Synthesis of eight stereoisomers of pochonicine: Nanomolar inhibition of β-N-acetylhexosaminidases

Jian She Zhu, Shinpei Nakagawa, Wei Chen, Isao Adachi, Yue Mei Jia, Xiang Guo Hu, George W J Fleet, Francis X. Wilson, Teruhiko Nitoda, Graeme Horne, Renate Van Well, Atsushi Kato, Chu Yi Yu

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Pochonicine, the first naturally occurring polyhydroxylated pyrrolizidine containing an acetamidomethyl group, which was isolated from Pochonia suchlasporia var. suchlasporia TAMA 87, together with its enantiomer and their C-1 and/or C-3 epimers, have been synthesized from the sugar-derived cyclic nitrones 9D and 9L, respectively. An in-depth NMR study showed that both the 1H and 13C NMR spectra of the synthetic pochonicines (1D and 1L) matched very well with those of natural pochonicine in D2O, which unequivocally determined the relative configuration of the natural product as 1D or 1L. In addition, comparison of the optical rotations of the synthetic pochonicines and that of the natural product, but more convincingly their glycosidase inhibition profiles, confirmed the absolute configuration of natural pochonicine as 1R,3S,5R,6R,7S,7aR. Thereby, the structure of natural pochonicine was unequivocally determined as (+)-(1R,3S,5R,6R,7S,7aR)-pochonicine (1D). Glycosidase inhibition experiments showed that natural pochonicine 1D and its epimers 2D, 3D, and 4D all are powerful inhibitors of hexosaminidases (five β-N-acetylglucosaminidases and two β-N-acetylgalactosaminidases) while their enantiomers 1L, 2L, 3L, and 4L are much weaker inhibitors of the same enzymes. (-)-3-epi-Pochonicine (2L) was found to be a potent and selective inhibitor of α-l-rhamnosidase. None of the compounds showed any inhibition of α-GalNAcase.

Original languageEnglish
Pages (from-to)10298-10309
Number of pages12
JournalJournal of Organic Chemistry
Volume78
Issue number20
DOIs
Publication statusPublished - Oct 18 2013

Fingerprint

Stereoisomerism
Enantiomers
Glycoside Hydrolases
Biological Products
Nuclear magnetic resonance
Optical rotation
5-acetamidomethyl-3-hydroxymethyl-1,6,7-trihydroxypyrrolizidine
Hexosaminidases
Acetylglucosaminidase
Enzyme Inhibitors
Sugars

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Zhu, J. S., Nakagawa, S., Chen, W., Adachi, I., Jia, Y. M., Hu, X. G., ... Yu, C. Y. (2013). Synthesis of eight stereoisomers of pochonicine: Nanomolar inhibition of β-N-acetylhexosaminidases. Journal of Organic Chemistry, 78(20), 10298-10309. https://doi.org/10.1021/jo401694e

Synthesis of eight stereoisomers of pochonicine : Nanomolar inhibition of β-N-acetylhexosaminidases. / Zhu, Jian She; Nakagawa, Shinpei; Chen, Wei; Adachi, Isao; Jia, Yue Mei; Hu, Xiang Guo; Fleet, George W J; Wilson, Francis X.; Nitoda, Teruhiko; Horne, Graeme; Van Well, Renate; Kato, Atsushi; Yu, Chu Yi.

In: Journal of Organic Chemistry, Vol. 78, No. 20, 18.10.2013, p. 10298-10309.

Research output: Contribution to journalArticle

Zhu, JS, Nakagawa, S, Chen, W, Adachi, I, Jia, YM, Hu, XG, Fleet, GWJ, Wilson, FX, Nitoda, T, Horne, G, Van Well, R, Kato, A & Yu, CY 2013, 'Synthesis of eight stereoisomers of pochonicine: Nanomolar inhibition of β-N-acetylhexosaminidases', Journal of Organic Chemistry, vol. 78, no. 20, pp. 10298-10309. https://doi.org/10.1021/jo401694e
Zhu, Jian She ; Nakagawa, Shinpei ; Chen, Wei ; Adachi, Isao ; Jia, Yue Mei ; Hu, Xiang Guo ; Fleet, George W J ; Wilson, Francis X. ; Nitoda, Teruhiko ; Horne, Graeme ; Van Well, Renate ; Kato, Atsushi ; Yu, Chu Yi. / Synthesis of eight stereoisomers of pochonicine : Nanomolar inhibition of β-N-acetylhexosaminidases. In: Journal of Organic Chemistry. 2013 ; Vol. 78, No. 20. pp. 10298-10309.
@article{c2fd6fbf69fd46418acfba121558978c,
title = "Synthesis of eight stereoisomers of pochonicine: Nanomolar inhibition of β-N-acetylhexosaminidases",
abstract = "Pochonicine, the first naturally occurring polyhydroxylated pyrrolizidine containing an acetamidomethyl group, which was isolated from Pochonia suchlasporia var. suchlasporia TAMA 87, together with its enantiomer and their C-1 and/or C-3 epimers, have been synthesized from the sugar-derived cyclic nitrones 9D and 9L, respectively. An in-depth NMR study showed that both the 1H and 13C NMR spectra of the synthetic pochonicines (1D and 1L) matched very well with those of natural pochonicine in D2O, which unequivocally determined the relative configuration of the natural product as 1D or 1L. In addition, comparison of the optical rotations of the synthetic pochonicines and that of the natural product, but more convincingly their glycosidase inhibition profiles, confirmed the absolute configuration of natural pochonicine as 1R,3S,5R,6R,7S,7aR. Thereby, the structure of natural pochonicine was unequivocally determined as (+)-(1R,3S,5R,6R,7S,7aR)-pochonicine (1D). Glycosidase inhibition experiments showed that natural pochonicine 1D and its epimers 2D, 3D, and 4D all are powerful inhibitors of hexosaminidases (five β-N-acetylglucosaminidases and two β-N-acetylgalactosaminidases) while their enantiomers 1L, 2L, 3L, and 4L are much weaker inhibitors of the same enzymes. (-)-3-epi-Pochonicine (2L) was found to be a potent and selective inhibitor of α-l-rhamnosidase. None of the compounds showed any inhibition of α-GalNAcase.",
author = "Zhu, {Jian She} and Shinpei Nakagawa and Wei Chen and Isao Adachi and Jia, {Yue Mei} and Hu, {Xiang Guo} and Fleet, {George W J} and Wilson, {Francis X.} and Teruhiko Nitoda and Graeme Horne and {Van Well}, Renate and Atsushi Kato and Yu, {Chu Yi}",
year = "2013",
month = "10",
day = "18",
doi = "10.1021/jo401694e",
language = "English",
volume = "78",
pages = "10298--10309",
journal = "Journal of Organic Chemistry",
issn = "0022-3263",
publisher = "American Chemical Society",
number = "20",

