Selective inhibition of β-N-acetylhexosaminidases by thioglycosyl-naphthalimide hybrid molecules

To develop selective inhibitors for β-N-acetylhexosaminidases which are involved in a myriad of physiological processes, a series of novel thioglycosyl-naphthalimide hybrid inhibitors were designed, synthesized and evaluated for inhibition activity against glycosyl hydrolase family 20 and 84 (GH20 and GH84) β-N-acetylhexosaminidases. These compounds which incorporate groups with varied sizes and lengths at the linker region between thioglycosyl moiety and naphthalimide moiety are designed to improve the selectivity and stacking interactions. The GH84 human O-GlcNAcase (hOGA) was sensitive to the subtle changes in the linker region and the optimal choice is a small size linker with six atoms length. And the GH20 insect β-N-acetylhexosaminidase OfHex1 could tolerate compounds with a hydrophobic bulky linker. Especially, the compound 5c (hOGA, K_i = 3.46 μM; OfHex1, K_i > 200 μM) and the compound 6f (hOGA, K_i > 200 μM; OfHex1, K_i = 21.81 μM) displayed high selectivity. The molecular docking results indicated that the inhibition mechanism was different between the two families due to their different structural characteristics beyond the active sites. These results provide some promising clues to improve selectivity of potent molecules against β-N-acetylhexosaminidases.