Ivangustin

Eur J Med Chem. 2015 Aug 1;102:256-265.

Synthesis, cytotoxicity and inhibition of NO production of ivangustin enantiomer analogues.[Pubmed: 26280922]

METHODS AND RESULTS:
The eight novel Ivangustin enantiomer analogues possessing α-methylene-γ-butyrolactone moiety have been synthesized using (4S6R, 4S6S)-4-tert-butyldimethylsilyloxy-6-methylcyclohex-2-en-1-one (1) as starting material. These transformations were mainly carried out by aldol condensation reaction and one-pot annelation procedure. The stereochemistry of these synthesized analogues was determined by NOE analysis. Their cytoxicity was evaluated against the human cancer cell lines HCT-116 (colon), HL-60 (leukemia), QGY-7701 (liver), SMMC-7721 (liver), A549 (lung), MCF-7 (breast). The results showed that these analogues were more selective against the cell lines HL-60 and QGY-7701. Analogue 17 exhibited potent cytotoxicity and high selectivity toward HL-60 cell line with IC50 value of 1.02 μM, which suggested that it might be a promising anti-cancer lead compound. The inhibitory activities against NO production and the cytotoxicities in RAW 264.7 macrophages were determined at the same time.
CONCLUSIONS:
All of the analogues significantly inhibited the NO production with IC50 value in the range of 3.44-6.99 μM. Analogues 17, 22, 23 and 7 showed higher cytotoxicities, indicated their inhibitory activities against NO production may be influenced by the cytotoxicities.

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

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

METHODS AND RESULTS:
In this study, five known sesquiterpene lactones (STL) with an α-methylene-γ-lactone motif, including two eudesmanolides, 1β-hydroxyalantolactone (1) and Ivangustin (2), and three 1,10-seco-eudesmanolides, 1-O-acetylbritannilactone (3), 1,6-O,O-diacetylbritannilactone (4), and 6α-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.
CONCLUSIONS:
The biological assays carried out with normal cells (CHO) revealed that all sesquiterpenes were weakly selective against the cancer cell lines tested.

J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Aug 15;903:40-5.

Simultaneous determination of three sesquiterpene lactones from Herba Inula extract in rat plasma by LC/MS/MS and its application to pharmacokinetic study.[Pubmed: 22819204]

METHODS AND RESULTS:
A rapid and sensitive liquid chromatography-tandem mass spectrometry method has been developed and validated for the determination of 1-acetoxy-6α-hydroxyeriolanolide, 1β-hydroxyalantolactone and Ivangustin from Herba Inula extract in rat plasma. Plasma samples were pretreated by protein precipitation with methanol. Chromatographic separation was accomplished on a TOSOH TSKgel ODS column with mobile phase consisting of methanol and 0.3% formic acid (80:20, v/v). The detection was carried out by multiple-reaction monitoring mode under positive electrospray ionization. The quantification was performed using the transitions of m/z 309.1/185.0 for 1-acetoxy-6α-hydroxyeriolanolide, m/z 249.0/231.1 for 1β-hydroxyalantolactone and Ivangustin and m/z 285.0/193.0 for diazepam, respectively. Calibration curves were linear over the concentration range of 4-800 ng/mL for 1-acetoxy-6α-hydroxyeriolanolide, 8-500 ng/mL for 1β-hydroxyalantolactone and Ivangustin. The limit of detection (LOD) was 1 ng/mL for 1-acetoxy-6α-hydroxyeriolanolide, 1.6 ng/mL for 1β-hydroxyalantolactone and Ivangustin (S/N=3). The intra-day and inter-day precisions (RSD%) for the three compounds were less than 7.8% and 8.6%, and the accuracy (RE%) ranged from -4.6 to 6.8%.
CONCLUSIONS:
The method was successfully applied to pharmacokinetic studies of the three sesquiterpene lactones after oral administration of 300 mg/kg Herba Inula extract to rats, the t(½) of 1-acetoxy-6α-hydroxyeriolanolide, 1β-hydroxyalantolactone and Ivangustin was 9.65±1.43, 14.88±0.82 and 13.93±2.74 (h). The AUC((0-t)) of 1-acetoxy-6α-hydroxyeriolanolide, 1β-hydroxyalantolactone and Ivangustin was 1102.46±247.04, 808.92±117.53 and 990.35±275.49 (ng h/mL), respectively.