Aza-C-disaccharides and analogs: Growth inhibitors of human glioblastoma and melanoma cells

CARB 28

Pierre Vogel, pierre.vogel@epfl.ch1, Sandrine Gerber-Lemaire2, Hélène Fiaux2, Florence Popowycz2, Sylvain Favre2, and Lucienne Juillerat-Jeanneret, lucienne-juillerat@chuv.hospvd.ch3. (1) Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of Technology (EPFL), BCH, Lausanne, CH 1015, Switzerland, (2) EPFL, LGSA, BCH, Lausanne, CH 1015, Switzerland, (3) CHUV, University Institute of Patology, Bugnon 25, Lausanne, CH 1011, Switzerland
Inhibitors of α-mannosidases such as swainsonine have shown promising anti-tumor activities. With the hope to generate highly potent and selective α-mannosidase inhibitors, aza-C-disaccacharides (dideoxyiminoalditols C-linked to monosaccharides) have been prepared via the condensation of aza-sugar-derived aldehydes with levoglucosenone or isolevoglucosenone under conditions similar to the Oshima-Nozaki condensation. As most disaccharide mimetics so-obtained showed deceiving inhibitory activities towards all kinds of glycosidases, simpler analogs were sought by submitting dynamic libraries of imines to the glycosidases. This led to the discovery of new and highly selective α-mannosidase inhibitors such as the (2R,3R,4S)- and (2S,3R,4S)-2-(aminomethyl)pyrrolidine-3,4-diol derivatives. Benzoates of (2R,3R,4S)-2-({[(1R)-2-hydroxy-1-phenylethyl]amino}methyl)pyrrolidine-3,4-diol were found to inhibit the growth of human glioblastoma and melanoma cells whereas primary human fibroblasts were much less sensitive. Interestingly, swainsonine did not inhibit the growth of the above tumor cells.

 

Iminosugars: Therapeutic Potential
8:30 AM-12:10 PM, Tuesday, 30 August 2005 Washington DC Convention Center -- 202A, Oral

Division of Carbohydrate Chemistry

The 230th ACS National Meeting, in Washington, DC, Aug 28-Sept 1, 2005