Targeted isolation of selaginellin derivatives using molecular networking strategy enhanced by in silico annotation

Selaginellins, unique pigments found in the genus Selaginella, were reported as potent phosphodiesterase-4 (PDE4) inhibitors in recent studies. To isolate diverse natural selaginellin derivatives, we applied a MS/MS based molecular networking strategy enhanced by in silico structural annotation to the Selaginella tamariscina extracts. It led to the prioritization of chromatographic peaks predicted as previously unknown selaginellin derivatives. As a result, we could isolate ten unknown compounds containing two unusual selaginellin analogs with 1H,3H-dibenzo[de,h]isochromene skeleton named selariscins A (1) and B (2) along with eight diarylfluorene derivatives, selaginpulvilins M−T (3−10). The absolute configurations were elucidated by computational electronic circular dichroism (ECD) spectral calculations. Some isolates showed PDE4 inhibitory activity with IC₅₀ values in the range of 2.8−33.8 μM, and their binding modes were suggested using a molecular docking study.

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