1. Design and Synthesis of Novel Betulin Derivatives Containing Thio-/Semicarbazone Moieties as Apoptotic Inducers through Mitochindria-Related Pathways.
- Author
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Wang J, Wu J, Han Y, Zhang J, Lin Y, Wang H, Wang J, Liu J, and Bu M
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Biomarkers, Cell Line, Tumor, Cell Proliferation drug effects, Flow Cytometry, Humans, Membrane Potential, Mitochondrial drug effects, Metabolic Networks and Pathways drug effects, Molecular Structure, Reactive Oxygen Species metabolism, Semicarbazones chemical synthesis, Apoptosis drug effects, Chemistry Techniques, Synthetic, Drug Design, Mitochondria drug effects, Mitochondria metabolism, Semicarbazones chemistry, Semicarbazones pharmacology, Triterpenes chemistry
- Abstract
Two new series of betulin derivatives with semicarbazone ( 7a - g ) or thiosemicarbazone ( 8a - g ) groups at the C-28 position were synthesized. All compounds were evaluated for their in vitro cytotoxicities in human hepatocellular carcinoma cells (HepG2), human breast carcinoma cells (MCF-7), human lung carcinoma cells (A549), human colorectal cells (HCT-116) and normal human gastric epithelial cells (GES-1). Among these compounds, 8f displayed the most potent cytotoxicity with an IC
50 value of 5.86 ± 0.61 μM against MCF-7 cells. Furthermore, the preliminary mechanism studies in MCF-7 cells showed that compound 8f could trigger the intracellular mitochondrial-mediated apoptosis pathway by losing MMP level, which was related with the upregulation of Bax, P53 and cytochrome c expression; the downregulation of Bcl-2 expression; activation of the expression levels of caspase-3, caspase-9, cleaved caspase-3 and cleaved caspase-9; and an increase in the amounts of intracellular reactive oxygen species. These results indicated that compound 8f may be used as a valuable skeleton structure for developing novel antitumor agents.- Published
- 2021
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