## 2 Sesquietpene Lactones with Significant In Vivo Activity
### Parthenolide
For this reason, the efficacy of parthenolide is very promising for a therapeutic promotion of nerve regeneration, since compound application and recurrent treatments are facilitated, compared to invasive local nerve injections [202]. Pulmonary fibrosis (PF) in general and idiopathic pulmonary fibrosis (IPF) in particular, is a disease for which there is no effective therapy. In vivo studies have shown that parthenolide (**10**), via intragastric administration, inhibited the NF-kB/Snail pathway, attenuating bleomycin-induced pulmonary fibrosis. Moreover, there were significant improvements in body weight and other pathological changes associated with this disease [203]. NF-kB has been associated with the cardiovascular system; in fact, its function is related to the protection of cardiovascular tissues against injuries. However, its activation can also contribute to tissue pathogenesis, depending on the type of cells in which it is activated [204]. It is known that myocardial infarct size could be reduced up to 60% by antagonizing NF-kB activity [205]. To achieve this, parthenolide (**10**) at 250 or 500 mg/kg (b.w.) was administered intraperitoneally before reperfusion in rats, and caused a significant improvement in myocardial injury, with a reduction in the oxidative and inflammation state, consequently reducing infarct size [206]. However, [PERSON] et al. [207] reported that a prolonged treatment in bEND.3 cells affected Ca2p signaling in the endothelial cells that regulate vascular tone; therefore, care should be taken on using this compound in experimental designs and clinically. Parthenolide (**10**) has relatively poor pharmacological properties, derived from its low solubility in water and consequently reduced bioavailability, which limit its potential clinical use as anticancer drug. To increase its solubility, a series of parthenolide derivatives were obtained by diastereoselective addition of several primary and secondary amines to the exocyclic double bond [208, 209]. \(N\),\(N\)-Dimethylaminopenthelide (DMAPT) (**11**) (Figure 9) was selected as a leader compound according to its pharmacokinetic, pharmacodynamic and bioavailability properties [209, 210]. When formulated as a fumarate salt, DMPAPT is 1000-fold more soluble in water than parthenolide and maintained the anticancer activity because, DMAPT (**11**) is rapidly converted back to parthenolide in body fluids (**10**). Recently, molecular studies indicate that DMAPT has a similar action to parthenolide [192, 211, 212, 213]. DMAPT has approximately 70% oral bioavailability and induces rapid death of primary human leukemia stem cells (LSCs) from both myeloid and lymphoid leukemias and is highly cytotoxic to bulk leukemic cell populations. Pharmacological studies carried out by [PERSON] et al. [210] using both mouse xenograft models and spontaneous acute canine leukemias demonstrate in vivo bioactivity. Indeed, DMAPT eliminates human AML stem and progenitor cells without harm to normal hematopoietic stem and progenitor cells, and eradicates phenotypically primitive blast-crisis chronic myeloid leukemia (bcCML) and acute lymphoblastic leukemia (ALL) cells. Moreover, it inhibited metastasis in a mouse xenograft model of breast cancer and enhanced the survival of treated mice [210]. DMAPT was assayed in a phase I trial against acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and other blood and lymph node cancers [12, 176]. However, a year later the clinical trials were suspended [214]. Radiotherapy is widely used in cancer treatment; however, the benefits can be reduced by radiation-induced damage to neighboring healthy tissues. [PERSON] et al. [215] demonstrated in mice that DMAPT (**11**) selectively induces radio-sensitivity in prostate cancer cell-lines, while protecting primary prostate epithelial cell lines from radiation-induced damage. Compound 11 has the advantage of being well-tolerated orally without the need to adjust the administration time to radiation exposure.