Syntheses and Glycosidase Inhibiting Activities of Nagstatin Analogs.

Abstract

Sir:Nagstatin (1)

Three-dimensional Structure of the Barley β-d-Glucan Glucohydrolase in Complex with a Transition State Mimic

“…PheGlcIm is a representative of the glucoimidazoles (GlcIm), which are excellent chemical tools for studying three-dimensional structures that mimic transition states. For example, PheGlcIm is a nagstatin-type mimic of the reactive intermediate that can be isolated from culture filtrates of Streptomyces amakusaensis (12), or prepared synthetically; nagstatin is an inhibitor of N-acetyl-␤-D-glucosaminidase (13). PheGlcIm has a trigonal anomeric center attached to an exocyclic N atom, which corresponds to the "glycosidic heteroatom," and an endocyclic N atom of the tetrahydropyridine moiety.…”

Synthesis of N‐Acetylglucosamine‐Derived Nagstatin Analogues and Their Evaluation as Glycosidase Inhibitors

“…We report the synthesis of 14 and 15, their evaluation as inhibitors of the hexosaminidases from bovine kidney (unknown family) and from Jack beans (family 18 [11] [12]), and a comparison of the inhibition to that of the unsubstituted GlcNAcimidazole 16 [2] [13].…”

“…± The nagstatin analogue 15 and the corresponding methyl ester 14 were tested as inhibitors of the N-acetyl-b-glucosaminidases from Jack beans (citrate buffer, pH 5.0, 258) and from bovine kidney (citrate buffer, pH 4.1, 378), the b-glucosidase from C. saccharolyticum (phosphate buffer, pH 6.8, 558), and the bmannosidase from snail (acetate buffer, pH 4.5, 258), using the corresponding 4-nitrophenyl glycopyranosides as substrates. The inhibition data of 14 and 15 for the hexosaminidases are summarized in Table 1 and compared to the inhibition by the parent acetamido-imidazole 16 and by nagstatin [2]. A comparison of the inhibition of the b-glucosidase and b-mannosidase by 14 and 15 to the inhibition by the glucose-and mannose-related analogues 6 ± 9 [9] is shown in Table 2.…”

“…The configuration of the alcohols 22 and 23 (and thus also of 20 and 21) was assigned on the basis of J(7,8) values (7.5 and 3.4 Hz, resp.). The structure the a-azido esters 24 was deduced on the basis of the replacement of a broad s at 3.67 ppm for CH 2 ÀC(2) by two broad ss at 4.87 and 4.88 ppm in the ratio 2 : 1, and of a d at 4.87 ppm for HÀC(8) for 22 by two dds at 3.00 and 3.25 ppm with J gem 16.8 Hz for CH 2 (8). The structure of 24 is supported by a strong IR band at 2109 cm À1 for the N 3 group and by the [M H] peak at m/z 568.2550.…”

“…± Nagstatin (1), a strong inhibitor of several hexosaminidases [1 ± 4], is a N-acetylgalactosamine-derived tetrahydropyridoimidazole-2-acetic acid [5]. Its inhibitory activity is essentially associated with the imidazole ring and not with the carboxymethyl substituent [2], although substituents on the imidazole ring may strongly affect the inhibition of b (and a-)-glycosidases [6 ± 8]. In the preceding paper [9], we described the influence of the hydrophobic character of C(2)-methyl ester and carboxylic acid substituents on the inhibition of b-glycosidases.…”