Molecular Networking Reveals the Chemical Diversity of Selaginellin Derivatives, Natural Phosphodiesterase-4 Inhibitors from Selaginella tamariscina

Abstract

Selaginellins are unique pigments found in the genus Selaginella, the largest genus of Lycopodiophyta. Recent studies reported that some selaginellin analogues have potent phosphodiesterase-4 (PDE4) inhibitory activity. In this study, the chemical diversity of natural selaginellin derivatives was revealed by an MS/MS molecular networking-based dereplication of the Selaginella tamariscina extract. It led to the prioritization of chromatographic peaks predicted as previously unknown selaginellin derivatives. Targeted isolation of these compounds afforded two unusual selaginellin analogues with a 1H,3H-dibenzo[de,h]isochromene skeleton, namely, selariscins A (1) and B (2), along with eight new diarylfluorene derivatives, selaginpulvilins M-T (3-10), and five known analogues, 11-15. The absolute configurations of 1, 2, and 8-10 were elucidated by spectroscopic data analyses including computational electronic circular dichroism data. Compounds 1 and 3-10 showed PDE4 inhibitory activity with IC50 values in the range of 2.8-33.8 mu M, and their binding modes are suggested by a molecular docking study.