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Chemotherapeutic Target (chemotherapeutic + target)
Selected AbstractsTelomere Higher-Order Structure and Genomic InstabilityIUBMB LIFE, Issue 8 2003Terace Fletcher Abstract Telomeres, nucleoprotein complexes at the end of eukaryotic chromosomes, have vital roles in chromosome integrity. Telomere chromatin structure is both intricate and dynamic allowing for a variety of responses to several stimuli. A critical determinant in telomere structure is the G-strand overhang. Facilitated by telomeric proteins, the G-strand overhang stabilizes telomere higher-order assemblies most likely by adopting unusual DNA structures. These structures influence activities that occur at the chromosome end. Dysfunctional telomeres induce signals resulting in cell growth arrest or death. To overcome telomere dysfunction, cancer cells activate the DNA polymerase, telomerase. The presence of telomerase at the telomere may establish a particular telomeric state. If the chromosome ends of cancer and normal cells exist in different states, cancer-specific telomere structures would offer a unique chemotherapeutic target. IUBMB Life, 55: 443-449, 2003 [source] Substrate analogs induce an intermediate conformational change in Toxoplasma gondii adenosine kinaseACTA CRYSTALLOGRAPHICA SECTION D, Issue 2 2007Yan Zhang Adenosine kinase (AK) is a key enzyme in purine metabolism in the ubiquitous intracellular parasite Toxoplasma gondii and is a potential chemotherapeutic target for the treatment of T. gondii infections. To better understand the structure,activity relationship of 6-substituted purine ribosides, the structures of the T. gondii AK,N6,N6 -dimethyladenosine (DMA) complex, the AK,DMA,AMP-PCP complex, the AK,6-methyl mercaptopurine riboside (MMPR) complex and the AK,MMPR,AMP-PCP complex were determined to 1.35, 1.35, 1.75 and 1.75,Å resolution, respectively. These structures reveal a conformation intermediate between open and closed, with a small lid-domain rotation of 12°. Residues Gly143- X - X -Gly146 undergo torsional changes upon substrate binding, which together with a Gly68-Gly69 switch induces a hinge bending of the lid domain. The intermediate conformation suggests that ATP binding is independent of adenosine binding. Orienting the ,-phosphate group of ATP into the optimal catalytic position may be the last step before the onset of chemical catalysis and may require the translocation of Arg136 following the complete closure of the lid domain. 6-Substituted purine-nucleoside analogs are accommodated in a hydrophobic cavity. Modification at the N6 or C6 position of the nucleoside would affect the interactions with the surrounding residues and the binding affinity. [source] Synthesis, Cruzain Docking, and in,vitro Studies of Aryl-4-Oxothiazolylhydrazones Against Trypanosoma cruziCHEMMEDCHEM, Issue 9 2007Cristina, Lima Leite Prof. Abstract Research in recent years has demonstrated that the Trypanosoma cruzi cysteine protease cruzain (TCC) is a valid chemotherapeutic target. Herein we describe a small library of aryl-4-oxothiazolylhydrazones that have been tested in assays against T.,cruzi cell cultures. The docking studies carried out suggest that these compounds are potential ligands for the TCC enzyme. The most promising compound of this series, N -(4-oxo-5-ethyl-2,-thiazolin-2-yl)- N,-phenylthio-(Z)-ethylidenehydrazone (6,f), was shown to be very active at non-cytotoxic concentrations in in,vitro assays with mammalian cells and has a potency comparable with reference drugs such as nifurtimox (Nfx) and benznidazole (Bdz). [source] Active and inactive metabolic pathways in tumor spheroids: Determination by GC,MSBIOTECHNOLOGY PROGRESS, Issue 3 2010Michael G. Hunnewell Abstract Active metabolic pathways in three-dimensional cancer-cell cultures are potential chemotherapeutic targets that would be effective throughout tumors. Chaotic vasculature creates cellular regions in tumors with distinct metabolic behavior that are only present in aggregate cell masses. To quantify cancer cell metabolism, transformed mouse fibroblasts were grown as spheroids and fed isotopically labeled culture medium. Metabolite uptake and production rates were measured as functions of time. Gas chromatography,mass spectrometry was used to quantify the extent of labeling on amino acids present in cytoplasmic extracts. The labeling pattern identified several active and inactive metabolic pathways: Glutaminolysis was found to be active, and malic enzyme and gluconeogenesis were inactive. Transformed cells in spheroids were also found to actively synthesize serine, cysteine, alanine, aspartate, glutamate, and proline; and not synthesize glutamine. The activities of these pathways suggest that cancer cells consume glutamine for biosynthesis and not to provide cellular energy. Determining active metabolic pathways indicates how cells direct carbon flow and may lead to the discovery of novel molecular targets for anticancer therapy. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2010 [source] | |||||||||||||