Synthesis of new bioactive mannostatin A analogues
Martin Kalník 1
Mária Zajičková 1
Sergej Šesták 1
Miroslav Koóš 1
Maroš Bella 1
1 Slovak Academy of Sciences, Institute of Chemistry, Dúbravská cesta 9, 845 38 Bratislava, Slovakia
|Section:||Organic, bioorganic and pharmaceutical chemistry, pharmacology|
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. It is well-known that abnormal N-glycans are involved in metastasis of breast, skin and colon cancer cells. 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. 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, 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.
 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.
 Zajičková, M.; Moncoľ, J.; Šesták, S.; Kóňa, J.; Koóš, M.; Bella, M. Eur. J. Org. Chem. 2019, 1114–1124.