Polygodial

Probing the Structure-Activity Relationship of the Natural Antifouling Agent Polygodial against both Micro- and Macrofoulers by Semisynthetic Modification.[Pubmed:28170258]

J Nat Prod. 2017 Feb 24;80(2):515-525.

The current study represents the first comprehensive investigation into the general antifouling activities of the natural drimane sesquiterpene Polygodial. Previous studies have highlighted a high antifouling effect toward macrofoulers, such as ascidians, tubeworms, and mussels, but no reports about the general antifouling effect of Polygodial have been communicated before. To probe the structural and chemical basis for antifouling activity, a library of 11 Polygodial analogues was prepared by semisynthesis. The library was designed to yield derivatives with ranging polarities and the ability to engage in both covalent and noncovalent interactions, while still remaining within the drimane sesquiterpene scaffold. The prepared compounds were screened against 14 relevant marine micro- and macrofouling species. Several of the Polygodial analogues displayed inhibitory activities at sub-microgram/mL concentrations. These antifouling effects were most pronounced against the macrofouling ascidian Ciona savignyi and the barnacle Balanus improvisus, with inhibitory activities observed for selected compounds comparable or superior to several commercial antifouling products. The inhibitory activity against the microfouling bacteria and microalgae was reversible and significantly less pronounced than for the macrofoulers. This study illustrates that the macro- and microfoulers are targeted by the compounds via different mechanisms.

Polygodial, a sesquiterpene isolated from Drimys brasiliensis (Winteraceae), triggers glucocorticoid-like effects on pancreatic beta-cells.[Pubmed:27645309]

Chem Biol Interact. 2016 Oct 25;258:245-56.

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 beta-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.

Synthetic and Biological Studies of Sesquiterpene Polygodial: Activity of 9-Epipolygodial against Drug-Resistant Cancer Cells.[Pubmed:26434977]

ChemMedChem. 2015 Dec;10(12):2014-26.

Polygodial, a terpenoid dialdehyde isolated from Polygonum hydropiper L., is a known agonist of the transient receptor potential vanilloid 1 (TRPV1). In this investigation a series of Polygodial analogues were prepared and investigated for TRPV1-agonist and anticancer activities. These experiments led to the identification of 9-epiPolygodial, which has antiproliferative potency significantly exceeding that of Polygodial. 9-EpiPolygodial was found to maintain potency against apoptosis-resistant cancer cells as well as those displaying the multidrug-resistant (MDR) phenotype. In addition, the chemical feasibility for the previously proposed mechanism of action of Polygodial, involving the formation of a Paal-Knorr pyrrole with a lysine residue on the target protein, was demonstrated by the synthesis of a stable Polygodial pyrrole derivative. These studies reveal rich chemical and biological properties associated with Polygodial and its direct derivatives. These compounds should inspire further work in this area aimed at the development of new pharmacological agents, or the exploration of novel mechanisms of covalent modification of biological molecules with natural products.

In vitro modulation of Drimys winteri bark extract and the active compound polygodial on Salmo salar immune genes after exposure to Saprolegnia parasitica.[Pubmed:27777106]

Fish Shellfish Immunol. 2016 Dec;59:103-108.

The rapid development of the aquaculture industry has global concerns with health management and control strategies to prevent and/or treat diseases and increase sustainability standards. Saprolegniosis is a disease caused by Saprolegnia parasitica, and is characterized by promoting an immunosuppression in the host. This study evaluated in vitro the extract and one active compound (Polygodial) of Drimys winteri, a Chilean medicinal tree as a potential early immunostimulatory aid in Saprolegniosis control. Atlantic salmon (Salmo salar) head kidney cells (ASK-1) were incubated with both extract and pure Polygodial before exposure to S. parasitica mycelium, and the expression of the immune-related genes interleukin 1beta (IL-1beta), interferon alpha (IFNalpha), and major histocompatibility complex II (MHCII) was evaluated. Both evidenced immunomodulatory capacities by increasing gene expressions. This immunomodulation related to a mitigatory action counteracting the immunosuppressing effects of S. parasitica. Despite that most immune-related genes were up-regulated, the down-regulation of MHCII, characteristic of S. parasitica infection, was lessened by pre-incubation with the compounds. This study provides the first insight on the potential of D. winteri bark extract as a possible immunomodulatory and defensive strategy against this oomycete infection in fish.

TRPA1 mediates the noxious effects of natural sesquiterpene deterrents.[Pubmed:18550530]

J Biol Chem. 2008 Aug 29;283(35):24136-44.

Plants, fungi, and animals generate a diverse array of deterrent natural products that induce avoidance behavior in biological adversaries. The largest known chemical family of deterrents are terpenes characterized by reactive alpha,beta-unsaturated dialdehyde moieties, including the drimane sesquiterpenes and other terpene species. Deterrent sesquiterpenes are potent activators of mammalian peripheral chemosensory neurons, causing pain and neurogenic inflammation. Despite their wide-spread synthesis and medicinal use as desensitizing analgesics, their molecular targets remain unknown. Here we show that isovelleral, a noxious fungal sesquiterpene, excites sensory neurons through activation of TPRA1, an ion channel involved in inflammatory pain signaling. TRPA1 is also activated by Polygodial, a drimane sesquiterpene synthesized by plants and animals. TRPA1-deficient mice show greatly reduced nocifensive behavior in response to isovelleral, indicating that TRPA1 is the major receptor for deterrent sesquiterpenes in vivo. Isovelleral and Polygodial represent the first fungal and animal small molecule agonists of nociceptive transient receptor potential channels.

Effect of polygodial on the mitochondrial ATPase of Saccharomyces cerevisiae.[Pubmed:10858359]

Antimicrob Agents Chemother. 2000 Jul;44(7):1943-53.

The fungicidal mechanism of a naturally occurring sesquiterpene dialdehyde, Polygodial, was investigated in Saccharomyces cerevisiae. In an acidification assay, Polygodial completely suppressed the glucose-induced decrease in external pH at 3.13 microgram/ml, the same as the fungicidal concentration. Acidification occurs primarily through the proton-pumping action of the plasma membrane ATPase, Pma1p. Surprisingly, this ATPase was not directly inhibited by Polygodial. In contrast, the two other membrane-bound ATPases in yeast were found to be susceptible to the compound. The mitochondrial ATPase was inhibited by Polygodial in a dose-dependent manner at concentrations similar to the fungicidal concentration, whereas the vacuolar ATPase was only slightly inhibited. Cytoplasmic petite mutants, which lack mitochondrial DNA and are respiration deficient, were significantly less susceptible to Polygodial than the wild type, as was shown in time-kill curves. A pet9 mutant which lacks a functional ADP-ATP translocator and is therefore respiration dependent was rapidly inhibited by Polygodial. The results of these susceptibility assays link enzyme inhibition to physiological effect. Previous studies have reported that plasma membrane disruption is the mechanism of Polygodial-induced cell death; however, these results support a more complex picture of its effect. A major target of Polygodial in yeast is mitochondrial ATP synthase. Reduction of the ATP supply leads to a suppression of Pma1 ATPase activity and impairs adaptive responses to other facets of Polygodial's cellular inhibition.