Synthesis of 5-benzylswainsonines as selective inhibitors of GH38 α-mannosidases
Martin Kalník 1
Ján Moncoľ 2
Juraj Kóňa 1
Miroslav Koóš 1
Maroš Bella 1
1 Institute of Chemistry, Slovak Academy of Sciences, Bratislava, Slovakia 2 Department of Inorganic chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology, Bratislava, Slovakia
|Section:||Organic, bioorganic and pharmaceutical chemistry, pharmacology and toxicology|
(−)-Swainsonine is an indolizidine alkaloid produced by many plants and fungi such as Fabaceae or Clavicipitaceae families. To date, this compound remains the most potent inhibitor (IC50 = 16 nM, Ki = 10 nM) of Golgi α-mannosidase II (GMII), which is an enzyme involved in the intracellular biosynthesis of N-glycans. As overexpression of N-glycans on the cell surface is a common trait in many types of cancer cells, inhibitors of GMII have become candidates for cancer treatment. Although swainsonine is the most potent inhibitor of the GH38 α-mannosidase family, it lacks selectivity which leads to severe side-effects. Therefore, our research focused on synthesis of 5-benzylswainsonines which, according to our in silico models, could be promising GMII inhibitors with enhanced selectivity.
The synthesis started from a known pyrrolidine aldehyde, which was prepared from L-ribose by a reaction sequence previously reported by us. The key steps in the generation of the 5-benzylswainsonine skeleton were stereoselective Grignard reaction with the pyrrolidine aldehyde, and intramolecular reductive amination with concomitant deprotection.
Optimisation of the synthesis and biological evaluation of 5-benzylswainsonines are currently in progress.
 a) Vasconcelos-dos-Santos, A.; Oliveira, I. A.; Lucena, M. C.; Mantuano, N. R.; Whelan, S. A.; Dias, W. B.; Todeschini, A. R. Front. Oncol. 2015, 5, 1–23; b) Newton, S. A.; White, S. L.; Humphries, M. J.; Olden, K. J. Natl. Cancer Inst. 1989, 81, 1024–1028.
 a) Dennis, J. W.; Koch, K.; Yousefi, S.; Vanderelst, I. Cancer Res. 1990, 50, 1867–1872; b) Goss, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin. Cancer Res. 1995, 1, 935–944; c) Goss, P. E.; Reid, C. L.; Bailey, D.; Dennis, J. W. Clin. Cancer. Res. 1997, 3, 1077–1086.
 Bella, M.; Šesták, S.; Moncoľ, J.; Koóš, M.; Poláková, M. Beilstein J. Org. Chem. 2018, 14, 2156–2162.