**3. Conclusions**

Taking into account the research described above, the sesquiterpene lactones dealt with in this review have proved to be very useful compounds with promising anticancer and anti-inflammatory bioactivities in particular. For instance, alantolactone (**1**) was shown in vivo to be able to reduce tumor size by over 50%, while increasing life expectancy and reducing pathological indicators across several different cancer types. In addition, synergistic effects with well-known cancer therapeutics were also reported. Arglabin (**2**) in salt form could be used to treat several cancers and possesses valuable pharmacokinetic characteristics highly sought for in therapeutic drugs. It has no adverse effects described in the literature. Antitrypanosomal, antitumor and anti-inflammatory activities are reported for cynaropicrin (**4**). Another compound, helenalin (**5**), inhibits essential factors in both cancer and inflammation, i.e., the NF-κB pathway and the transcription of inflammatory cytokines. Inuviscolide (**6**) demonstrates potential as an anti-inflammatory therapeutic compound, being able to reduce rat ear and paw edema and LTB4 generation in intact cells. Lactucin (**7**) and derivatives lactupicrin (**8**) and lactucopicrin (**9**) have a strong potential as phytopharmaceutical agents for treatment of anxiety and sleep disorders, being the main active components of long commercialized substances, e.g., Sedan®, without observing side-effects.

Of all the sesquiterpene lactones reviewed in this work, parthenolide (**10**) and its derivatives DMAPT (**11**) and HMPPPT (**12**) are those most mentioned in the literature, with several studies particularly reporting their excellent anti-inflammatory and antitumor activities. Some work reveals synergistic effects of these compounds with current anticancer drugs, favoring more potent and selective antitumor action. Parthenolide derivatives have been designed and DMAPT (**11**) is 1000-fold more soluble in water than the natural product, while maintaining a similar mechanism of action with improved anticancer and anti-inflammatory activities.

Thapsigargin (**13**) has the particular capacity to cause endoplasmic reticulum stress and thus cell apoptosis, an interesting pharmacological property to be retained or potentiated in derivatives aimed at anticancer therapy. An example is mipsagargin (**14**), which is currently undergoing preclinical evaluation for selective toxicity against cancer cells in tumor sites, with minimal side-effects for the host. Another active compound is tomentosin (**15**), additionally with potential applications in cancer but also as antifungal and antifeedant.

In summary, given the activities described in this review these sesquiterpene lactones exhibit properties that justify more research by the scientific community, to drive preclinical and clinical studies leading to development of new drugs.

**Author Contributions:** Conceptualization, A.M.L.S. and L.M.; writing—original draft preparation, A.M.L.S., L.M., O.C., P.M.C.S., F.S.; writing—review and editing, L.M., O.C., A.M.L.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by FCT–Fundação para a Ciência e a Tecnologia, the European Union, QREN, FEDER, COMPETE, by funding the cE3c centre (UIDB/00329/2020), the LAQV-REQUIMTE (UIDB/50006/2020) and QOPNA (UID/QUI/00062/2019) research units, and by the Spanish Ministry Science and Research (MINECO RTI2018-094356-B-C21).

**Acknowledgments:** Thanks are due to the University of Azores and University of La Laguna. AbbVie participated in the revision of the manuscript.

**Conflicts of Interest:** O.C. is an employee of AbbVie and owns AbbVie stock. The authors L.M., P.M.C.S., F.S., and A.M.L.S. declare they have no conflict of interest.
