Synthesis of 5-thio-D-glycopyranosylamines and amidines: A new class of glycosidase inhibitors

This thesis describes the synthesis and glycosidase inhibitory activities of 5-thio-D-glycosylamines and 5-thio-glycosylamidinium salts of D-glucose and D-mannose. The 5-thio- D-glycosylamines and their amidinium salts bear a positive charge adjacent to C-1, which is presumed to mimic the positive charge at the transition state during glycoside hydrolysis while maintaining the stereochemistry at C-2, thereby making them potential selective inhibitors of glucosidase or mannosidase enzymes. The 5-thio-D-glycopyranosylamidines were successfully synthesized in 2 steps: the 5-thio-D-glycopyranoses were first converted to their 5-thio-D-glycopyranosylamines, which on treatment with a thioimidate gave the corresponding glycopyranosylamidinium salts.; The intermediates and final compounds have been characterized by detailed two-dimensional 1H/1H, 1H/ 13C and 1H/1H NOESY correlation spectra, as well as microanalysis or high resolution mass spectrometry. The conformation for the α and β isomers was inferred from the NOESY spectra.; The 5-thio-D-mannopyranosylamine was found to be a moderate inhibitor of Golgi α-mannosidase II with an IC₅₀ value of 7.0 × 10−2 mM and the 5-thio-D-mannopyranosylamidinium bromide was found to be a weak inhibitor with an IC₅₀ value of 0.9 mM. The 5-thio-D-glucopyranosylamine was found to be a moderate inhibitor of glucoamylase G2 with a Ki value of 9.8 × 10−2 mM and the 5-thio-D-glucopyranosylamidinium bromide was found to be a good inhibitor with a Ki value 1.5 × 10−2 mm. (Abstract shortened by UMI.)...