期刊
ARCHIV DER PHARMAZIE
卷 354, 期 6, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/ardp.202000448
关键词
antitumor activity; apoptosis inducer; NO donor prodrug; ursolic acid derivatives
资金
- Guangzhou University of Chinese Medicine [AFD01820Z0373]
The newly synthesized NO-releasing ursolic acid-arylidene derivative compound 5c showed potent broad-spectrum antitumor activity in various tumor cell lines, especially exhibiting the strongest apoptosis-inducing effect in MCF-7 cells. Compound 5c affected cell cycle, activated caspase, decreased the Bcl-2/Bax ratio, led to changes in mitochondrial membrane potential, and accumulation of reactive oxygen species in the cells. Additionally, a docking study revealed a potential interaction between the nitroxyethyl moiety of compound 5c and caspase-8 amino acid residues.
Continuing our studies on NO-donating ursolic acid-benzylidene derivatives as potential antitumor agents, we designed and synthesized a series of new arylidene derivatives containing NO-donating ursolic acid and aromatic heterocyclic units. Compounds 5c and 6c showed a significant broad-spectrum antitumor activity. Compound 5c exhibited nearly three- to nine-fold higher cytotoxicity as compared with the parent drug in A549, MCF-7, HepG-2, HT-29, and HeLa cells, and it was also found to be the most potent apoptosis inducer of MCF-7 cells. More importantly, compound 5c arrested the MCF-7 cell cycle in the G1 phase, which was associated with caspase activation and a decrease of the Bcl-2/Bax ratio. Meanwhile, compound 5c caused changes in morphological features, dissipation of the mitochondrial membrane potential, and accumulation of reactive oxygen species. A docking study revealed that the nitroxyethyl moiety of compound 5c may form hydrogen bonds with caspase-8 amino acid residues (SER256 and HIS255). Together, these data suggest that NO-donating ursolic acid-arylidene derivatives are potent apoptosis inducers in tumor cells.
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