(−)-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.[1] 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.[2] Although swainsonine is the most potent inhibitor of the GH38 α-mannosidase family, it lacks selectivity which leads to severe side-effects.[3] 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.[4] 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.
The authors are grateful to the Scientific Grant Agency (VEGA 2/0031/19), SAS-Taiwan project (SAS-MOST/JRP/2019/882/GM-INHIB), Slovak Research and Development Agency (APVV-0484-12) and Doktogrant project of SAS (2020-APP0201) for the financial support. This contribution is the result of the project implementation: Centre of Excellence for Glycomics, ITMS26240120031, supported by the Research & Development Operational Program funded by the ERDF. Peter Gabko, MSci is gratefully acknowledged for helpful discussions. Authors are also gratefull to Reaxys Advisors project for the access to the database.
[1] Chen, W.-A.; Sayyad, A.; Chen, C.-W.; Chen, Y.-H.; Cheng, T.-J. R.; Cheng, W.-C. Asian J. Org. Chem. 2019, 8, 2233–2242.
[2] 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.
[3] 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.
[4] Bella, M.; Šesták, S.; Moncoľ, J.; Koóš, M.; Poláková, M. Beilstein J. Org. Chem. 2018, 14, 2156–2162.