Scientists from the University of Innsbruck, including Ondřej Kováč from the UP Faculty of Science Department of Organic Chemistry, were the first in the world to use a new method to synthetically prepare the complex chemical substance ganoapplanin from a group of complex polycyclic meroterpenoids contained in fungi of the genus Ganoderma. Decoctions of these mushrooms (reishi) are already known in traditional Chinese medicine, as they have significant antioxidant, anti-tumour, anti-inflammatory, and antimicrobial effects due to their natural meroterpenoid content. The synthetic production of polycyclic meroterpenoids opens the door to their further research and possible use in the pharmaceutical industry. The results of scientific work on the chemical organic synthesis of meroterpenoids were published in the prestigious Journal of the American Chemical Society (JACS).
“Using a synthetic strategy I co-developed with colleagues in Innsbruck, complex polycyclic meroterpenoids can be prepared in the laboratory. This will allow us further targeted study of these biologically active natural products,” said Kováč. Scientists at the University of Innsbruck have already started biological testing of synthetically prepared ganoapplanin, which should reveal its potential for new drug development. They have also applied the developed method for synthetic production to the preparation of other Ganoderma meroterpenoids.
From a biological point of view, ganoapplanin exhibits inhibitory activity towards the CaV3 ion channel, which plays an important role especially for heart and brain function. “Since these ion channels are involved in a wide range of physiological functions, they are one of the main molecular targets in biomedical research. Ganoapplanin is therefore ranked among the potential new drugs against neurodegenerative diseases such as epilepsy or Parkinson’s disease. It may thus become a starting point for the development of new, more effective drugs,” pointed out Kováč.
Meroterpenoids contained in the fungi of the genus Ganoderma belong to a large group of natural products characterized by their wide structural diversity. “More than 100 isolated representatives of meroterpenoids from fungi belonging to the genus Ganoderma are now known. The significant biological activity of extracts from these fungi prompted scientists to isolate individual compounds and study them. Some isolated natural substances were subsequently classified as candidates with significant therapeutic potential,” said Kováč.
However, further research and potential use of meroterpenoids has so far been limited by their availability. For example, for a possible clinical phase of testing the effects of meroterpenoids, scientists need to have large quantities of these substances available. This, however, would require processing huge quantities of this fungus, which could threaten the entire Ganoderma ecosystem. Scientists have therefore turned their attention to organic synthesis in the laboratory some time ago, as this is one of the most feasible ways to secure the necessary amount of meroterpenoids.
Complex meroterpenoids, which include ganoapplanin, have resisted their efforts for synthetic production due to their complicated structure. “Although ganoapplanin was already isolated in 2016 by a scientific team from China, its complex structure containing a number of oxygenated functional groups has made it a major synthetic challenge and a very difficult to obtain natural product,” Kováč pointed out.
The first total synthesis of ganoapplanin was carried out by a team of scientists at the University of Innsbruck led by Prof Thomas Magauer. He used the “cascade” reaction linking an aromatic and a bicyclic terpenoid fragment of ganoapplanin. “This innovative approach allowed us to prepare a key structural motif containing a polycyclic skeleton in a single step. Interestingly, nature itself guided us to this step, as biosynthesis occurs similarly inside the fungus from which the natural product was isolated. It was up to us to find suitable conditions in the laboratory to simulate this step in the reaction flask, which was not easy at all,” said Kováč.
At the same time, Innsbruck scientists found an efficient way to prepare the bicyclic terpenoid fragment itself, which is also a component of other Ganoderma meroterpenoids. “These results are under peer review and will soon be published in another scientific paper. In general, the developed synthetic strategy offers an effective tool to prepare complex polycyclic meroterpenoids and, in particular, enables further targeted study of these biologically active natural products,” added Kováč.