N-[[1-[(2-Nitrophenyl)sulfonyl]-1H-indole-3-yl]methyl]-N-[1-[1-[(2-nitrophenyl)sulfonyl]-1H-indole-3-yl]-2-oxo-2-(tert-butylamino)ethyl]-1-(2-diazo-3-oxobutyryl)-2-oxo-3-methylpiperidine-3beta-carboxamide

Involvement of MAPK, Bcl-2 family, cytochrome c, and caspases in induction of apoptosis by 1,6-O,O-diacetylbritannilactone in human leukemia cells.[Pubmed:17262884]

Mol Nutr Food Res. 2007 Feb;51(2):229-38.

1,6-O,O-diacetylbritannilactone (OODBL) isolated from Inula britannica, exhibits potent antitumor activity against several human cancer cell lines. However, the molecular mechanism of OODBL in the induction of anticancer activity is still unclear. In the present study, we demonstrated that OODBL induced the occurrence of apoptosis in human leukemic (HL-60) cells and cell arrest at the S phase. On the other hand, activation of caspase-8, -9, and -3, phosphorylation of Bcl-2 and Bid, and increased release of cytochrome c from mitochondria into cytosolic fraction were detected in OODBL-treated HL-60 cells. We further demonstrated that production of reactive oxygen species (ROS), activation of mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) signaling pathways may play an important role in OODBL-induced apoptosis. The results from the present study highlight the molecular mechanisms underlying OODBL-induced anticancer activity.

Cytotoxic and Pro-apoptotic Activities of Sesquiterpene Lactones from Inula britannica.[Pubmed:26996005]

Nat Prod Commun. 2016 Jan;11(1):7-10.

In this study, five known sesquiterpene lactones (STL) with an alpha-methylene-gamma-lactone motif, including two eudesmanolides, 1beta-hydroxyalantolactone (1) and ivangustin (2), and three 1,10-seco-eudesmanolides, 1-O-acetylbritannilactone (3), 1,6-O,O-diacetylbritannilactone (4), and 6alpha-O-(2- methylbutyryl)britannilactone (5) were isolated from the flower heads of the medicinal plant Inula britannica. Their structures were characterized by spectroscopic methods. X-ray data of 2 is reported for the first time. Among them, eudesmanolides 1 and 2 exhibited remarkable cytotoxicity against HEp2, SGC-7901 and HCT116 human cancer cell lines, comparable with etoposide (Vp-16) used as reference drug. Furthermore, treatment of HEp2 cells with 1 induced apoptosis associated with cleaved procaspase-3 and PARP. The biological assays carried out with normal cells (CHO) revealed that all sesquiterpenes were weakly selective against the cancer cell lines tested.

1,6-O,O-diacetylbritannilactones inhibits IkappaB kinase beta-dependent NF-kappaB activation.[Pubmed:18926678]

Phytomedicine. 2009 Mar;16(2-3):156-60.

To determine the chemical constituents responsible for pharmacological effects of Inula britannica-F., three specific sesquiterpene lactones in Inula britannica were isolated from chloroform extract and identified, including britannilactone (BL), 1-O-acetylbritannilactone (ABLO), and 1,6-O,O-diacetylbritannilactone (ABLOO). Electrophoretic mobility shift assay (EMSA) was performed to detect the nuclear translocation of nuclear factor-kappaB (NF-kappaB) p65. The expressions of IkappaBalpha, pIkappaBalpha, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), IkappaB kinase alpha/beta (IKKalpha/beta) and NF-kappaB kinase (NIK) were detected by Western blot and RT-PCR. We found that acetyl side groups enhanced the inhibitory action of the agents on LPS/IFN-gamma-induced iNOS and COX-2 expression. Their inhibiting activity was positive correlation with the acetyl side group number. The effects of LPS/IFN-gamma were reversed by ABLOO, and BL without acetyl side groups showed only a weak inhibitory action. Further study indicated that ABLOO markedly inhibited the phosphorylation of IKKbeta down to based level, but not IKKalpha, corresponding with decreased in IkappaBalpha degradation and phosphorylation induced by LPS/IFN-gamma, resulting in the suppression of NF-kappaB nuclear translocation and activity. These results suggest that the acetyl moieties add to the lipophilicity, and consequently enhance cellular penetration, so that ABLOO possess the most anti-inflammatory effect and may be a potent lead structure for the development of therapeutic and cytokine-suppressing remedies valuable for the treatment of various inflammatory diseases.