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Synthesis and Evaluation of Indolizine‐Type Inhibitors ofN‐acetyl‐β‐D‐glucosaminidases

 

作者: Narendra Panday,   Thierry Granier,   Andrea Vasella,  

 

期刊: Helvetica Chimica Acta  (WILEY Available online 1998)
卷期: Volume 81, issue 3‐4  

页码: 475-490

 

ISSN:0018-019X

 

年代: 1998

 

DOI:10.1002/hlca.19980810303

 

出版商: WILEY‐VCH Verlag GmbH

 

数据来源: WILEY

 

摘要:

AbstractTo check if the strong inhibition ofN‐acetyl‐β‐D‐glucosaminidase by the tetrazole8and the imidazoles9and10correlates with the presence of a heteroatom corresponding to the glycosidic O‐atom, we prepared the GlcNAc‐derived pyrroles (tetrahydroindolizines)18,19,27,28,34, and35, lacking such a heteroatom. For this. the glucose‐derived pyrroles11–13were treated with aLewisacid in the presence of trimethylsilyl azide. Conditions of kinetic control favored the formation of thegluco‐azides14,23, and30, while thermodynamic control favoured themanno‐azides20,29, and36.Reduction of the azides14,20,23,30, and36by Pd/C‐catalyzed hydrogenolysis or, better, with propanedithiol and Et3N, followed by acetylation or trifluoroacetylation and hydrogenolytic debenzylation, gave the deprotected acetamido‐ and trifluoroacetamido‐pyrroles18,19,22,27,28,34,3540, and41. As compared to the tetrazole8and the imidazole9, the pyrroles18,19,27,28,34, and35are only modest inhibitors ofN‐acetyl‐β‐D‐glucosaminidase from bovine kidney (Kivalues between 10 and 75 μM). indicating the necessity of a heteroatom at the glycosidic position.KiValues between 100 and 160 μM for the inhibition ofN‐acetyl‐β‐D‐glucosaminidase from jack beans were determined for the pyrroles19,34, and35.The trifluoroacetamides inhibited both enzymes about twi

 

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