Eur J Med Chem. 2026 Apr 2;311:118825. doi: 10.1016/j.ejmech.2026.118825. Online ahead of print.

ABSTRACT

The natural steroidal compound diosgenin possesses neuroprotective pharmacological activity. To obtain compounds with enhanced activity, this study, based on the molecular hybridization strategy, firstly synthesized a series of C-3 position substituted derivatives (DG1-DG15) via esterification reactions between diosgenin and cinnamic acid derivatives. Given the limited modifiable sites on diosgenin, this study then innovatively combined biotransformation and chemical semi-synthesis for its structural modification, integrating the high regio- and stereoselectivity of biocatalysis with the flexibility of chemical synthesis. The newly introduced hydroxyl group by biotransformation served as a versatile handle to install various functional groups at the C-7 position through simple chemical reactions. Consequently, a series of C-7 substituted derivatives (DG16-DG24) and novel C-3,7 disubstituted derivatives (DG25-DG33) were obtained. In vitro cell experiments identified candidate compound DG23 as exhibiting the superior activity. Further mechanistic studies indicated that DG23 likely exerts its neuroprotective effects by inhibiting neuronal apoptosis through the AKT/mTOR and JAK2/STAT3 signaling pathways.

PMID:41936800 | DOI:10.1016/j.ejmech.2026.118825