BIBLIOS

Tipo
Artigos em Revista

Tipo de Documento
Artigo Completo

Título
C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations

Participantes na publicação
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

Resumo
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.


Instituição
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA

Suporte
Scientific Reports

Identificadores da Publicação
ISSN - 2045-2322

Editora
Springer Science and Business Media LLC



Identificadores do Documento
DOI - https://doi.org/10.1038/s41598-021-83032-3
URL - http://dx.doi.org/10.1038/s41598-021-83032-3

Identificadores de Qualidade
Web Of Science Q1 (2020) - 3.998 - Multidisciplinary

Anotações
Rauter AP and Almeida R are the corresponding authors

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