New Serratane Triterpenoid and Musashi2 inhibitors from Huperzia serrata

Forgetting and memory formation are 2 distinct processes, both essential for the survival of humans and other animals. The protein Musashi2 (MSI2) was recently discovered as a key regulator of forgetting in the model organism Caenorhabditis elegans, making it an attractive therapeutic target for drug discovery and development.

Here, we report a fluorescence polarization assay-based screening campaign aimed at identifying MSI2 inhibitors from 2,844 plant extracts. The dichloromethane extract of the aerial parts of Huperzia serrata, a plant traditionally used in Chinese medicine for the treatment of memory dysfunction, was identified as a hit and subsequently subjected to HPLC-based activity profiling. Scale-up isolation identified fatty acids, namely linoleic acid (11: ) and palmitoleic acid (12: ), both eluting within the main active window. As other fractions also seem to display activity, although weaker, their minor constituents were also investigated, revealing 1 new serratane triterpenoid (1: ) and 7 known serratene triterpenoids 2: -8: , their biosynthetic precursor α-onocerin (9: ), as well as an abietane diterpene (10: ). The absolute configuration of compound 1: was established by X-ray crystallography. All isolated compounds were evaluated for their activity, revealing that linoleic acid (11: ) and palmitoleic acid (12: ) inhibited MSI2 with IC₅₀ values of 14.6 and 23.1 µM, respectively, while compound 10: only showed moderate activity (IC₅₀ of 34.4 µM).