Document type
Journal articles
Document subtype
Full paper
Title
C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations
Participants in the publication
Ana Marta de Matos (Author)
CQE
Maria Teresa Blázquez-Sánchez (Author)
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA
Carla Sousa (Author)
Maria Conceição Oliveira (Author)
Rodrigo F. M. de Almeida (Author)
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA
Dep. Química e Bioquímica
CQE
Amélia P. Rauter (Author)
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA
Summary
The concept of Pan-Assay Interference Compounds (PAINS) is regarded as a threat to the recognition of the broad bioactivity of natural products. Based on the established relationship between altered membrane dipole potential and transmembrane protein conformation and function, we investigate now polyphenol ability to induce changes in cell membrane dipole potential. Ultimately, we are interested in finding a tool to prevent polyphenol PAINS-type behavior and produce compounds less prone to untargeted and promiscuous interactions with the cell membrane. Di-8-ANEPPS fluorescence ratiometric measurements suggest that planar lipophilic polyphenols - phloretin, genistein and resveratrol - act by decreasing membrane dipole potential, especially in cholesterol-rich domains such as lipid rafts, which play a role in important cellular processes. These results provide a mechanism for their labelling as PAINS through their ability to disrupt cell membrane homeostasis. Aiming to explore the role of C-glucosylation in PAINS membrane-interfering behavior, we disclose herein the first synthesis of 4-glucosylresveratrol, starting from 5-hydroxymethylbenzene-1,3-diol, via C-glucosylation, oxidation and Horner-Wadsworth-Emmons olefination, and resynthesize phloretin and genistein C-glucosides. We show that C-glucosylation generates compounds which are no longer able to modify membrane dipole potential. Therefore, it can be devised as a strategy to generate bioactive natural product derivatives that no longer act as membrane dipole modifiers. Our results offer a new technology towards rescuing bioactive polyphenols from their PAINS danger label through C-C ligation of sugars.
Date of Publication
2021-02-24
Institution
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA
Where published
Scientific Reports
Publication Identifiers
ISSN - 2045-2322
Publisher
Springer Science and Business Media LLC
Document Identifiers
DOI -
https://doi.org/10.1038/s41598-021-83032-3
URL -
http://dx.doi.org/10.1038/s41598-021-83032-3
Rankings
Web Of Science Q1 (2020) - 3.998 - Multidisciplinary
Notes
Rauter AP and Almeida R are the corresponding authors
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