Mannostatin A is pentasubstituted carbocyclic alkaloid produced by Streptoverticillium verticillus var. quintum. With IC₅₀ = 10-15 nM, this natural compound is so far second most potent inhibitor of Golgi α-mannosidase II (GMII), which is an important enzyme involved in N-glycosylation pathway.[1] It is well-known that abnormal N-glycans are involved in metastasis of breast, skin and colon cancer cells.[2] Therefore, inhibitors of GMII became candidates for development of anticancer drugs. Unfortunately, mannostatin A showed little selectivity among α-mannosidases from GH38 family and its application as a drug could cause serious side effects.[3] New synthetic approach to similar structures with increased selectivity towards GMII is therefore needed.

In our recent research, we prepared three new analogues of mannostatin A. Bicyclic ketone, a common intermediate prepared from D-lyxose in our previous work,[4] was used as a substrate in synthesis of target compounds. In series of substrate-controlled stereoselective reactions, 5-O-methyl, 5-O-benzyl and 5-hydroxy analogues of mannostatine A were prepared.

Biological properties of prepared compounds were tested against three α-mannosidases – lysosomal and Golgi enzymes from fruit fly Drosophila melanogaster and against Jack bean α-mannosidase. All analogues showed inhibitory activity with IC₅₀ values in µM range.

The authors are grateful to the Scientific Grant Agency (VEGA 2/0031/19), SAS-Taiwan project (SAS-MOST/JRP/2019/882/GM-INHIB) and Slovak Research and Development Agency (APVV-0484-12) 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.

[1] Vassela, A.; Hu, G. Helv. Chim. Acta, 2004, 87, 2405–2433.
[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] Zajičková, M.; Moncoľ, J.; Šesták, S.; Kóňa, J.; Koóš, M.; Bella, M. Eur. J. Org. Chem. 2019, 1114–1124.