Synthesis of 5-benzylswainsonines as selective inhibitors of GH38 α-mannosidases

Authors: 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   
Year: 2021
Section: Organic, bioorganic and pharmaceutical chemistry, pharmacology and toxicology
Abstract No.: 2093
ISBN: ISBN 978-80-972360-7-6

(−)-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.
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