The prenylation code regulating estrogenic activity of synthetic and natural product derivatives of resveratrol

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ID: 331929
2026
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Abstract
Abstract Prenylation of phenolic and aromatic natural products across plants, bacteria, and higher organisms contributes to their lipophilicity and bioavailability. The process also enhances host defense and serves as a building block for chemical diversity, with medicinal chemistry mimicking these effects to create more effective compounds. While phytoestrogens, particularly those from licorice, are established as key natural regulators of estrogen receptor (ER) biology, the specific mechanisms by which prenylated polyphenolics in licorice regulate ER ligand binding and activity remain unknown. Herein, we show that the widespread prenylation of stilbenes from two commonly used licorice species reveals a broad spectrum of ER interaction profiles in the context of different scaffolds. To identify structural rules for how prenylation modulates ligand binding, we synthesized sixteen constitutional isomers of mono- or diprenylated stilbenes based on common resveratrol or dihydroresveratrol cores. These variously prenylated stilbenoid compounds exhibited ER agonistic effects on cell growth with a remarkable five-log range of cellular potencies. X-ray crystal structures of these compounds with ERα showed that this wide range of activities were found in essentially identical ligand-receptor structural states, except for differing side chain rotamers in one region of the binding pocket that accommodates the prenyl substituents. Thus, chemical diversity from a simple class of stilbenoids generated biological diversity through the modular combination of prenyl substitutions that revealed localized structural flexibility in an otherwise highly stable ER agonist conformation. The emergence of this prenylation code provides guidance for understanding and predicting the effect of prenyl-like substitution on phytoestrogens and other ER ligands.
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Authors Manal Alhusban, Saqlain Haider, Pankaj Pandey, Abidah Parveen, Ashley T Arbesfeld, Jerome C. Nwachukwu, Tina Izard, K.W. Nettles, Benita S. Katzenellenbogen, Ikhlas Ahmed Khan, Amar Gopal Chittiboyina
Journal PNAS nexus
Year 2026
DOI
10.1093/pnasnexus/pgag351
URL
https://academic.oup.com/pnasnexus/advance-article-pdf/doi/10.1093/pnasnexus/pgag351/71753488/pgag351.pdf
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