Synthesis and discovery of a drug candidate for treatment of idiopathic pulmonary fibrosis through inhibition of TGF-ß1 pathway.

In this study, anti-IPF lead compounds 42 and 44, derived from natural sesquiterpene lactones Isoalantolactone and alantolactone, were discovered by screening from a high-throughput TGF-ß1 reporter luciferase assay. Notably, they could reduce the myofibroblast activation and extracellular matrix deposition both in vitro and in vivo. Additionally, compounds 42 and 44 could significantly attenuate bleomycin-induced pulmonary fibrosis in mice. Further validation of pharmacokinetics study and toxicity evaluation indicated that compound 44 might be a promising anti-IPF drug candidate.

Semisynthesis, an Anti-Inflammatory Effect of Derivatives of 1ß-Hydroxy Alantolactone from Inula britannica.

1ß-hydroxy alantolactone, a sesquiterpene lactone mainly isolated from Inula genus plants, exhibits potent anti-inflammatory and anticancer activities. In this work, 1ß-hydroxy alantolactone was isolated and five derivatives were prepared through different reactions at the C1-OH and C13-methylene motifs. The structure-activity relationships (SAR) of anti-inflammatory effects against NO production in RAW264.7 cells showed that the α-methylene-γ-butyrolactone motif was essential for NO production suppression and that retaining the C1-OH group can remarkably improve this effect. The NF-κB signaling pathway plays a pivotal role in the regulation of NO expression. Moreover, the levels of p65 and p50 phosphorylation were investigated and active compound 1 inhibited phosphorylation of p65 and p50 in TNF-α-induced NF-κB signaling. Further molecular docking suggested that 1 may target the p65 of NF-κB.

Synthesis of 13-amino telekin derivatives and their cytotoxic activity.

Telekin is a eudesmane sesquiterpene-lactone naturally occurring in many medicinal plants with antitumour and anti-inflammatory activity. In this study, a series of 13-amino derivatives of telekin have been synthesised through Michael addition reaction, and their relative configurations were exemplified by the single crystal X-ray diffraction of the dimethylamine adduct. The in vitro cytotoxicity against three tumour cell lines of these amine derivatives was evaluated. The piperidine and 4-hydroxypiperidine adducts displayed stronger cytotoxic activity than telekin.

Eudesmanes from Pluchea sagittalis. Their antifeedant activity on Spodoptera frugiperda.

Eudesmane-type sesquiterpenoids 3alpha-(2,3-epoxy-2-methylbutyryloxy)-4alpha-formoxy-11-hydroxy-6,7-dehydroeudesman-8-one (1) and 3alpha-(2,3-epoxy-2-methylbutyryloxy)-4alpha,7alpha,11-trihydroxyeudesman-8-one (2), together with 10 known structurally related eudesmanes were isolated from the CHCl3 extract of aerial parts of Pluchea sagittalis (Lamarck) Cabrera. Their structures were deduced by extensive application of 1 and 2D NMR spectroscopic techniques and high and low resolution CIMS. X-ray crystallographic analysis of the known compound 3alpha-(2,3-epoxy-2-methylbutyryloxy)-4alpha-formoxycuauthemone (9) is reported here for the first time, and confirms the structural features for the series of the reported eudesmanes. All eudesmanes were tested for their antifeedant activity by incorporating them to an artificial diet of larvae of the polyphagous insect Spodoptera frugiperda at a concentration of 100ppm. Our results, from feeding choice tests, indicated that most of the compounds deter larval feeding at the cited concentration.