}

TY - JOUR

T1 - Synthesis of eight stereoisomers of pochonicine

T2 - Nanomolar inhibition of β-N-acetylhexosaminidases

AU - Zhu, Jian She

AU - Nakagawa, Shinpei

AU - Chen, Wei

AU - Adachi, Isao

AU - Jia, Yue Mei

AU - Hu, Xiang Guo

AU - Fleet, George W J

AU - Wilson, Francis X.

AU - Nitoda, Teruhiko

AU - Horne, Graeme

AU - Van Well, Renate

AU - Kato, Atsushi

AU - Yu, Chu Yi

PY - 2013/10/18

Y1 - 2013/10/18

N2 - Pochonicine, the first naturally occurring polyhydroxylated pyrrolizidine containing an acetamidomethyl group, which was isolated from Pochonia suchlasporia var. suchlasporia TAMA 87, together with its enantiomer and their C-1 and/or C-3 epimers, have been synthesized from the sugar-derived cyclic nitrones 9D and 9L, respectively. An in-depth NMR study showed that both the 1H and 13C NMR spectra of the synthetic pochonicines (1D and 1L) matched very well with those of natural pochonicine in D2O, which unequivocally determined the relative configuration of the natural product as 1D or 1L. In addition, comparison of the optical rotations of the synthetic pochonicines and that of the natural product, but more convincingly their glycosidase inhibition profiles, confirmed the absolute configuration of natural pochonicine as 1R,3S,5R,6R,7S,7aR. Thereby, the structure of natural pochonicine was unequivocally determined as (+)-(1R,3S,5R,6R,7S,7aR)-pochonicine (1D). Glycosidase inhibition experiments showed that natural pochonicine 1D and its epimers 2D, 3D, and 4D all are powerful inhibitors of hexosaminidases (five β-N-acetylglucosaminidases and two β-N-acetylgalactosaminidases) while their enantiomers 1L, 2L, 3L, and 4L are much weaker inhibitors of the same enzymes. (-)-3-epi-Pochonicine (2L) was found to be a potent and selective inhibitor of α-l-rhamnosidase. None of the compounds showed any inhibition of α-GalNAcase.

AB - Pochonicine, the first naturally occurring polyhydroxylated pyrrolizidine containing an acetamidomethyl group, which was isolated from Pochonia suchlasporia var. suchlasporia TAMA 87, together with its enantiomer and their C-1 and/or C-3 epimers, have been synthesized from the sugar-derived cyclic nitrones 9D and 9L, respectively. An in-depth NMR study showed that both the 1H and 13C NMR spectra of the synthetic pochonicines (1D and 1L) matched very well with those of natural pochonicine in D2O, which unequivocally determined the relative configuration of the natural product as 1D or 1L. In addition, comparison of the optical rotations of the synthetic pochonicines and that of the natural product, but more convincingly their glycosidase inhibition profiles, confirmed the absolute configuration of natural pochonicine as 1R,3S,5R,6R,7S,7aR. Thereby, the structure of natural pochonicine was unequivocally determined as (+)-(1R,3S,5R,6R,7S,7aR)-pochonicine (1D). Glycosidase inhibition experiments showed that natural pochonicine 1D and its epimers 2D, 3D, and 4D all are powerful inhibitors of hexosaminidases (five β-N-acetylglucosaminidases and two β-N-acetylgalactosaminidases) while their enantiomers 1L, 2L, 3L, and 4L are much weaker inhibitors of the same enzymes. (-)-3-epi-Pochonicine (2L) was found to be a potent and selective inhibitor of α-l-rhamnosidase. None of the compounds showed any inhibition of α-GalNAcase.

UR - http://www.scopus.com/inward/record.url?scp=84886396366&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84886396366&partnerID=8YFLogxK

U2 - 10.1021/jo401694e

DO - 10.1021/jo401694e

M3 - Article

C2 - 24032658

AN - SCOPUS:84886396366

VL - 78

SP - 10298

EP - 10309

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

SN - 0022-3263

IS - 20

ER -