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  3. Synthesis and neuroprotective activity evaluation of diosgenin derivatives based on a biocatalytic-chemosynthetic combinatorial strategy

Synthesis and neuroprotective activity evaluation of diosgenin derivatives based on a biocatalytic-chemosynthetic combinatorial strategy

  • Eur J Med Chem. 2026 Jul 5:311:118825. doi: 10.1016/j.ejmech.2026.118825.
Chi Li 1,  Jinxiu Sun 2,  Jiarong Han 1,  Yeyin Lin 2,  Ruolan Fan 2,  Jie Yang 3,  Yaqian Feng 4,  Wei Xu 5,  Hua Li 6,  Shaohua Xu 7
Affiliations

Affiliations

  • 1 The Affiliated People's Hospital, College of Integrative Medicine, Fujian-Hong Kong-Macau-Taiwan Collaborative Laboratory for the Inheritance and Innovation of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China.
  • 2 Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China.
  • 3 Yichang Humanwell Pharmaceutical CO., LTD., Yichang, 443000, China.
  • 4 The Affiliated People's Hospital, College of Integrative Medicine, Fujian-Hong Kong-Macau-Taiwan Collaborative Laboratory for the Inheritance and Innovation of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China. Electronic address: [email protected].
  • 5 Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Health College, Fuzhou, Fujian, 350101, China. Electronic address: [email protected].
  • 6 Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China. Electronic address: [email protected].
  • 7 Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China. Electronic address: [email protected].
PMID: 41936800 DOI: 10.1016/j.ejmech.2026.118825
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.

Keywords

AKT; Biocatalytic–chemosynthetic combinatorial strategy; Diosgenin derivatives; Neuroprotective; STAT3.

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