production of adenosine during hypoxia that precedes and accompanies depression of excitatory transmission within area CA1. Simultaneous measurement of adenosine release and synaptic transmission gives an estimated IC50 for adenosine on transmission in the low micromolar range. However, on reoxygenation, synaptic transmission recovers in the face of elevated extracellular adenosine and despite a post-hypoxic surge of adenosine release. This may indicate the occurrence of apparent adenosine A1 receptor desensitization during metabolic stress. In addition, adenosine release is unaffected by pharmacological blockade of glutamate receptors and shows depletion on repeated exposure to hypoxia. Our results thus suggest that adenosine release is not a consequence of excitotoxic glutamate release. The potential for adenosine A1 receptor desensitization during metabolic stress implies that its prevention may be beneficial in extending adenosine-mediated neuroprotection in a variety of clinically relevant conditions. [source] Copper binding to octarepeat peptides of the prion protein monitored by mass spectrometryPROTEIN SCIENCE, Issue 2 2000Randy M. Whittal Abstract Electrospray ionization mass spectrometry (ESI-MS) was used to measure the binding of Cu2+ ions to synthetic peptides corresponding to sections of the sequence of the mature prion protein (PrP). ESI-MS demonstrates that Cu2+ is unique among divalent metal ions in binding to PrP and defines the location of the major Cu2+ binding site as the octarepeat region in the N-terminal domain, containing multiple copies of the repeat ProHisGlyGlyGlyTrpGlyGln. The stoichiometries of the complexes measured directly by ESI-MS are pH dependent: a peptide containing four octarepeats chelates two Cu2+ ions at pH 6 but four at pH 7.4. At the higher pH, the binding of multiple Cu2+ ions occurs with a high degree of cooperativity for peptides C-terminally extended to incorporate a fifth histidine. Dissociation constants for each Cu2+ ion binding to the octarepeat peptides, reported here for the first time, are mostly in the low micromolar range; for the addition of the third and fourth Cu2+ ions to the extended peptides at pH 7.4, KD's are <100 nm. n-terminal acetylation of the peptides caused some reduction in the stoichiometry of binding at both ph's. cu2+ also binds to a peptide corresponding to the extreme N-terminus of PrP that precedes the octarepeats, arguing that this region of the sequence may also make a contribution to the Cu2+ complexation. Although the structure of the four-octarepeat peptide is not affected by pH changes in the absence of Cu2+, as judged by circular dichroism, Cu2+ binding induces a modest change at pH 6 and a major structural perturbation at pH 7.4. It is possible that PrP functions as a Cu2+ transporter by binding Cu2+ ions from the extracellular medium under physiologic conditions and then releasing some or all of this metal upon exposure to acidic pH in endosomes or secondary lysosomes. [source] N -(Indazolyl)benzamido Derivatives as CDK1 Inhibitors: Design, Synthesis, Biological Activity, and Molecular Docking StudiesARCHIV DER PHARMAZIE, Issue 5 2009Demetrio Raffa Abstract A series of N -1H -indazole-1-carboxamides has been synthesized and their effects on both CDK1 / cyclin B and the K-562 (human chronic myelogenus leukemia) cell line were evaluated. Using a computational model, we have observed that all the most active compounds 9e, f, i,n exhibited the same binding mode of purvanalol A in the ATP-binding cleft. Although they were able to moderately inhibit the leukemic cell line K-562 and to show inhibitory activity against the Cdc2-Cyclin B kinase in the low micromolar range, they turned out to be non-cytotoxic against HuDe (IZSL) primary cell cultures from human derm. These preliminary results are quite encouraging in view of the low toxicity demonstrated by the above-mentioned compounds. [source] An Efficient Method for the Synthesis of Peptide Aldehyde Libraries Employed in the Discovery of Reversible SARS Coronavirus Main Protease (SARS-CoV Mpro) InhibitorsCHEMBIOCHEM, Issue 7 2006Samer I. Al-Gharabli Dr. Abstract A method for the parallel solid-phase synthesis of peptide aldehydes has been developed. Protected amino acid aldehydes obtained by the racemization-free oxidation of amino alcohols with Dess,Martin periodinane were immobilized on threonyl resins as oxazolidines. Following Boc protection of the ring nitrogen to yield the N-protected oxazolidine linker, peptide synthesis was performed efficiently on this resin. A peptide aldehyde library was designed for targeting the SARS coronavirus main protease, SARS-CoV Mpro(also known as 3CLpro), on the basis of three different reported binding modes and supported by virtual screening. A set of 25 peptide aldehydes was prepared by this method and investigated in inhibition assays against SARS-CoV Mpro. Several potent inhibitors were found with IC50 values in the low micromolar range. An IC50 of 7.5 ,M was found for AcNSTSQ-H and AcESTLQ-H. Interestingly, the most potent inhibitors seem to bind to SARS-CoV Mpro in a noncanonical binding mode. [source] A Novel Cytotoxic Cerium Complex: Aquatrichloridobis(1,10-phenanthroline)cerium(III) (KP776).CHEMISTRY & BIODIVERSITY, Issue 12 2009Antiproliferative Activity, Behavior in H2O, Binding towards Biomolecules, Characterization, Synthesis Abstract The lanthanide complex aquatrichloridobis(1,10-phenanthroline)cerium(III) [Ce(phen)2(H2O)Cl3] (KP776) was fully characterized by elemental analysis, IR-, and 1H- and 13C-NMR spectroscopy, as well as TG/DTA measurements, and its behavior in H2O, important for the application as a chemotherapeutic, was studied. In addition, the binding of KP776 to nucleotides and single serum proteins was investigated by capillary electrophoresis, whereas binding to proteins in human plasma was observed by ICP-MS. The compound shows promising anticancer properties in vitro: proliferation of human cancer cell lines is strongly inhibited with IC50 values in the very low micromolar range. [source] Thiazolopyrimidine Inhibitors of 2-Methylerythritol 2,4-Cyclodiphosphate Synthase (IspF) from Mycobacterium tuberculosis and Plasmodium falciparumCHEMMEDCHEM, Issue 7 2010Julie Abstract A library of 40,000 compounds was screened for inhibitors of 2-methylerythritol 2,4-cyclodiphosphate synthase (IspF) protein from Arabidopsis thaliana using a photometric assay. A thiazolopyrimidine derivative resulting from the high-throughput screen was found to inhibit the IspF proteins of Mycobacterium tuberculosis, Plasmodium falciparum, and A.,thaliana with IC50 values in the micromolar range. Synthetic efforts afforded derivatives that inhibit IspF protein from M.,tuberculosis and P.,falciparum with IC50 values in the low micromolar range. Several compounds act as weak inhibitors in the P.,falciparum red blood cell assay. [source] | ||||||||||