69 research outputs found
Synthesis and Evaluation of Structural Analogs of Escherichia coli Lipid A for Application Towards CD14-Targeting Glycotherapeutics
Lipid A is a glucosamine-based phospholipid that anchors carbohydrate molecules to the outer membrane of most Gram-negative bacteria. During severe infection, this amphiphilic macromolecule invoke a strong and acute pro-inflammatory response that leads to sepsis and ultimately to septic shock, organ failure and death. Thus, following the convention that the best antidote is often a derivative of the parent agonistic molecule, researchers have actively pursued the idea of creating an analog of Lipid A that can block the cellular receptor for this molecule and thereby arrest the cascade of events that lead to sepsis. Consequently, we became interested in creating monosaccharide and disaccharide analogs of Lipid A, anticipating that our targeted design may exhibit the desired antagonistic effect without being harmful to the host cell. Since our target compounds share a structural motif prevalent in biologically relevant carbohydrates ? the presence of 1,2-trans linked residues of 2-amino-2-deoxysugars - we investigated the application of our novel thioimidoyl methodology to the synthesis of 1,2-trans glycosides of 2-amino-2-deoxysugars. We reported previously that, along with providing a flexible approach to the synthesis 2-amino-2-deoxyglucopyranosides, our method allowed for the chemoselective assembly of oligosaccharides containing multiple residues of 2-amino-2-deoxyglycoses. Herein, the application of the aforementioned thioimidoyl methodology to the selective activation approach to oligosaccharide assembly is described. More importantly, this dissertation will detail the synthesis of Lipid A analogs that contain three interesting structural features ? the aminosugar core, (R)-3-hydroxy-fatty acids, and amino acids. This unique structural configuration has never before been synthesized and tested for antagonistic activity against enteric Lipid A. Therefore, it is to be anticipated that the synthetic approaches described herein could pave the way for expanding the range of antiendotoxic compounds prepared to date
Fishing and Rural Livelihood: A Philippine Context
The Municipality of Lake Sebu in Mindanao; Philippines offers various opportunities for income-generating fishing activities with its abundant surface water bodies. Lake Sebu is particularly known for good quality tilapia; farmed in fish cages. This study employed primary data collection methods; namely key informant interview; focus group discussion and a comprehensive livelihood household survey to assess the conditions and problems constraining fishing households in Lake Sebu. The study found that fishing-related benefits were mainly derived from aquaculture. Capture fisheries are essentially very small-scale; low gear open fishing done by local fisher folk that generates only subsistence income. Local residents are mostly engaged in retail fish trading that likewise generate only subsistence income. Survey results also revealed large variations in the scale of aquaculture operations. Fish cage owners; who are not originally from Lake Sebu or have residences outside Lake Sebu; are usually the large-scale fish farm operators; while the locals are only engaged in small-scale aquaculture due to limited financial sources. The study found that on the average; fishing-dependent households earned an annual income of PHP 132,800 (US$ 2619); which was 15% lower than the average for all household respondents; and that a substantial 63% of fishing-dependent households live below the poverty line. It appears; therefore; that the rich water resources in the municipality have not contributed substantially to poverty alleviation. These findings point to the need for government assistance such as aquaculture financing programs and the formation of fish farming cooperatives to enable locals to engage in large-scale fish farming and reap the benefits of economies of scale
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Synthesis of Chondroitin Sulfate Oligosaccharides Using N-(Tetrachlorophthaloyl)- and N-(Trifluoroacetyl)galactosamine Building Blocks
We have explored synthetic routes for the preparation of chondroitin sulfate (CS) oligosaccharides based on the use of N-tetrachlorophthaloyl- (N-TCP) and N-trifluoroacetyl-substituted (N-TFA) galactosamine building blocks. Using N-TCP units, we carried out the total synthesis of two CS disaccharides, demonstrating the compatibility of TCP protection with the final deprotection/sulfation steps. However, an attempted 2 + 2 coupling of N-TCP-containing disaccharides for the synthesis of CS tetrasaccharides failed. In contrast, a synthetic route using N-TFA galactosamine units efficiently led to biologically relevant CS-like oligosaccharides. The N-TFA groups could easily be removed at the end of the synthesis, and microwave irradiation greatly facilitated the sulfation reactions. The utility of this approach is illustrated with the total synthesis of two CS-like tetrasaccharides with different sulfate distribution patterns. Finally, we used a fluorescence polarization assay to estimate the relative abilities of the synthesized compounds to inhibit the interaction between FGF-2 and heparin.Peer reviewe
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Chemical and chemoenzymatic synthesis of glycosyl-amino acids and glycopeptides related to <i>Trypanosoma cruzi</i> mucins
This study describes the synthesis of the α-and β-linked N-acetyllactosamine (Galp-β-1,4-GlcNAc; LacNAc) glycosides of threonine (LacNAc-Thr). LacNAc-α-Thr was prepared by direct chemical coupling of a 2-azido-2-deoxy-lactose disaccharide donor to a suitable partially protected threonine unit. In contrast, stepwise chemical generation of β-linked N-acetylglucosamine followed by enzymatic galactosylation to give LacNAc-β-Thr proved effective, whereas use of a 2-azido-2-deoxy-lactose donor in acetonitrile failed to give the desired β-linked disaccharyl glycoside. This study illustrates that it is possible to overcome the inherent stereoselection for 1,2-trans chemical glycosylation with a GlcNAc donor, and that the well-established preference of bovine β-1,4-galactosyltransferase for β-linked acceptor substrates can also be overcome. Using this knowledge, short glycopeptide fragments based on T. cruzi mucin sequences, Thr-Thr-[LacNAcThr]-Thr-Thr-Gly, were synthesised. All LacNAc-based compounds outlined were shown to serve as acceptor substrates for sialylation by T. cruzi trans-sialidase
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