Abstract
Mutated glycosidases cannot be transported into the lysosome where they should function because the amino acid substitution causes misfolding of the enzymes. As a result, substrates such as glycolipids accumulate inside and outside the cell and cause severe symptoms. These diseases are known as lysosomal storage disorders (LSDs). Valid treatments for intractable LSDs are desired. Chaperone therapy is one of the novel approaches to remedy LSDs. This therapy uses low-molecular-weight molecules called pharmacological chaperones (PCs), which interact with the enzymes and render their folding correct. The authors have developed valienamine derivatives as PCs. The initial synthesis of these valienamine derivatives, however, required cumbersome chiral resolution. We therefore conducted convenient syntheses of the valienamine derivatives using chiral quercitols, where the stereochemical configurations of the hydroxy groups are similar to those of the valienamine derivatives. Meanwhile, many PCs have been designed based on glycosidase inhibitors. Those chaperone compounds need to strongly interact with the mutated enzymes and typically show inhibitory activity. Our valienamine derivatives also possess strong inhibitory activity. Such strong inhibitory action should be removed because PCs originally aim to increase the activity of the mutated enzymes. Therefore, we first simplified the main ring configuration from that of valienamine to that of conduramine to reduce the inhibitory activity. Next, to enhance the chaperone effect and increase the activity of the mutated enzyme, a structure–activity relationship study on the side chain of the conduramine derivatives was conducted. As a result, we found a novel PC for which the inhibitory activity was less than that of the seed compound while its chaperone effect was greater.
