Nine of 16 Stereoisomeric Polyhydroxylated Proline Amides Are Potent β-N-Acetylhexosaminidase Inhibitors

被引：30

作者：

Ayers, Benjamin J. ^{[1
]}

Glawar, Andreas F. G. ^{[1
,2
]}

Martinez, R. Fernando ^{[1
]}

Ngo, Nigel ^{[1
]}

Liu, Zilei ^{[1
]}

Fleet, George W. J. ^{[1
]}

Butters, Terry D. ^{[2
]}

Nash, Robert J. ^{[3
]}

Yu, Chu-Yi ^{[4
]}

Wormald, Mark R. ^{[2
]}

Nakagawa, Shinpei ^{[5
]}

Adachi, Isao ^{[5
]}

Kato, Atsushi ^{[5
]}

Jenkinson, Sarah F. ^{[1
]}

机构：

[1] Univ Oxford, Dept Chem, Chem Res Lab, Oxford OX1 3TA, England

[2] Univ Oxford, Oxford Glycobiol Inst, Oxford OX1 3QU, England

[3] Phytoquest Ltd, IBERS, Aberystwyth SY23 3EB, Dyfed, Wales

[4] Chinese Acad Sci, Inst Chem, CAS Key Lab Mol Recognit & Funct, Beijing 100190, Peoples R China

[5] Toyama Univ, Dept Hosp Pharm, Toyama 9300194, Japan

来源：

JOURNAL OF ORGANIC CHEMISTRY | 2014年 / 79卷 / 08期

关键词：

LOOKING-GLASS INHIBITORS; PHARMACOLOGICAL CHAPERONES; GLYCOSIDASE INHIBITORS; O-GLCNACYLATION; HEXOSAMINIDASE INHIBITORS; BIOLOGICAL EVALUATION; EFFICIENT SYNTHESIS; SCALABLE SYNTHESES; ENANTIOMERS; DERIVATIVES;

D O I：

10.1021/jo500157p

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

All 16 stereoisomeric N-methyl 5-(hydroxymethyl)-3,4-dihydroxyproline amides have been synthesized from lactones accessible from the enantiomers of glucuronolactone. Nine stereoisomers, including all eight with a (3R)-hydroxyl configuration, are low to submicromolar inhibitors of beta-N-acetylhexosaminidases. A structural correlation between the proline amides is found with the ADMDP-acetamide analogues bearing an acetamidomethylpyrrolidine motif. The proline amides are generally more potent than their ADMDP-acetamide equivalents. beta-N-Acetylhexosaminidase inhibition by an azetidine ADMDP-acetamide analogue is compared to an azetidine carboxylic acid amide. None of the amides are good alpha-N-acetylgalactosaminidase inhibitors.

引用

页码：3398 / 3409

页数：12

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