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Biological Testing (biological + testing)
Selected AbstractsComputational Design and Biological Testing of Highly Cytotoxic Colchicine Ring A ModificationsCHEMICAL BIOLOGY & DRUG DESIGN, Issue 6 2010John Torin Huzil Microtubules are the primary target for many anti-cancer drugs, the majority of which bind specifically to ,-tubulin. The existence of several ,-tubulin isotypes, coupled with their varied expression in normal and cancerous cells provides a platform upon which to construct selective chemotherapeutic agents. We have examined five prevalent human ,-tubulin isotypes and identified the colchicine-binding site as the most promising for drug design based on specificity. Using this binding site as a template, we have designed several colchicine derivatives and computationally probed them for affinity to the ,-tubulin isotypes. These compounds were synthesized and subjected to cytotoxicity assays to determine their effectiveness against several cancerous cell lines. We observed a correlation between computational-binding predictions and experimentally determined IC50 values, demonstrating the utility of computational screening in the design of more effective colchicine derivatives. The most promising derivative exhibited an IC50 approximately threefold lower than values previously reported for either colchicine or paclitaxel, demonstrating the utility of computational design and assessment of binding to tubulin. [source] Prediction of Activity, Synthesis and Biological Testing of anti-HSV Active PeptidesCHEMICAL BIOLOGY & DRUG DESIGN, Issue 1 2006Håvard Jenssen Herpes simplex virus infections can be treated with a number of drugs, but as for all pathogens, there is a constant need for new therapies. In the search for lead compounds some peptides have proven to possess an antiviral effect, but it is still unclear what mechanisms are responsible for this effect. We wish to report on the use of principal properties of amino acids for developing quantitative structure,activity relationships (QSAR:s) as a tool for modelling peptide activity and predicting the activity of new peptides. In order to test the reliability of the method, new peptides have been designed by using multivariate methodology, synthesized and tested for a number of responses. Two of the new peptides synthesized were active at lower concentrations than experienced before regarding entry and herpes simplex virus activity, but they were not able to completely inhibit viral infection. This may reflect differences in mode of action of peptides depending on the amino acid content. [source] Synthesis and Biological Testing of N -Aminoimidazole-Based p38, MAP Kinase InhibitorsCHEMMEDCHEM, Issue 7 2010Claudia Bracht Abstract The p38 mitogen-activated protein (MAP) kinase,, plays a central role in the regulation of cellular responses such as differentiation, proliferation, apoptosis, and inflammation. Inhibition of p38 results in decreased synthesis of pro-inflammatory cytokines. To date, diverse p38, inhibitors are in phase,II clinical trials for numerous cytokine-dependent diseases. 2-Sulfanylimidazole derivatives offer advantages over the prototype inhibitor SB,203580, including fewer cytochrome P450 interactions and better kinetic properties. The aim of this study was to develop novel 1,2,4,5-tetrasubstituted pyridinylimidazoles with acyl residues at the imidazole N1 position that can interact with the kinase's hydrophobic region,II (HR,II) or sugar pocket (SP) to improve both selectivity and activity. The substitution pattern was optimized by variation of the acyl moiety at the N1 position of the N -aminoimidazole core. Acylation of the amino function was used for optimization and led to potent p38, MAPK inhibitors. [source] Thiobarbiturates as Sirtuin Inhibitors: Virtual Screening, Free-Energy Calculations, and Biological TestingCHEMMEDCHEM, Issue 12 2008Urszula Uciechowska Abstract NAD+ -dependent histone deacetylases (sirtuins) are enzymes that cleave acetyl groups from lysine residues in histones and other proteins. Potent selective sirtuin inhibitors are interesting tools for the investigation of the biological functions of these enzymes and may be future drugs for the treatment of cancer or neurodegenerative diseases. Herein we present the results from a protein-based virtual screen of a commercial database with subsequent biological testing of the most promising compounds. The combination of docking and in,vitro experimental testing resulted in the identification of novel sirtuin inhibitors with thiobarbiturate structure. To rationalize the experimental results, free-energy calculations were carried out by molecular mechanics Poisson,Boltzmann/surface area (MM-PBSA) calculations. A significant correlation between calculated binding free energies and measured Sirt2 inhibitory activities was observed. The analyses suggested a molecular basis for the interaction of the identified thiobarbiturate derivatives with human Sirt2. Based on the docking and MM-PBSA calculations we synthesized and tested five further thiobarbiturates. The MM-PBSA method correctly predicted the activity of the novel thiobarbiturates. The identified compounds will be used to further explore the therapeutic potential of sirtuin inhibitors. [source] Lipophilic methotrexate conjugates with glucose-lipoamino acid moieties: Synthesis and in vitro antitumor activityDRUG DEVELOPMENT