A novel class of glycosidase inhibitors related to salacinol

This thesis focuses on the design and synthesis of analogues of salacinol, together with the investigation of their enzyme inhibitory activities. Salacinol is a naturally occurring sulfonium ion with an internal sulfate counterion, and is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The syntheses of two novel amino acids, nitrogen analogues of salacinol, containing a carboxylate inner salt are described, along with the X-ray crystal structure of one of these analogues in the active site of Drosophila melanogaster Golgi mannosidase II (dGMII). The compound derived from 1,4-dideoxy-1,4-imino-D-arabinitol inhibits dGMII, one of the critical enzymes in the glycoprotein processing pathway, with an IC50 of 0.3 ± 0.01 mM. Inhibition of GMII has been identified as a target for control of metastatic cancer. The X-ray crystal structure of the complex of this compound with dGMII provides insight into the requirements for an effective inhibitor. The same compound inhibits recombinant human maltase glucoamylase (MGA), one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, and a target for the treatment of Type 2 diabetes, with a Ki value of 21 ± 1 M. The syntheses of two sulfonium compounds, analogues of salacinol containing a carboxylate inner salt, are also described. The compound derived from 1,4-anhydro-4-thio-D-arabinitol inhibits recombinant human maltase glucoamylase (MGA) with a Ki value of 10 ± 1 M. The binding of the nanomolar inhibitor swainsonine to Drosophila melanogaster Golgi α-mannosidase II (dGMII) involves a large contribution of interactions between the six-membered ring of the inhibitor and the hydrophobic pocket within the enzyme active site. Spiro aza- and thia-heterocycles and a spiro-analogue of salacinol were designed with the expectation that the hydrocarbon portions would make hydrophobic contributions to binding. The former sets of compounds were synthesized successfully but the salacinol analogue proved to be elusive. The stereochemistry of the final compounds was determined by means of 1D-NOESY experiments. Unfortunately, the aza- and thia-heterocycles were not effective inhibitors of Golgi α-mannosidase II or human maltase glucoamylase.