Design and Synthesis of Novel Betulin Derivatives Containing Thio-/Semicarbazone Moieties as Apoptotic Inducers through Mitochindria-Related Pathways
Two new series of betulin derivatives with semicarbazone (<b>7a</b>–<b>g</b>) or thiosemicarbazone (<b>8a</b>–<b>g</b>) groups at the C-28 position were synthesized. All compounds were evaluated for their in vitro cytotoxicities in human hepatocellular...
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| Autores principales: | , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/089ba256ef8142eab819af0367c6873a |
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| Sumario: | Two new series of betulin derivatives with semicarbazone (<b>7a</b>–<b>g</b>) or thiosemicarbazone (<b>8a</b>–<b>g</b>) 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, <b>8f</b> displayed the most potent cytotoxicity with an IC<sub>50</sub> value of 5.86 ± 0.61 μM against MCF-7 cells. Furthermore, the preliminary mechanism studies in MCF-7 cells showed that compound <b>8f</b> 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 <b>8f</b> may be used as a valuable skeleton structure for developing novel antitumor agents. |
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