RESEARCH, Issue 3 2001Rosario Pignatello Abstract To obtain methotrexate (MTX) derivatives with a balanced hydrolipophilic character, we synthesized a series of conjugates in which the drug was linked to lipoamino acid (LAA)-glucose residues (LAAG-MTX). These conjugates displayed increased solubility in polar media compared with the corresponding LAA-MTX conjugates previously described. In vitro biological testing of LAAG-MTX indicated that the introduction of the sugar moiety decreased the biological activity of these MTX conjugates. The tetradecyl derivative 6b, however, was effective in inhibiting the dihydrofolate reductase activity in vitro and showed an inhibitory effect on human lymphoblastoid cell growth. Drug Dev. Res. 52:454,461, 2001. © 2001 Wiley-Liss, Inc. [source] Activity against drug resistant-tuberculosis strains of plants used in Mexican traditional medicine to treat tuberculosis and other respiratory diseasesPHYTOTHERAPY RESEARCH, Issue 1 2008María del Rayo Camacho-Corona Abstract Tuberculosis (TB) kills about 3 million people per year worldwide. Furthermore, TB is an infectious disease associated with HIV patients, and there is a rise in multidrug-resistant TB (MDR-TB) cases around the world. There is a need for new anti-TB agents. The study evaluated the antimycobacterial activity of nine plants used in Mexican traditional medicine to treat tuberculosis and other respiratory diseases. Nasturtium officinale showed the best activity (MIC = 100 µg/mL) against the sensitive Mycobacterium tuberculosis. The following plants were active also but at 200 µg/mL: Citrus sinensis, Citrus aurantifolia, Foeniculum vulgare, Larrea tridentata, Musa acuminata and Olea europaea. Contrary to the above data, activity against drug-resistant variants of M. tuberculosis was more evident, e.g. N. officinale was the most potent (MIC , 100 µg/mL) against the four mono-resistant variants tested; F. vulgare and O. europaea were active against all the resistant variants (MICs , 100 µg/mL). The most susceptible variant was the isoniazid resistant, being inhibited by C. aurantifolia, C. sinensis and O. europaea (MIC = 25 µg/mL). These data point to the importance of biological testing of extracts against drug-resistant M. tuberculosis isolates, and the bioguided assay of these extracts for the identification of lead compounds against MDR-TB isolates. Copyright © 2007 John Wiley & Sons, Ltd. [source] Melectin: A Novel Antimicrobial Peptide from the Venom of the Cleptoparasitic Bee Melecta albifronsCHEMBIOCHEM, Issue 17 2008Václav, ovský Dr. Abstract A novel antimicrobial peptide designated melectin was isolated from the venom of the cleptoparasitic bee Melecta albifrons. Its primary sequence was established as H-Gly-Phe-Leu-Ser-Ile-Leu-Lys-Lys-Val-Leu-Pro-Lys-Val-Met-Ala-His-Met-Lys-NH2 by Edman degradation and ESI-QTOF mass spectrometry. Synthetic melectin exhibited antimicrobial activity against both Gram-positive and -negative bacteria and it degranulated rat peritoneal mast cells, but its hemolytic activity was low. The CD spectra of melectin measured in the presence of trifluoroethanol and sodium dodecyl sulfate showed a high content ,-helices, which indicates that melectin can adopt an amphipathic ,-helical secondary structure in an anisotropic environment such as the bacterial cell membrane. To envisage the role of the proline residue located in the middle of the peptide chain on biological activity and secondary structure, we prepared several melectin analogues in which the Pro11 residue was either replaced by other amino acid residues or was omitted. The results of biological testing suggest that a Pro kink in the ,-helical structure of melectin plays an important role in selectivity for bacterial cells. In addition, a series of N- and C-terminal-shortened analogues was synthesized to examine which region of the peptide is related to antimicrobial activity. [source] Thiobarbiturates as Sirtuin Inhibitors: Virtual Screening, Free-Energy Calculations, and Biological TestingCHEMMEDCHEM, Issue 12 2008Urszula Uciechowska Abstract NAD+ -dependent histone deacetylases (sirtuins) are enzymes that cleave acetyl groups from lysine residues in histones and other proteins. Potent selective sirtuin inhibitors are interesting tools for the investigation of the biological functions of these enzymes and may be future drugs for the treatment of cancer or neurodegenerative diseases. Herein we present the results from a protein-based virtual screen of a commercial database with subsequent biological testing of the most promising compounds. The combination of docking and in,vitro experimental testing resulted in the identification of novel sirtuin inhibitors with thiobarbiturate structure. To rationalize the experimental results, free-energy calculations were carried out by molecular mechanics Poisson,Boltzmann/surface area (MM-PBSA) calculations. A significant correlation between calculated binding free energies and measured Sirt2 inhibitory activities was observed. The analyses suggested a molecular basis for the interaction of the identified thiobarbiturate derivatives with human Sirt2. Based on the docking and MM-PBSA calculations we synthesized and tested five further thiobarbiturates. The MM-PBSA method correctly predicted the activity of the novel thiobarbiturates. The identified compounds will be used to further explore the therapeutic potential of sirtuin inhibitors. [source] | |||||||||||||