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

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

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PoužívateľVedecká prácaDizajnDiskusná interakcia
Ing. Lucia Pažitná100%100%-
RNDr. Veronika Pinková Gajdošová PhD.100%100%100%
Ing. Kristína Kianičková100%100%100%
Ing. Zuzana Brnoliaková PhD.60%60%100%
Ing. Radka Štadániová100%100%100%
RNDr. Kristína Krochtová100%100%100%
Bc. Daniela Máčalová100%100%100%
Ing. Peter Haluz100%100%100%
Ing. Jakub Masác100%100%100%
Michaela Marčeková100%100%100%
Ing. Monika Biela100%100%100%
Michaela Čierna100%100%100%
ISBN: ISBN 978-80-972360-7-6

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

Martin Kalník1 , Ján Moncoľ2 , Juraj Kóňa , Miroslav Koóš , Maroš Bella ,
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
martin.kalnik@savba.sk

(−)-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.

Poďakovanie: 

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.

Zdroje: 

[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.

Diskusia

Dobry den, blahozelam k vysledkom, drzim place s optimalizaciou syntezy. Mohli by ste, prosim Vas specifikovat ako planujete hodnotit ucinnost vasej latky, v akych biologickych systemoch, akymi metódami? Vo.pred dakujem za odpoved.

Dobrý deň, ďakujem veľmi pekne za otázku. Biologické aktivity našich látok plánujeme stanoviť testami na izolovaných enzýmoch. Žiaľ, z ľudskými enzýmami GMII a LMan sa nepracuje jednoducho a nemáme ich k dispozícii. Preto budú naše látky otestované na viacerých príbuzných enzýmoch - na enzýmch GMIIb a LManII z ovocnej mušky Drosophila melanogaster a na enzýme JBMan z rastliny Canavalia ensiformis.

Dakujem za promptnu odpoved, vela stastia a uspechov do vasej dalsej prace. S pozdravom, ZB