AUTHOR=Quiros-Guerrero Luis-Manuel , Marcourt Laurence , Chaiwangrach Nathareen , Koval Alexey , Ferreira Queiroz Emerson , David Bruno , Grondin Antonio , Katanaev Vladimir L. , Wolfender Jean-Luc 

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

JOURNAL=Frontiers in Chemistry

VOLUME=12

YEAR=2024

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2024.1371982

DOI=10.3389/fchem.2024.1371982

ISSN=2296-2646

ABSTRACT=<p>In natural products (NPs) research, methods for the efficient prioritization of natural extracts (NEs) are key for discovering novel bioactive NPs. In this study a biodiverse collection of 1,600 NEs, previously analyzed by UHPLC-HRMS<sup>2</sup> 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 IC<sub>50</sub> ≤ 5 <italic>μ</italic>g/mL. To increase the chance of finding structurally novel bioactive NPs, <italic>Inventa</italic>, a computational tool for automated scoring of NEs based on structural novelty was used to mine the HRMS<sup>2</sup> analysis and dereplication results. After this, four out of the 30 bioactive NEs were shortlisted by this approach. The most promising sample was the ethyl acetate extract of the leaves of <italic>Hymenocardia punctata</italic> (Phyllanthaceae). Further phytochemical investigations of this species resulted in the isolation of three known prenylated flavones (<bold>3</bold>, <bold>5</bold>, <bold>7</bold>) and ten novel bicyclo[3.3.1]non-3-ene-2,9-diones (<bold>1</bold>, <bold>2</bold>, <bold>4</bold>, <bold>6</bold>, <bold>8</bold>–<bold>13</bold>), named <italic>Hymenotamayonins</italic>. 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 <italic>Inventa</italic>’s structural novelty scores with biological screening results to effectively discover novel bioactive NPs in large NE collections.</p>