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

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41 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

ASJC Scopus subject areas

  • Organic Chemistry

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    Zhu, J. S., Nakagawa, S., Chen, W., Adachi, I., Jia, Y. M., Hu, X. G., Fleet, G. W. J., Wilson, F. X., Nitoda, T., Horne, G., Van Well, R., Kato, A., & 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