The synthesis and biological evaluation of selenium containing carbohydrates
AffiliationScience, School of Chemistry
Document TypePhD thesis
CitationsStorkey, C. (2011). The synthesis and biological evaluation of selenium containing carbohydrates. PhD thesis, Science, School of Chemistry, The University of Melbourne.
Access StatusThis item is currently not available from this repository
© 2011 Dr. Corin Storkey
Carbohydrates play essential roles in a number of cell host-microorganism interactions, recognition processes and maturation of glycoproteins, in particular during the N-glycosylation pathway. Carbohydrate-dependent pathways are important for the diagnosis, prognosis and progression of a wide range of diseases, and therefore represent targets for therapeutic approaches. As well as their biochemical roles, dietary carbohydrates are important in the prognosis of diseases associated with postprandial hyperglycemia, such as cardiovascular disease, hypertension and diabetes. Described are the syntheses of sulfur and selenium containing derivatives of deoxynojirimycin, mannodeoxynojirimycin and their corresponding C-5 epimers L-idodeoxynojirimycin and L-gulodeoxynojirimycin, as well as methylated salts of the D-sugar derivatives. The target 1,5-deoxy-5-thio-L-gulitol 82 and 1,5-deoxy-5-seleno-L- gulitol 83 were prepared in 5 steps with overall yields of 31% and 19% respectively. While the corresponding C-5 epimers 1,5-deoxy-5-thio-D-mannitol 43 and 1,5-deoxy-5- seleno-D-mannitol 101 were prepared in 9 steps with overall yields of 26% and 16% respectively, employing a highly selective oxidation-reduction method of inversion at the C-5 position to obtain the desired stereoisomers. 1,5-deoxy-5-thio-L-iditol 106 and 1,5-deoxy-5-seleno-L-iditol 110 were synthesized in overall yields of 37% and 23% respectively, while the C-5 epimers 1,5-deoxy-5-thio-D-glucitol 42 and 1,5-deoxy-5- seleno-D-glucitol 124 were prepared in 10 steps with overall yields of 30% and 19%. These compounds were evaluated as potential glycosidase inhibitors against the mammalian enzymes golgi mannosidase II (GMII) and maltase glucoamylase (MGA). Inhibition of the free sugars was only exhibited by the seleno-deoxynojirimycin analogue 144 against MGA at concentrations above 1 mM. However, methylated salts of thio- mannodeoxynojirimycin 156 and seleno-mannodeoxynojirimycin 158 showed a high specificity against GMII, with IC50 values of 35 μM and 600 μM respectively. It has been shown that sulfur and selenium analogues of L-gulodeoxynojirimycin, namely L-thio-gulitol 82 and L-seleno-gulitol 83 can be used as potent water soluble scavengers of hypohalous acids in vitro. The second order rate constants for the reactions of thio- gulose 82 and seleno-gulose 83 with HOBr and HOCl were measured using competitive kinetics by preventing chloro- or bromotyrosine formation in vitro. In both cases the rates observed for Se-gulitol 83 were shown to be some of the fastest known biologically relevant reactions. For HOBr the rate constant was determined to be 1.1 ±(0.3) x 107 M-1s-1 and for HOCl the rate could not be measured as HOCl scavenging by Se-gulitol 83 completely prevented the formation of chlorotyrosine. Protein protection assays demonstrated that Se-gulitol 83 exhibited a dose-dependent protection of all HOCl targeted amino acid residues in human plasma, with complete protection of amino acid residues seen from as low as 50 μM, in the case of histidine up to 500 μM in the case of methionine. Se-gulose was also shown to exhibit a dose-dependent decrease in observed 3-chlorotyrosine levels in human plasma subjected to high doses of HOCl, with complete protection from 3-chlorotyrsoine formation observed above 200 μM. Toxicity studies revealed both thio- 82 and seleno-gulose 83 to be non-toxic when tested in an MTT assay against glial cells at a concentration of 1 mM. Seleno-gulose 83 therefore has potential as a non-toxic water-soluble GPx mimetic, exhibiting potent antioxidant properties against the myeloperoxidase (MPO) derived hypohalous acids, with many possible applications in the treatment of diseases involving oxidative stress.
Keywordsselenium; carbohydrates; glycosidase inhibitors; maltase glucoamylase (MGA); golgi mannosidase (GMII); atherosclerosis; myeloperoxidase; antioxidant
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