RESUMO
Hepatocellular carcinoma (HCC), one of the most common malignant cancers with a low 5-year survival rate, is the third leading cause of cancer-related deaths worldwide. The finding of novel agents and strategies for the treatment of HCC is an urgent need. Sesquiterpene lactones (SLs) have attracted extensive attention because of their potent antitumor activity. In this study, a new series of SL derivatives (3-18) were synthesized using epimers 1 and 2 as parent molecules, isolated from Sphagneticola trilobata, and evaluated for their anti-HCC activity. Furthermore, the structures of 4, 6, and 14 were confirmed by X-ray single-crystal diffraction analyses. The cytotoxic activities of 3-18 on two HCC cell lines, including HepG2 and Huh7, were evaluated using the CCK-8 assay. Among them, compound 10 exhibited the best activity against the HepG2 and Huh7 cell lines. Further studies showed that 10 induced cell apoptosis, arrested the cell cycle at the S phase, and induced the inhibition of cell proliferation and migration in HepG2 and Huh7. In addition, absorption, distribution, metabolism, and excretion (ADME) properties prediction showed that 10 may possess the properties to be a drug candidate. Thus, 10 may be a promising lead compound for the treatment of HCC.
Assuntos
Butiratos , Carcinoma Hepatocelular , Furanos , Neoplasias Hepáticas , Sesquiterpenos , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Isobutiratos , Neoplasias Hepáticas/tratamento farmacológico , Sesquiterpenos/farmacologia , Lactonas/farmacologiaRESUMO
Currently available therapies for hepatocellular carcinoma (HCC), with a high morbidity and high mortality, are only marginally effective and with sharp adverse side effects, which makes it compulsory to explore novel and more effective anticancer molecules. Chinese medicinal herbs exhibited prominent anticancer effects and were applied to supplement clinical cancer treatment. Here, we reported a compound, trilobolide-6-O-isobutyrate (TBB), isolated from the flowers of Wedelia trilobata with a markedly cytotoxic effect on HCC cells. We found that TBB time- and dose-dependently inhibited HCC cells' growth and colony formation in vitro. Moreover, TBB induced cell cycle arrest at the G2/M phase, mitochondrial caspase-dependent apoptosis, and suppressed migration and invasion, as well as the glycolysis of HCC cells. Mechanistically, our data indicated that TBB inhibited the STAT3 pathway activation by directly interacting with the TYR 640/657 sites of the STAT3 protein and decreasing the level of p-STAT3. TBB also regulated the expression of PCNA, Ki67, Cyclin B1, Cyclin E, Bax, Bcl2, MMP2/9, and PGK1 through the inhibition of the IL-6/STAT3 signaling pathway. Lastly, we confirmed that TBB effectively eliminated tumor growth without causing overt toxicity to healthy tissues in the xenograft tumor model. The exploration of anticancer activity and the underlying mechanism of TBB suggested its usage as a promising chemotherapeutic agent for HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptose , Butiratos , Carcinogênese , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Furanos , Humanos , Interleucina-6/metabolismo , Isobutiratos , Neoplasias Hepáticas/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Transdução de SinaisRESUMO
A new bicyclic lactam derivatives penicilactam B (1) and a new monocyclic amide penicillamide D (2), along with four known compounds (3-6), were isolated from the fermentation broth of the derived fungus Penicillium rubens PQJ-2. Their structures and stereochemistry were elucidated by comprehensive spectroscopic analyses and quantum ECD calculations. All the compounds were evaluated for their antibacterial activities against Staphylococcus aureus subsp, Candida albicans, Escherichia coli and insecticidal activity against Helicoverpa armigera Hubner. Compounds 1-3 exhibited modest insecticidal activity against H. armigera Hubner.
RESUMO
Chemical investigations of the flowers of Praxelis clematidea resulted in the isolation of 12 known compounds (1-12). Their structures were elucidated by extensive spectroscopic studies and chemical evidence. The structure and absolute configuration of 1 was precisely determined by a combination of 2 D NMR and quantum chemical calculations of ECD spectra analysis. Compounds 1, 4, 11 were isolated from the genus Praxelis for the first time, while 1-6, 8-12 were isolated from P. clematidea for the first time. The antibacterial activity of compounds 1, 2, 7, 9 were evaluated.