Design, synthesis and cytotoxic activity of novel lipophilic cationic derivatives of diosgenin and sarsasapogenin

• Published in: Bioorganic & medicinal chemistry letters Vol. 119; pp. 130094 - 130103
• Main Authors: An, Ren-Feng, Wu, Kai-Tian, Pan, Jie, Zhang, Wen-Jin, Qin, Hui-Ying, Li, Xiao-Rui, Liu, Wei, Huang, Xue-Feng
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.04.2025; Elsevier
• Subjects: A549 Cells; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cations - chemical synthesis; Cations - chemistry; Cations - pharmacology; Cell cycle arrest and apoptosis; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cytotoxicity; Diosgenin; Diosgenin - chemical synthesis; Diosgenin - chemistry; Diosgenin - pharmacology; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Lipophlic cations; Molecular Docking Simulation; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Reactive Oxygen Species - metabolism; Sarsasapogenin; Science & Technology; Spirostans - chemical synthesis; Spirostans - chemistry; Spirostans - pharmacology; Structure-Activity Relationship; Lipophlic cations; Diosgenin; Cytotoxicity; Cell cycle arrest and apoptosis; Sarsasapogenin; PATHWAYS; APOPTOSIS; CELLS; MITOCHONDRIA
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2025.130094

[Display omitted] •To improve cytotoxicity and selectivity, use diosgenin and sarsasapogenin as substrates.•Tumour cells have a lower mitochondrial transmembrane potential (MTP) than normal cells.•Compound 13 stops cells from dividing and kills them by making them produce more reactive oxygen species.•Molecular docking analysis showed that compound 13 could well enter the active site of p38α-MAPK. Novel lipophilic cationic derivatives including quaternary ammonium salt and triphenylphosphine series were designed and synthesized using diosgenin (1) and sarsasapogenin (2) as substrates to improve the cytotoxicity and selectivity. Most of the derivatives showed higher cytotoxicity against all cancer cell lines tested, compound 13 exhibited the most superior activity against A549 cells with an IC50 value of 0.95 μM, which was 34-fold of diosgenin. Preliminary cellular mechanism studies elucidated that compound 13 might arrest cell cycle at G0/G1 phase, trigger apoptosis via up-regulating the expression of Bax, down-regulating the expression of Bcl-2 and caspase-3, and induce an increase in the generation of intracellular reactive oxygen species (ROS) in A549 cells. In addition, molecular docking analysis revealed that compound 13 could occupy the active site of p38α-MAPK well and interact to the surrounding amino acids by salt bridge and conjugation. These results suggested that compound 13 had the potential to serve as an antitumor lead agent, probably exert antitumor effect through mitochondrial pathway and p38α MAPK pathway.