Polygodial, a sesquiterpene isolated from Drimys brasiliensis (Winteraceae), triggers glucocorticoid-like effects on pancreatic ß-cells.

Despite its common use, the synthetic glucocorticoid dexamethasone can cause several adverse effects, such as diabetes and insulin-related metabolic impairment. Thus, research on molecules that could provide the same anti-inflammatory response with milder side effects is constant. In this work the anti-inflammatory activity of the natural sesquiterpene polygodial, extracted from the endemic Brazilian plant Drimys brasiliensis Miers (Winteraceae), was investigated. Employing a pancreatic ß-cell model (INS 1E), the effect of polygodial on signaling pathways is similar to that caused by dexamethasone - both increased MKP1 and decreased ERK1/2 expression in a dose-response and time-dependent manner. Relating to such finding, nuclear translocation of the glucocorticoid receptor was also discovered to be induced by the sesquiterpene. Molecular modeling results indicated that polygodial was capable of docking to the glucocorticoid receptor, but presented preference for the Arg611 binding site rather than Thr739 when set to bind freely inside the pocket. At last, fragmentation of DNA was verified as consequence of sesquiterpene-induced cell death. Altogether, our results suggest that, like dexamethasone, polygodial interacts the glucocorticoid receptor ligand binding domain but create fewer ligand-protein interactions at the site, yielding a weaker effector response. Such property provides an advantage when regarding the adverse effects resulting from stronger affinity ligands of the glucocorticoid receptor, such as in the case of the current standard dexamethasone-based treatment. This aspect, also, turns polygodial an interesting hit compound to the development of new drugs based on its backbone structure providing less harmful anti-inflammatory treatments.

Alchornedine, a new anti-trypanosomal guanidine alkaloid from Alchornea glandulosa.

Bioactivity-guided fractionation of the MeOH extract from the leaves of Alchornea glandulosa afforded a new guanidine alkaloid named alchornedine, as well as two other inactive derivatives (pteroginine and pteroginidine). The structure of alchornedine, which shows a very rare ring system, was elucidated based on NMR, IR, and MS spectral analyses. This compound displayed antiprotozoal activity against Trypanosoma cruzi (Y strain). By using the MTT assay, the trypomastigotes showed an IC50 value of 93 µg/mL (443 µM), a similar effectiveness to the standard drug benznidazole. Alchornedine also showed activity against the intracellular amastigotes, with an IC50 value of 27 µg/mL (129 µM). Using benznidazole as a standard drug, this guanidine alkaloid was approximately 3-fold more effective against the intracellular form of T. cruzi. The mammalian cytotoxicity of alchornedine was verified against NCTC cells and demonstrated an IC50 of 50 µg/mL (237 µM), but this compound demonstrated a selective elimination of parasites inside macrophages without affecting the morphology of the host cells. Alchornedine was effective against both clinical forms of T. cruzi and could be used as a scaffold for future drug design studies against American trypanosomiasis.

Structure-activity association of flavonoids in lung diseases.

Flavonoids are polyphenolic compounds classified into flavonols, flavones, flavanones, isoflavones, catechins, anthocyanidins, and chalcones according to their chemical structures. They are abundantly found in Nature and over 8,000 flavonoids have from different sources, mainly plant materials, have been described. Recently reports have shown the valuable effects of flavonoids as antiviral, anti-allergic, antiplatelet, antitumor, antioxidant, and anti-inflammatory agents and interest in these compounds has been increasing since they can be helpful to human health. Several mechanisms of action are involved in the biological properties of flavonoids such as free radical scavenging, transition metal ion chelation, activation of survival genes and signaling pathways, regulation of mitochondrial function and modulation of inflammatory responses. The anti-inflammatory effects of flavonoids have been described in a number of studies in the literature, but not frequently associated to respiratory disease. Thus, this review aims to discuss the effects of different flavonoids in the control of lung inflammation in some disorders such as asthma, lung emphysema and acute respiratory distress syndrome and the possible mechanisms of action, as well as establish some structure-activity relationships between this biological potential and chemical profile of these compounds.