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Publication details

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)
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA
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-Ciências - Centro de Química Estrutural-Ciências
Amélia P. Rauter (Author)
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA

Scope
International

Refereeing
Yes

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

Volume
11
Number
1

Number of pages
15

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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APA
Ana Marta de Matos, Maria Teresa Blázquez-Sánchez, Carla Sousa, Maria Conceição Oliveira, Rodrigo F. M. de Almeida, Amélia P. Rauter, (2021). C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations. Scientific Reports, 11, ISSN 2045-2322. eISSN . http://dx.doi.org/10.1038/s41598-021-83032-3

IEEE
Ana Marta de Matos, Maria Teresa Blázquez-Sánchez, Carla Sousa, Maria Conceição Oliveira, Rodrigo F. M. de Almeida, Amélia P. Rauter, "C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations" in Scientific Reports, vol. 11, 2021. 10.1038/s41598-021-83032-3

BIBTEX
@article{48725, author = {Ana Marta de Matos and Maria Teresa Blázquez-Sánchez and Carla Sousa and Maria Conceição Oliveira and Rodrigo F. M. de Almeida and Amélia P. Rauter}, title = {C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations}, journal = {Scientific Reports}, year = 2021, volume = 11 }