Marine Fungi as Producers of Benzocoumarins, a New Class of Inhibitors of Glycogen-Synthase-Kinase 3β.

Jutta Wiese,Tobias Gulder,Rolf Schmaljohann,Johannes Imhoff,Antje Labes

doi:10.3390/md14110200

Abstract

The glycogen-synthase-kinase 3 (GSK-3) is an important target in drug discovery. This enzyme is involved in the signaling pathways of type 2 diabetes, neurological disorders, cancer, and other diseases. Therefore, inhibitors of GSK-3 are promising drug candidates for the treatment of a broad range of diseases. Here we report pannorin (1), alternariol (2), and alternariol-9-methylether (3) to be promising inhibitors of the isoform GSK-3β showing sub-μM IC50 values. The in vitro inhibition is in the range of the known highly active GSK-3β inhibitor TDZD-8. Compounds 1–3 have a highly oxygenated benzocoumarin core structure in common, which suggests that this may be a new structural feature for efficient GSK-3β inhibition.

Highlights

Marine environments such as deep sea habitats and macroorganisms provide a great diversity of fungi which are still an underrepresented resource for new drug candidates [1,2]
The glycogen synthase-kinase GSK-3β provides a valuable target for drug discovery
GSK-3β is a therapeutic target for neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and for diabetes [4,5,6,7]

Summary

Introduction

Marine environments such as deep sea habitats and macroorganisms provide a great diversity of fungi which are still an underrepresented resource for new drug candidates [1,2]. Natural products produced by marine fungi comprise a large variety of compound classes. As there is a strong need for the discovery of new drugs, for a number of important diseases, the search for bioactive compounds in marine fungi is a timely task. The glycogen synthase-kinase GSK-3β provides a valuable target for drug discovery. GSK-3β is a therapeutic target for neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and for diabetes [4,5,6,7]. GSK-3β has been discussed as a potential target for the treatment of cancer [8]. Among them are 6-bromoindirubin, dibromocantherelline, and meridianine A, isolated from a marine mollusk, sponge, and tunicate, respectively [9]

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Discussion

Conclusion