Synthesis of new bioactive mannostatin A analogues

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.