Structure-activity relationships for unsaturated dialdehydes 7. The membrane toxicity of 15 sesquiterpenoids measured as the induction of ATP leakage in ELD cells. The correlation of the activity with structural descriptors by the multivariate PLS method

Andersson, Marianne; Bocchio, Fabienne; Sterner, Olov; Forsby, Anna; Lewan, Lillemor

doi:10.1016/0887-2333(93)90106-f

Cited by 14 publications

(13 citation statements)

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“…It was proposed before that the activity of unsaturated dialdehydes depends on their accumulation in lipophilic parts of cells (e.g. membranes), their chemical reactivity towards SH groups of proteins associated with membranes and the way they may orient themselves within membrane structures . As we found our mutant strains to be resistant to marasmic acid, we further tested a set of unsaturated dialdehyde compounds.…”

Section: Resultsmentioning

confidence: 91%

“…Marasmic acid is a sesquiterpenoid with unsaturated dialdehyde functionality and was first isolated from the basidiomycete Marasmus conigenus more than half a century ago . The antibacterial, antifungal, cytotoxic and mutagenic activity was reported previously, and the suggested structure for the broad spectrum of activity was revealed to be the α , β ‐unsaturated aldehyde moiety . However, the detailed biological mode of action of marasmic acid was not elucidated.…”

Section: Introductionmentioning

confidence: 99%

“…However, the detailed biological mode of action of marasmic acid was not elucidated. Toxicity was assumed only regarding effects observed in membrane leakage assays, the AMES Salmonella test or an in vitro test for inhibition of RNA polymerase II . Structure–activity relationships were conducted with marasmic acid and sesquiterpenoid derivatives to understand structural features necessary for biological activity, but the molecular mechanism for the biological activity of marasmic acid has not been clarified in detail to date.…”

Section: Introductionmentioning

confidence: 99%

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Hog1p activation by marasmic acid through inhibition of the histidine kinase Sln1p

Jacob

Schüffler

Thines

2016

Pest Management Science

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BACKGROUNDThe histidine kinase (HK) MoHik1p within the high‐osmolarity glycerol (HOG) pathway is known to be the target of the fungicide fludioxonil. Treatment of the fungus with fludioxonil causes an uncontrolled hyperactivation of the pathway and cell death. In this study, we used a target‐based in vivo test system with mutant strains of the rice blast fungus Magnaporthe oryzae to search for new fungicidal compounds having various target locations within the HOG pathway. Mutants with inactivated HOG signalling are resistant to fungicides having the target located in the HOG pathway.RESULTSThe HK MoSln1p was identified as being involved in the new antifungal mode of action of marasmic acid, as single inactivation of the genes MoSLN1, MoSSK1, MoSSK2, MoPBS2 and MoHOG1 resulted in mutant strains resistant against the sesquiterpenoid, whereas the wild‐type strain and the ΔMohik1 mutant were susceptible. Western blot analysis of phosphorylated MoHog1p confirmed the hypothesis that marasmic acid interferes with the HOG pathway, as a strong phosphorylation of MoHog1p was detectable after sesquiterpenoid treatment in the wild‐type strain but not in the ΔMosln1 mutant.CONCLUSIONThis study provides evidence for marasmic acid activating the HOG pathway via the HK MoSln1p, and we propose that the sesquiterpenoid has a new mode of action in M. oryzae that differs from that of known HOG inhibitors, e.g. fludioxonil. © 2016 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

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Section: Resultsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hog1p activation by marasmic acid through inhibition of the histidine kinase Sln1p

Jacob

Schüffler

Thines

2016

Pest Management Science

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“…The plates were incubated for 2 days at 30°C before the number of CFU/ml was determined. Cells treated with polygodial grow on YPD plates even with a direct plating of 100 l, so CFU per milliliter can be read down to 10 1 . Results presented are the means of results of at least two independent assays.…”

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confidence: 99%

Effect of Polygodial on the Mitochondrial ATPase of Saccharomyces cerevisiae

Lunde¹,

Kubo

2000

Antimicrob Agents Chemother

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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 g/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.Systemic fungal infections are increasingly important causes of high morbidity and mortality (9, 18). Fungi are significantly affecting the growing population of patients with impaired immune systems due to AIDS, cancer chemotherapy, or immunosuppressive drugs. In addition to life-threatening systemic infection, superficial mycoses can clinically present as persistent infections that require continual treatment. Oropharyngeal and esophageal candidiasis occurs in over 70% of people with AIDS (46). With the increasing incidence of both systemic and superficial mycoses, it is critical that we develop new antifungal agents. Additionally, antifungal drug resistance has become an important problem and even further intensifies the need for new compounds (42, 54). Therefore, identifying promising cellular targets and understanding their physiological roles and basic biochemistry are critical for successful antifungal development (21,36).Polygodial (Fig. 1), a sesquiterpene dialdehyde, was originally isolated from the plant Polygonum hydropiper (3) and subsequently from Warburgia ugandensis and Warburgia stuhlmannii exhibiting insect antifeedant activity (28) and antimicrobial activity (48), as well as from Pseudowintera colorata exhibiting antimicrobial activity (34). Polygodial is a component of the "hot taste" in peppery spices of traditional Japanese cuisine (26). Unlike many other antifungal agents, polygodial has fungicidal activity against yeasts and...

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“…Compound 1 tastes hot to the human tongue and possesses antifeedant activities [45–47], both of which are evidently mediated through TRPV1-targeting [38–43] possibly through the formation of a covalent complex [38]. Encouraged by several earlier reports of cytotoxic activity associated with 1 [49–54], we prepared a series of its chemical derivatives and studied their TRPV1 agonistic and anticancer activities in detail. A related publication resulting from this study describes the discovery of useful anticancer activities associated with 9-epipolygodial [55].…”

Section: Introductionmentioning

confidence: 99%

Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines

Dasari

Carvalho

Medellin

et al. 2015

European Journal of Medicinal Chemistry

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Many types of cancer, including glioma, melanoma, non-small cell lung cancer (NSCLC), among others, are resistant to proapoptotic stimuli and thus poorly responsive to current therapies based on the induction of apoptosis in cancer cells. The current investigation describes the synthesis and anticancer evaluation of unique C12-Wittig derivatives of polygodial, a terpenenoid dialdehyde isolated from Persicaria hydropiper (L.) Delabre. These compounds were found to undergo an unprecedented pyrrole formation with primary amines in a chemical model system, a reaction that could be relevant in the biological environment and lead to the pyrrolation of lysine residues in the target proteins. The anticancer evaluation of these compounds revealed their promising activity against cancer cells displaying various forms of drug resistance, including resistance to proapoptotic agents. Mechanistic studies indicated that compared to the parent polygodial, which displays fixative general cytotoxic action against human cells, the C12-Wittig derivatives exerted their antiproliferative action mainly through cytostatic effects explaining their activity against apoptosis-resistant cancer cells. The possibility for an intriguing covalent modification of proteins through a novel pyrrole formation reaction, as well as useful activities against drug resistant cancer cells, make the described polygodial-derived chemical scaffold an interesting new chemotype warranting thorough investigation.

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Structure-activity relationships for unsaturated dialdehydes 7. The membrane toxicity of 15 sesquiterpenoids measured as the induction of ATP leakage in ELD cells. The correlation of the activity with structural descriptors by the multivariate PLS method

Cited by 14 publications

References 20 publications

Hog1p activation by marasmic acid through inhibition of the histidine kinase Sln1p

Hog1p activation by marasmic acid through inhibition of the histidine kinase Sln1p

Effect of Polygodial on the Mitochondrial ATPase of Saccharomyces cerevisiae

Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines

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