## 2 Sesquietpene Lactones with Significant In Vivo Activity
### Tometosin  
Tomentosin (**15**) (Figure 11), known also as xanthalongin, is a xanthalotide sesquiterpene lactone with the same chemical formula as invusicolide (**6**) and parthenolide (**10**) (C\({}_{15}\)H\({}_{20}\)O\({}_{3}\)). It has been isolated from plants such as _Dittrichia viscosa_ ([PERSON]) [PERSON], _Carpesium faberi_ [PERSON]. [PERSON] and _Carpesium macrocephalum_ [PERSON] and [PERSON]. [254], _Leucophyta brownii_ [PERSON]. [255], the sunflower (_Helianthus annuus_ L.) [256] and _Inula_ species [254; 257]. _Inula viscosa_ was widely used as a medicinal plant. A steam distilled extract of its leaves and flowers yielding 2% of tometosin (**15**) [258] exhibited anti-inflammatory, antibacterial, and anticancer activities [257]. Figure 10: Structure of thapsigargin (**13**) and its derivative mipsagargin (**14**). The biological activities of tomentosin (**15**) have been addressed in several studies focused on anticancer, antifungal, and insecticidal activities. Anticancer activity observed in vitro tests was confirmed by in vitro and in vivo studies performed by [PERSON] et al. [259]. The authors found that application of an aqueous extract of _Inula viscosa_ leaves at a concentration of 300 \(\mu\)g/mL to colorectal cancer cells induced apoptosis, through activation of caspases. During the subsequent in vivo study, mice transplanted with MC38 cells were treated intraperitoneally with the extract at concentrations of 150 and 300 mg/kg. The results indicated that tumor weight and volume were reduced significantly by this treatment after comparison with the untreated control group. Furthermore, staining the paraffin section of the tumors showed inhibition of cell proliferation, as well as induction of apoptosis. Interestingly, side effects, which often include weight loss, impact on fur, and changes in behavior or kidney or liver functions, were not observed. This suggests that the extract was non-toxic at the concentrations applied. However, this remains to be confirmed [259]. Fungal infection of grapevines causes severe economic damage to grape producers. As several fungicide-resistant strains of the pathogens have developed, efective fungicide application is becoming more and more difficult. Therefore, natural products such as sesquiterpene lactones and plant extracts may provide alternatives to current synthetic fungicides. The antifungal activity of six _Inula viscosa_ leaf extracts on downy mildew under field conditions was addressed in the study performed by [PERSON] et al. [260]. This mildew is caused by the fungus _Plasmopara viticola_ (Berk. and Curt.). The results established that the effective concentration of oily paste extract in water required to control 90% of the treated shoots in the field was lower than 0.125%. For whole vines, the required concentration ranged between 0.30% and 0.37%. Additionally, the results did not appear to depend on seasonal fluctuations. The evaluated leaf extracts contained 10.6% of tomentosin (**15**) and 10.6% of cystic acid, which were identified as the active principles with antifungal activity. The overall results indicated that _Inula viscosa_ extracts can be of great value as an alternative source for non-synthetic fungicidal preparations to treat downy mildew infestations of grapes [260]. In an in vivo investigation performed by [PERSON] et al. [261] on insecticidal activity, the effect of the stereochemistry of the lactone ring on feeding behavior of the herbivorous polyphagous grassshopper _Schistocerca americana_ (Drury) was addressed. _Schistocerca americana_ is locally related in the south of the U.S. to significant damage to crops when temporary mass populations occur. To evaluate the antifeedant activity of diastereomeric sesquiterpene lactones, the study focused on tomentosin (**15**) with a _cis_-configuration and the corresponding isomer xanthinosin with a _trans_-configuration. The results showed both compounds were able to reduce plant consumption by the insects.