## 2 Sesquietpene Lactones with Significant In Vivo Activity
### Thapsigargin  
In 1978, the structure of thapsigargin (**13**) (C\({}_{34}\)H\({}_{50}\)O\({}_{12}\)) (Figure 10) was elucidated [230] for the first time. It was found as the main component of _Thapsia garganica_ L. [230,231], an umbelliferous Apiaceae species distributed in the Mediterranean area. This plant has long been used in folk medicine for treating common lung diseases (acute bronchitis and pneumonia) and dental pains [232]. The resin from _Thapsia garganica_ root was described in the French Pharmacopoeia [232].  
Thapsigargin (**13**) yield ranged between 0.2-4.91% of the dry weight of leaves and roots of _Thapsia garganica_ and depends on the plant tissue, collection site (locality) and extraction methods [231,233]. For example, classical maceration was more efficient than other methods such as microwave-assisted extraction or simple extraction with liquid nitrogen [233].  
Due to the importance of thapsigargin's biological activities, there is great interest in its synthetic and semi-synthetic preparation, thus several studies have been published on this subject [234,235].  
Thapsigargin (**13**) is an inhibitor of the sarco/endoplasmic reticulum (ER) calcium ATPase (SERCA) pump. The blockage of the SERCA pump results in malfunction of cellular calcium homeostasis and exerts a critical role in normal cell metabolism, leading to apoptosis [236,237]. Moreover, this sesquiterpene lactone causes apoptosis at all stages of the cell cycle.  
Compound **13** strongly inhibited all the subtypes of SERCA. The inhibitory constants (Ki) of thapsigargin (**13**) were 0.21, 1.3, and 12 nm for SERCA1b, SERCA2b, and SERCA3a, respectively [238; 239]. Its affinity with the SERCA1a pump is significantly reduced by removal of the acyl groups at O-3, O-8 and O-10 [240].  
Thapsigargin (**13**) possesses interesting pharmacological properties; for instance, it induces expression of the L-histidine decarboxylase enzyme responsible for converting L-histidine to histamine in cells [241]. It also evokes ROS generation in cells through calcium-ion mediated changes (mitochondrial depolarization), which can result in cell dysfunction and damage [242; 243]. In addition, compound **13** is known for its cytotoxic action against different cancer cell-lines, for instance melanoma [244], insulinoma [245; 246], neuronal [247], and breast [248].  
The thapsigargin LD\({}_{100}\) value is 0.8 mg/kg in mice [249]. [PERSON] et al. [250] proposed that thapsigargin causes vomiting by triggering the phosphorylation of CaMKII (Ca\({}^{2+}\)/calmodulin kinase II\(\alpha\)) and ERK1/2 (extracellular signal-regulated protein kinase 1/2) cascade in the brainstem. Pharmacological preconditioning with the cell-stress inducer thapsigargin (0.3 mg/kg) protects against experimental sepsis in male KM (Kunming) mice [237].  
Thapsigargin (**13**) is widely used as an experimental tool for endoplasmic reticulum stress inhibition and the discovery of new active therapeutic derivatives [232; 251]. A new thapsigargin (**13**) derivative named mipsagargin, (8-O-(12-aminododecanoyll)-8-O-debutanoyll thapsigargin)-Asp-\(\gamma\)-Glu-\(\gamma\)-GluGluOH (**14**) (Figure 10), has been developed for anticancer therapy, notably for the treatment of prostate cancer. Mipsagargin (**14**) has the ability to link the C-8 with prostate-specific membrane antigen (PSMA) peptide. It is a brand new example of a thapsigargin prodrug, which is currently undergoing preclinical evaluation as a targeted chemotherapeutic agent with selective toxicity against cancer cells [232; 249]. [PERSON] and coauthors reported that mipsagargin (**14**) has an acceptable pharmacokinetic profile in patients with solid tumors [252]. It is relatively well tolerated, promoting prolonged disease stabilization in patients with advanced liver cancer [253].