Abstract
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 here polyphenols' 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 potential modifiers. Our results offer a new technology towards rescuing bioactive polyphenols from their PAINS danger label through C–C ligation of sugars.
Highlights
The concept of Pan-Assay Interference Compounds (PAINS) is regarded as a threat to the recognition of the broad bioactivity of natural products
We have studied a set of polyphenols with known PAINS-type behavior related to membrane perturbation or membrane dipole modifying activity
We do have consistent results allowing to deduce that they are related to a membrane dipole modifying activity, as shown by di-8-ANEPPS fluorescence spectroscopy ratiometric measurements, with greater differences observed for cholesterol-containing membranes when compared to controls
Summary
The concept of Pan-Assay Interference Compounds (PAINS) is regarded as a threat to the recognition of the broad bioactivity of natural products. 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. PAINS were originally described by Baell & Holloway[1] as promiscuous molecules capable of interfering with high-throughput screening results, either by behaving as metal chelators, by perturbing membranes, or by nonspecific interactions with proteins, amongst other relevant phenomena Many of these compounds are natural products, among which genistein, resveratrol, epigallocatechin gallate (EGCG), quercetin or curcumin stand out for having been widely studied as potential therapeutic agents against a number of pathophysiological processes and conditions, including cancer2–4, inflammation5, diabetes[6], and Alzheimer’s disease[7,8,9,10].
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