Nine of 16 stereoisomeric polyhydroxylated proline amides are potent β-N-acetylhexosaminidase inhibitors

Benjamin J. Ayers; Andreas F.G. Glawar; R. Fernando Martínez; Nigel Ngo; Zilei Liu; George W.J. Fleet; Terry D. Butters; Robert J. Nash; Chu Yi Yu; Mark R. Wormald; Shinpei Nakagawa; Isao Adachi; Atsushi Kato; Sarah F. Jenkinson

doi:10.1021/jo500157p

Nine of 16 stereoisomeric polyhydroxylated proline amides are potent β-N-acetylhexosaminidase inhibitors

Benjamin J. Ayers^*, Andreas F.G. Glawar, R. Fernando Martínez, Nigel Ngo, Zilei Liu, George W.J. Fleet, Terry D. Butters, Robert J. Nash, Chu Yi Yu, Mark R. Wormald, Shinpei Nakagawa, Isao Adachi, Atsushi Kato, Sarah F. Jenkinson

^*Corresponding author for this work

Hospital Pharmacy

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

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 β-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. β-N-Acetylhexosaminidase inhibition by an azetidine ADMDP-acetamide analogue is compared to an azetidine carboxylic acid amide. None of the amides are good α-N-acetylgalactosaminidase inhibitors.

Original language	English
Pages (from-to)	3398-3409
Number of pages	12
Journal	Journal of Organic Chemistry
Volume	79
Issue number	8
DOIs	https://doi.org/10.1021/jo500157p
State	Published - 2014/04/18

ASJC Scopus subject areas

Organic Chemistry

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Ayers, B. J., Glawar, A. F. G., Martínez, R. F., Ngo, N., Liu, Z., Fleet, G. W. J., Butters, T. D., Nash, R. J., Yu, C. Y., Wormald, M. R., Nakagawa, S., Adachi, I., Kato, A., & Jenkinson, S. F. (2014). Nine of 16 stereoisomeric polyhydroxylated proline amides are potent β-N-acetylhexosaminidase inhibitors. Journal of Organic Chemistry, 79(8), 3398-3409. https://doi.org/10.1021/jo500157p

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title = "Nine of 16 stereoisomeric polyhydroxylated proline amides are potent β-N-acetylhexosaminidase inhibitors",

abstract = "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 β-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. β-N-Acetylhexosaminidase inhibition by an azetidine ADMDP-acetamide analogue is compared to an azetidine carboxylic acid amide. None of the amides are good α-N-acetylgalactosaminidase inhibitors.",

author = "Ayers, {Benjamin J.} and Glawar, {Andreas F.G.} and Mart{\'i}nez, {R. Fernando} and Nigel Ngo and Zilei Liu and Fleet, {George W.J.} and Butters, {Terry D.} and Nash, {Robert J.} and Yu, {Chu Yi} and Wormald, {Mark R.} and Shinpei Nakagawa and Isao Adachi and Atsushi Kato and Jenkinson, {Sarah F.}",

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doi = "10.1021/jo500157p",

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T1 - Nine of 16 stereoisomeric polyhydroxylated proline amides are potent β-N-acetylhexosaminidase inhibitors

AU - Ayers, Benjamin J.

AU - Glawar, Andreas F.G.

AU - Martínez, R. Fernando

AU - Ngo, Nigel

AU - Liu, Zilei

AU - Fleet, George W.J.

AU - Butters, Terry D.

AU - Nash, Robert J.

AU - Yu, Chu Yi

AU - Wormald, Mark R.

AU - Nakagawa, Shinpei

AU - Adachi, Isao

AU - Kato, Atsushi

AU - Jenkinson, Sarah F.

PY - 2014/4/18

Y1 - 2014/4/18

N2 - 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 β-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. β-N-Acetylhexosaminidase inhibition by an azetidine ADMDP-acetamide analogue is compared to an azetidine carboxylic acid amide. None of the amides are good α-N-acetylgalactosaminidase inhibitors.

AB - 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 β-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. β-N-Acetylhexosaminidase inhibition by an azetidine ADMDP-acetamide analogue is compared to an azetidine carboxylic acid amide. None of the amides are good α-N-acetylgalactosaminidase inhibitors.

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U2 - 10.1021/jo500157p

DO - 10.1021/jo500157p

M3 - 学術論文

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SN - 0022-3263

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EP - 3409

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

IS - 8

ER -

Nine of 16 stereoisomeric polyhydroxylated proline amides are potent β-N-acetylhexosaminidase inhibitors

Abstract

ASJC Scopus subject areas

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