*2.10. Tomentosin*

Tomentosin (**15**) (Figure 11), known also as xanthalongin, is a xanthanolide sesquiterpene lactone with the same chemical formula as inuviscolide (**6**) and parthenolide (**10**) (C15H20O3). It has been isolated from plants such as *Dittrichia viscosa* (L.) Greuter, *Carpesium faberi* C. Winkl. and *Carpesium macrocephalum* Franch. and Sav. [254], *Leucophyta brownii* Cass. [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 tomentosin (**15**) [258] exhibited anti-inflammatory, antibacterial, and anticancer activities [257].

**Figure 11.** Structure of tomentosin (**15**).

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 Bar-Shalom et al. [259]. The authors found that application of an aqueous extract of *Inula viscosa* leaves at a concentration of 300 μg/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 Cohen 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 costic acid, which were identified as the active principles with antifungal activity. The overall results indicated that *Inula viscosa* extracts can be of grea<sup>t</sup> 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 Ahern et al. [261] on insecticidal activity, the effect of the stereochemistry of the lactone ring on feeding behavior of the herbivorous polyphagous grasshopper *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. However, the *trans*-fused compounds were consumed less than the corresponding *cis*-fused compounds. The results of this study not only permitted conclusions on the importance of the stereochemistry-dependence of diastereomeric sesquiterpene lactones for insecticidal activity, but also might help to understand the geographical distribution and evolution of different clades among the Asteraceae family. The distribution of *cis*- and *trans*-fused compounds within plants of this family is still not fully understood, in this study, 12.5% of the sampled Asteraceae genera contained only *cis*-fused sesquiterpene lactones, 64% only *trans*-fused sesquiterpene lactones, and 23% both types [261].
