Synthesis of new bioactive mannostatin A analogues

Authors: 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   
Year: 2020
Section: Organic, bioorganic and pharmaceutical chemistry, pharmacology
Abstract No.: 1886
ISBN: 978-80-972360-6-9

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.
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