Showing papers by "Seiichiro Ogawa published in 2016"

From Quercitols to Biologically Active Valienamine and Conduramine Derivatives: Development of Pharmacological Chaperones

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. A. Introduction Ogawa, one of the authors, has studied the synthesis and activity of carbasugars, where the oxygen atom in the pyranose ring is replaced by a carbon atom (1). The structure of carbasugars resembles that of real sugars, but carbasugars show diferente characters from sugars due to the replacement of oxygen with carbon in the ring. Among these compounds, valienamine derivatives resemble the six-membered oxocarbenium ion, the activated intermediate in the hydrolysis of glycosides, and show strong inhibition of glycosidases (2). Furthermore, interesting compounds that are effective for the treatment of LSDs were found from those valienamine derivatives (3). The synthesis of these carbasugars and valienamine derivatives was conducted using the racemic Diels–Alder adducts as starting materials, and optical resolution was necessary (1, 4, 5). Inositols are cyclohexanehexols, which have a hydroxy group on each of the six carbon atoms. Cyclohexanepentols, where one hydroxy group is removed from an inositol, are called quercitols. Some combinations of hydroxy configuration in inositols or quercitols are similar to those in sugars. These similarities in the stereochemical configuration of the hydroxy groups would be useful for the synthesis of carbasugars and valienamines. Moreover, quercitols are optically active. In this minireview, the authors describe the convenient synthesis of valienamine derivatives using quercitols as starting materials and the development of a novel drug candidate for LSDs. Based on this, quercitols, valienamines, and conduramines as cyclitols/aminocyclitols, and genetically rare LSDs will be highlighted. B. Chemical and Microbial Synthesis of Quercitols There are nine isomers of inositols based on the stereochemistry of the hydroxy groups (6). Only two isomers, D-chiro-inositol and L-chiro-inositol, are optically active. The remaining are meso compounds. Each isomer has its own name, but myo-inositol may be the most important in the biochemistry field and the easiest inositol to obtain. For example, rice bran contains a certain amount of myo-inositol as phytic acid (7), which can be isolated. Cyclohexanepentols, or deoxy-inositols, are called quercitols. There are 12 optical isomers among the 16 quercitol isomers (8), as the removal of one hydroxy group reduces their symmetry. Each MINIREVIEW doi: 10.4052/tigg.1435.1E