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Synthesis and Evaluation of Indolizine‐Type Inhibitors of N ‐acetyl‐β‐ D ‐glucosaminidases
Author(s) -
Panday Narendra,
Granier Thierry,
Vasella Andrea
Publication year - 1998
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19980810303
Subject(s) - chemistry , trimethylsilyl azide , heteroatom , tetrazole , hydrogenolysis , indolizine , stereochemistry , glycosidic bond , hydrolysis , medicinal chemistry , trimethylsilyl cyanide , hydrazine (antidepressant) , azide , enzyme , organic chemistry , catalysis , biochemistry , ring (chemistry)
To check if the strong inhibition of N ‐acetyl‐β‐ D ‐glucosaminidase by the tetrazole 8 and the imidazoles 9 and 10 correlates with the presence of a heteroatom corresponding to the glycosidic O‐atom, we prepared the GlcNAc‐derived pyrroles (tetrahydroindolizines) 18 , 19 , 27 , 28 , 34 , and 35 , lacking such a heteroatom. For this. the glucose‐derived pyrroles 11 – 13 were treated with a Lewis acid in the presence of trimethylsilyl azide. Conditions of kinetic control favored the formation of the gluco ‐azides 14 , 23 , and 30 , while thermodynamic control favoured the manno ‐azides 20 , 29 , and 36. Reduction of the azides 14 , 20 , 23 , 30 , and 36 by Pd/C‐catalyzed hydrogenolysis or, better, with propanedithiol and Et 3 N, followed by acetylation or trifluoroacetylation and hydrogenolytic debenzylation, gave the deprotected acetamido‐ and trifluoroacetamido‐pyrroles 18 , 19 , 22 , 27 , 28 , 34 , 35 40 , and 41 . As compared to the tetrazole 8 and the imidazole 9 , the pyrroles 18 , 19 , 27 , 28 , 34 , and 35 are only modest inhibitors of N ‐acetyl‐β‐ D ‐glucosaminidase from bovine kidney ( K i values between 10 and 75 μM). indicating the necessity of a heteroatom at the glycosidic position. K i Values between 100 and 160 μM for the inhibition of N ‐acetyl‐β‐ D ‐glucosaminidase from jack beans were determined for the pyrroles 19 , 34 , and 35. The trifluoroacetamides inhibited both enzymes about twice as strongly as the corresponding acetamides.