Synthesising nature-based drugs
Natural products based drugs are valuable source of drugs, and their structural diversity and mode of action helps to gain ground in the fight against various important diseases, including viral and bacterial infections as well as cancer. Lycorine type natural products are encountered in various forms of lilies that can be highly toxic if ingested in large quantities. One of the known modes of actions of lycorine alkaloids is the inhibition of protein synthesis. However, exploration of the full repertoire of the biological activities of lycorine products is hampered by very low availability from naturals source of many alkaloids of this family and also due to the absence of efficient chemical synthesis. The EU-funded METALK project proposed a novel methodology to enable an efficient chemical synthesis of these complex natural products and their derivatives for future biological testing. The synthetic approach should be flexible and versatile in order to obtain a variety of lycorine alkaloids, as well as analogues. A particular imidate aldolization step has been explored and developed, using a Lewis acid to prevent the inherent reversibility of the reaction. This step generates a crucial precursor for the synthetic route toward lycorine alkaloids. Remarkably, this novel method also allowed accessing in enantiomerically pure form a neurotransmitter inhibitor in just four steps. The METALK has enabled a crucial step toward the synthesis of a variety of lycorine alkaloids. It should now lead to the synthesis of many congeners and therefore to their comprehensive characterisation. It should be of particular interest to the pharmaceutical sector and facilitate the broad testing of lycorine products and analogues as drug candidates.
Keywords
Cancer, lycorine, alkaloid, neurotransmitter inhibitor, drug
