Semisynthetic Sesquiterpene Lactones Generated by the Sensibility of Glaucolide B to Lewis and Brønsted-Lowry Acids and Bases: Cytotoxicity and Anti-Inflammatory Activities.

Sesquiterpene lactone (SL) subtypes including hirsutinolide and cadinanolide have a controversial genesis. Metabolites of these classes are either described as natural products or as artifacts produced via the influence of solvents, chromatographic mobile phases, and adsorbents used in phytochemical studies. Based on this divergence, and to better understand the sensibility of these metabolites, different pH conditions were used to prepare semisynthetic SLs and evaluate the anti-inflammatory and antiproliferative activities. Therefore, glaucolide B (1) was treated with various Brønsted-Lowry and Lewis acids and bases-the same approach was applied to some of its derivatives-allowing us to obtain 14 semisynthetic SL derivatives, 10 of which are hereby reported for the first time. Hirsutinolide derivatives 7a (CC50 = 5.0 µM; SI = 2.5) and 7b (CC50 = 11.2 µM; SI = 2.5) and the germacranolide derivative 8a (CC50 = 3.1 µM; SI = 3.0) revealed significant cytotoxic activity and selectivity against human melanoma SK-MEL-28 cells when compared with that against non-tumoral HUVEC cells. Additionally, compounds 7a and 7c.1 showed strongly reduced interleukin-6 (IL-6) and nitrite (NOx) release in pre-treated M1 macrophages J774A.1 when stimulated with lipopolysaccharide. Despite the fact that hirsutinolide and cadinanolide SLs may be produced via plant metabolism, this study shows that acidic and alkaline extraction and solid-phase purification processes can promote their formation.

Octyl and dodecyl gallates induce oxidative stress and apoptosis in a melanoma cell line.

This study investigated the mechanism of cytotoxicity of octyl (G8) and dodecyl (G12) gallates in a murine melanoma cell line (B16F10). For this purpose, several methods to measure cell viability were used to determine if the cytotoxicity induced by these gallates corresponds to a general or an organelle-specific effect. Furthermore, the mechanisms related to apoptosis were examined, by studying the caspase-3 activity, oxidative stress, mitochondrial potential and the expression of anti- or proapoptotic proteins. When comparing the various methods of assessing cell viability, the tested gallates showed a higher cytotoxicity in the assay that indicates lysosomal activity, compared with the assays that indicate mitochondrial and ribosomal activities. Both gallates promoted the release of lactate dehydrogenase into the medium, indicating an effect on cell membrane integrity. The gallates also promoted cellular oxidative stress, mitochondrial depolarization and an increase in caspase-3 activity. Furthermore, the gallates induced an increase in proapoptotic (Bax) and a decrease in antiapoptotic (Bcl-2) proteins expression. Our results indicate that the apoptotic cell death induced by G8 and G12 in B16F10 cells involves lipid membrane damages, lysosomal and mitochondrial dysfunction, which was accompanied by alterations in apoptotic proteins expression and seems to be triggered by cellular oxidative stress.