Synthesis and evaluation of two mannosamine-derived lactone-type inhibitors of snail β-mannosidase

Abstract The inhibition of snail β-mannosidase by the manno -configured amino- and hydroxy-lactams and -imidazoles 7 – 10 was compared to the inhibition of the β-glucosidases from Caldocellum saccharolyticum and from sweet almonds by the gluco -configured amino- and hydroxy-lactams and -imidazoles 1 , 2 , 5 and 6 [ΔΔ G diss. (OH → NH 3 + )]. Substitution in the gluco -configured 1 , 3 and 5 , of C(2)–OH by an ammonium group strengthens the interaction of the inhibitor with the catalytic nucleophile of retaining β-glucosidases, and weakens the interaction with the catalytic acid. The analogous substitution in the manno -configured inhibitors 7 and 9 , leading to 8 and 10 , respectively, was expected to only reflect the impaired interaction of the inhibitor with the catalytic acid, as the catalytic nucleophile and the C(2) substituent are located on opposite sides of the average ring plane. The mannonolactam 10 was synthesized from the known hydroxy-lactam 11 by O -mesylation followed by azidation and hydrogenation. Sultone 13 was formed as side product upon mesylation of 11 . The imidazole 8 was obtained from 11 , similarly to the synthesis of the known gluco -isomer 2 , via the hydroxy-imidazoles 22 and 23 ; best results were obtained by protecting 11 as the triisopropylsilyl ether 29 . The resulting inhibition by the imidazoles 7 and 8 was interpreted as reflecting an improved binding of the catalytic nucleophile of snail β-mannosidase with the protonated imidazole ring of 8 and an impaired interaction with the catalytic acid, while a comparison of the inhibition by the lactams 9 and 10 is in keeping with the results that are expected if there is no significant interaction between the catalytic nucleophile of snail β-mannosidase and the C(2)–OH group of β-mannosides. The amino-imidazole 8 is a surprisingly strong inhibitor of the α-mannosidase from Jack beans [ K i  = 1.22 μM; mixed-type ( α  = 2.3)].