Design and Synthesis of Novel Betulin Derivatives Containing Thio-/Semicarbazone Moieties as Apoptotic Inducers through Mitochindria-Related Pathways

• Published in: Molecules (Basel, Switzerland) Switzerland), 2021-10, Vol.26 (21), p.6356
• Main Authors: Wang, Jiafeng, Wu, Jiale, Han, Yinglong, Zhang, Jie, Lin, Yu, Wang, Haijun, Wang, Jing, Liu, Jicheng, Bu, Ming
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antitumor; Apoptosis; Apoptosis - drug effects; Bcl-2 protein; betulin derivatives; Biomarkers; Breast cancer; Breast carcinoma; Cancer therapies; Caspase-3; Caspase-9; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry Techniques, Synthetic; Colorectal carcinoma; Cytochrome c; Cytotoxicity; Drug Design; Epithelial cells; Epithelium; Flow Cytometry; Hepatocellular carcinoma; Humans; Intracellular; Leukemia; Lung carcinoma; Membrane Potential, Mitochondrial - drug effects; Metabolic Networks and Pathways - drug effects; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Molecular Structure; Prostate; Reactive oxygen species; Reactive Oxygen Species - metabolism; semicarbazone; Semicarbazones - chemical synthesis; Semicarbazones - chemistry; Semicarbazones - pharmacology; thiosemicarbazone; Triterpenes - chemistry
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26216356

Two new series of betulin derivatives with semicarbazone ( - ) or thiosemicarbazone ( - ) 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, displayed the most potent cytotoxicity with an IC value of 5.86 ± 0.61 μM against MCF-7 cells. Furthermore, the preliminary mechanism studies in MCF-7 cells showed that compound 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 may be used as a valuable skeleton structure for developing novel antitumor agents.