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Abstract
In natural products (NP) research, methods for the efficient prioritization of natural extracts (NEs) are key for discovering novel bioactive NPs. In this study a biodiverse collection of 1600 NEs, previously analyzed by UHPLC-HRMS2 metabolite profiling was screened for Wnt pathway regulation. The results of the biological screening drove the selection of a subset of 30 non-toxic NEs with an inhibitory IC50 ≤ 5 μg/mL. To increase the chance of finding structurally novel bioactive NPs, Inventa, a computational tool for automated scoring of NEs based on structural novelty was used to mine the HRMS2 analysis and dereplication results. After this, 4 out of the 30 bioactive NEs were shortlisted by this approach. The most promising sample was the ethyl acetate extract of the leaves of Hymenocardia punctata (Phyllanthaceae). Further phytochemical investigations of this species resulted in the isolation of three known prenylated flavones (3, 5, 7) and ten novel bicyclo[3.3.1]non-3-ene-2,9-diones (1, 2, 4, 6, 8-13), named Hymenotamayonins. Assessment of the Wnt inhibitory activity of these compounds revealed that two prenylated flavones and three novel bicyclic compounds showed interesting activity without apparent cytotoxicity. This study highlights the potential of combining Inventa's structural novelty scores with biological screening results to effectively discover novel bioactive NPs in large NE collections.
Supplementary materials
Title
Integration of Wnt-inhibitory Activity and Structural Novelty Scoring Results to Uncover Novel Bioactive Natural Products: New Bicyclo[3.3.1]non-3-ene-2,9-diones from the Leaves of Hymenocardia punctata. Supporting Information
Description
The Supplementary Material for this article can be found online at:
Table SI shows a resume of selected annotations for HPE extract in PI mode.
Table SII shows the Wnt-regulation bioactivity results for the pooled fraction derived from the micro fractionation of the HPE extract.
Figure S1 shows the Molecular Networking and dereplication results for H. punctacta original extract.
Figure S2-S3 show the Molecular Networking and dereplication results for H. punctacta de novo extracts.
Figure S4 describes the micro fractionation strategy.
Figure S5 shows the Tautomeric equilibrium present in compounds 2, 8, 10 and 11.
Figure S6 shows the comparisons between the experimental and calculate Electronic Circular Dichroism (ECD) spectra for compounds 1-13 in methanol.
Figures S7 shows the Wnt-regulation bioactivity curves results for the active compounds 1, 2, 3, 4 and 7.
Figures S8− S84 show the 1D and 2D NMR analysis for the isolated compounds 1-13.
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Supplementary weblinks
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YARETA repository
Description
The raw data files for the NMR and ECD (calculated and experimental) analysis
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