Hapalindoles from the Cyanobacterium Fischerella: Potential Sodium Channel Modulators

Abstract

Hapalindoles make up a large group of bioactive metabolites of the cyanobacterial order Stigonematales. 12-epi -Hapalindole E isonitrile, 12-epi -hapalindole C isonitrile, 12-epi -hapalindole J isonitrile, and hapalindole L from Fischerella are acutely toxic for insect larvae; however, the biochemical targets responsible for the biological activities of hapalindoles are not understood. We describe here the electron impact mass spectra of these four hapalindole congeners; their structures were confi rmed by nuclear magnetic resonance spectroscopy. In combination with the presented mass spectra of 15 N-labeled species and their retention times on a gas chromatography capillary column, a rapid and reliable determination should be possible in future research. The bioactivity of these hapalindoles was tested on mammalian cells focusing on their eff ects in the BE(2)-M17 excitable human neuroblastoma cell line. The fl uorescent dye Alamar Blue was applied to monitor cytotoxicity, fura-2 to evaluate changes in the cytosolic calcium concentrations, and bis-oxonol to detect eff ects on membrane potential. Data showed that the hapalindoles did not aff ect cell viability of the neuroblastoma cells, even when they were incubated for 72 h. Neither depolarization nor initiation of calcium infl ux was observed in the cells upon hapalindole treatment. However, the data provide evidence that hapalindoles are sodium channel-modulating neurotoxins. They inhibited veratridine-induced depolarization in a manner similar to that of neosaxitoxin. Our data suggest hapalindoles should be added to the growing number of neurotoxic secondary metabolites, such as saxitoxins and anatoxins, already known in freshwater cyanobacteria. As stable congeners, hapalindoles may be a risk in freshwater ecosystems or agricultural water usage and should therefore be considered in water quality assessment.

Published in

Chemical Research in Toxicology
2014, volume: 27, number: 10, pages: 1696–1706

SLU Authors

• Becher, Paul

  • University of Zürich

Associated SLU-program

Organic risk substances and metals (until May 2010)
Eutrophication
Lakes and watercourses

Global goals (SDG)

SDG6 Clean water and sanitation

UKÄ Subject classification

Zoology
Microbiology
Ecology

Publication identifier

• DOI: https://doi.org/10.1021/tx500188a

Permanent link to this page (URI)

https://res.slu.se/id/publ/66155