Functional dereplication of marine natural products by integrative high-content image-based cytological screening and computational-assisted untargeted metabolomics

Abstract

Metabolomics-based approaches using modern mass spectrometry techniques have been recognized as the most powerful strategy to explore the chemical and bioactivity diversities in natural products. In marine NP, issues to access marine life and elucidate the usual complex structures at small scale demand new tools to improve the identification of bioactive compounds. In this context, dereplication methods using modern mass spectrometry techniques and high throughput screening (HTS) bioassays has emerge as a rapid way of identifying known compounds in bioactive marine extracts. Still, the lack of general HPLC-MS databases restricts the possibility of prediction and automation in the dereplication process. In addition, most HTS bioassays are incapable of directly predicting the modes of action of bioactive constituents at early stages of NP discovery. Here we propose development of new approaches for in silico annotation of natural product libraries based on MS/MS fragmentation pathways, considering the 'marine metabolite-likeness' properties, and questions related to gas-phase reactivity, as differential ionization, and concomitant acid-base and/or redox reactions. Additionally, we intent to apply the Compound Activity Mapping concept to assess the cytological potential and possible mechanisms of action of complex matrices from Brazilian marine organisms via integrative image-based phenotypic screening in HeLa cells with high-resolution untargeted metabolomics analysis. (AU)