PMID: 2499316May 1, 1989Paper

Structure-activity relationship of swainsonine. Inhibition of human alpha-mannosidases by swainsonine analogues

The Biochemical Journal
I Cenci di BelloB G Winchester

Abstract

The inhibitory properties of a series of synthetic epimers and analogues of swainsonine towards the multiple forms of human alpha-mannosidases were studied in vitro and in cells in culture. Of the five epimers tested, only the 8a-epimer and 8,8a-diepimer of swainsonine were specific and competitive inhibitors (Ki values of 7.5 x 10(-5) and 2 x 10(-6) M respectively) of lysosomal alpha-mannosidases in vitro and induced storage of mannose-rich oligosaccharides in human fibroblasts in culture. The structures of these storage products indicated that processing alpha-mannosidases had also been inhibited. This was consistent with the observed inhibition in vitro of these enzymes by these compounds. In contrast, the 8-epimer, 1,8-diepimer and 2,8a-diepimer of swainsonine had no appreciable effect on any alpha-mannosidases. The corresponding open-chain analogues of swainsonine, namely 1,4-dideoxy-1,4-imino-D-mannitol, of the 8a-epimer, namely 1,4-dideoxy-1,4-imino-D-talitol, and of the 8,8a-diepimer, namely 1,4-dideoxy-1,4-imino-L-allitol, were weaker competitive inhibitors of lysosomal alpha-mannosidase, with Ki values of 1.3 x 10(-5), 1.2 x 10(-4) and 1.2 x 10(-4) M respectively. These analogues also proved less effective at inducing...Continue Reading

Citations

Apr 1, 2005·Chembiochem : a European Journal of Chemical Biology·Aloysius SiriwardenaGeert-Jan Boons
May 29, 2000·Chirality·T PunniyamurthyT Katsuki
Mar 26, 2004·Natural Product Reports·Birgit Dräger
Feb 2, 2008·The Journal of Organic Chemistry·Jason N AbramsGeorge A O'Doherty
Oct 4, 1996·The Journal of Organic Chemistry·William H. Pearson, Erik J. Hembre
May 10, 2003·The Journal of Organic Chemistry·Ana T CarmonaAna L Winters
Feb 20, 2004·Journal of the American Chemical Society·Marie-Pierre HeckCharles Mioskowski
Aug 9, 2003·Journal of Agricultural and Food Chemistry·Mitsue HaraguchiNaoki Asano
Jul 12, 1996·The Journal of Organic Chemistry·María-Jesús Blanco, F. Javier Sardina
Mar 28, 2006·Journal of Natural Products·Sudhakararao ThammanaYuzuru Shimizu

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