The prenylation code regulating estrogenic activity of synthetic and natural product derivatives of resveratrol
6 affiliations
- 1National Center for Natural Products Research, School of Pharmacy, University of Mississippi , University, MS 38677 ,
- 2Faculty of Pharmacy, Philadelphia University , Amman 19392 ,
- 3Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi , University, MS 38677 ,
- 4Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , Jupiter, FL 33458 ,
- 5Department of Chemistry, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , Jupiter, FL 33458 ,
- 6Department of Chemistry, University of Illinois , Urbana, IL 61801 ,
Abstract
Prenylation of phenolic and aromatic natural products across plants, bacteria, and higher organisms contributes to their lipophilicity and biological function. 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 16 mono- or diprenylated stilbennoid analogs based on common resveratrol or dihydroresveratrol cores. These variously prenylated stilbenoid compounds exhibited ER agonistic effects on cell growth with a remarkable 5-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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BibTeX
@article{alhusban2026prenylation,
title = {{The prenylation code regulating estrogenic activity of synthetic and natural product derivatives of resveratrol}},
author = {Manal Alhusban and Saqlain Haider and Pankaj Pandey and Abidah Parveen and Ashley T Arbesfeld and Jerome C Nwachukwu and Tina Izard and Kendall W Nettles and John A Katzenellenbogen and Ikhlas A Khan and Amar G Chittiboyina},
journal = {PNAS Nexus},
year = {2026},
month = oct,
doi = {10.1093/pnasnexus/pgag351},
url = {https://academic.oup.com/pnasnexus/article/doi/10.1093/pnasnexus/pgag351/8892677},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - The prenylation code regulating estrogenic activity of synthetic and natural product derivatives of resveratrol
AU - Manal Alhusban
AU - Saqlain Haider
AU - Pankaj Pandey
AU - Abidah Parveen
AU - Ashley T Arbesfeld
AU - Jerome C Nwachukwu
AU - Tina Izard
AU - Kendall W Nettles
AU - John A Katzenellenbogen
AU - Ikhlas A Khan
AU - Amar G Chittiboyina
PY - 2026
DA - 2026/10/09
JO - PNAS Nexus
DO - 10.1093/pnasnexus/pgag351
UR - https://academic.oup.com/pnasnexus/article/doi/10.1093/pnasnexus/pgag351/8892677
AB - Prenylation of phenolic and aromatic natural products across plants, bacteria, and higher organisms contributes to their lipophilicity and biological function. 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 16 mono- or diprenylated stilbennoid analogs based on common resveratrol or dihydroresveratrol cores. These variously prenylated stilbenoid compounds exhibited ER agonistic effects on cell growth with a remarkable 5-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.
SN - 2752-6542
ER -