Probing the Interaction of the Hydroxy Group at C(4) of Lactone‐Type Inhibitors with β‐Glucosidases and β‐Galactosidases

Abstract

The inhibition of the β‐glucosidases from sweet almonds and from Caldocellum saccharolyticum by the 4‐amino‐4‐deoxy lactam 11, the 4‐deoxy lactam 12, and the corresponding imidazoles 13 and 14 was compared to the inhibition by the hydroxy analogues 1 and 3. Substitution of the OH group at C(4) by an amino group or by hydrogen weakened the inhibition by ΔΔGdiss = + 1.9 to + 3.1 kcal/mol. Similarly, the inhibition of the β‐galactosidase from bovine liver and from E. coli by the 4‐deoxy lactam 12 and the imidazole 14, as compared to the one by the galacto‐configured lactam 9 and imidazole 10, is weakened by deoxygenation at C(4) (ΔΔGdiss = + 2.6 and 4.5 kcal/mol, resp.). The effect of these substitutions on the inhibition of the C. saccharolyticum β‐glucosidase is slightly stronger than the one on the sweet almonds β‐glucosidases. The effect is also stronger on the inhibition by the imidazoles than by the lactams, and depends on the flexibility of the inhibitors. The amino and deoxy lactams 11 and 12 were prepared from the galactonolactam‐derived triflate 17 by substitution with azide and hydride, respectively, followed by hydrogenation. Azidation of the galacto‐configured imidazopyridine‐derived triflate 24 and hydrogenation gave the amino‐imidazole 13. The deoxy lactam 20 was transformed to the manno‐ and gluco‐configured deoxy‐imidazoles 29 and 30 via the thionolactam 28. Hydrogenolytic deprotection of 30 gave the deoxy‐imidazole 14.