Intestinal Microbial Metabolic Activation Converts Soy Isoflavones into Potent Direct Antioxidants: First Total Synthesis and Mechanistic Characterization of 5-Hydroxydehydroequol.
- 1Division of Organic and Medicinal Chemistry, Showa Medical University School of Pharmacy, Shinagawa-ku, Tokyo 142-8555, Japan.
- 2Quantum RedOx Chemistry Team, Quantum Life Spin Group, Institute for Quantum Life Science (iQLS), National Institutes for Quantum Science and Technology (QST), Chiba-shi 263-8555, Chiba, Japan.
- 3Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka, Suita 565-0871, Osaka, Japan.
Abstract
Soy isoflavones exhibit diverse health-promoting effects, including antioxidant and anti-inflammatory activities. However, these biological effects have largely been attributed to the modulation of cellular signaling pathways, whereas the influence of intestinal microbial metabolism on their direct radical-scavenging properties remains poorly understood. In this study, synthetic routes were established for the major intestinal bacterial metabolites daidzein and genistein, equol (Eq), dehydroequol (DEq), 5-hydroxyequol (5-OH-Eq), and, for the first time, 5-hydroxydehydroequol (5-OH-DEq), and their direct radical-scavenging activities, reaction mechanisms, radical-scavenging capacities, and DNA protective effects were systematically evaluated. Introduction of a C-ring double bond markedly enhanced direct radical-scavenging activity, whereas the parent isoflavones and their reduced metabolites exhibited little or no activity. Among the compounds examined, 5-OH-DEq exhibited the highest antioxidant activity, scavenging radicals predominantly through hydrogen atom transfer, with a second-order rate constant of 1.44 × 10³ M⁻¹ s⁻¹, exceeding that of Trolox and a radical-scavenging capacity of approximately three radical equivalents per molecule. Moreover, 5-OH-DEq protected plasmid DNA against radiation-induced oxidative damage. These findings demonstrate that intestinal microbial metabolism can function as a form of metabolic activation, converting dietary isoflavones into potent direct antioxidants. 5-OH-DEq was identified as a previously unexplored antioxidant metabolite and a promising lead scaffold for further development of next-generation phenolic antioxidants.
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BibTeX
@article{okada2026intestinal,
title = {{Intestinal Microbial Metabolic Activation Converts Soy Isoflavones into Potent Direct Antioxidants: First Total Synthesis and Mechanistic Characterization of 5-Hydroxydehydroequol.}},
author = {Sakurako Okada and Yoshimi Shoji and Masao Morita and Mika Hayashi and Wakana Shimizu and Kei Ohkubo and Hiromu Ito and Ikuo Nakanishi and Kiyoshi Fukuhara},
journal = {Antioxidants (Basel, Switzerland)},
year = {2026},
month = sep,
doi = {10.3390/antiox15101240},
url = {https://europepmc.org/article/MED/42939813},
note = {CC BY},
}
RIS
TY - JOUR
TI - Intestinal Microbial Metabolic Activation Converts Soy Isoflavones into Potent Direct Antioxidants: First Total Synthesis and Mechanistic Characterization of 5-Hydroxydehydroequol.
AU - Sakurako Okada
AU - Yoshimi Shoji
AU - Masao Morita
AU - Mika Hayashi
AU - Wakana Shimizu
AU - Kei Ohkubo
AU - Hiromu Ito
AU - Ikuo Nakanishi
AU - Kiyoshi Fukuhara
PY - 2026
DA - 2026/09/25
JO - Antioxidants (Basel, Switzerland)
DO - 10.3390/antiox15101240
UR - https://europepmc.org/article/MED/42939813
AB - Soy isoflavones exhibit diverse health-promoting effects, including antioxidant and anti-inflammatory activities. However, these biological effects have largely been attributed to the modulation of cellular signaling pathways, whereas the influence of intestinal microbial metabolism on their direct radical-scavenging properties remains poorly understood. In this study, synthetic routes were established for the major intestinal bacterial metabolites daidzein and genistein, equol (Eq), dehydroequol (DEq), 5-hydroxyequol (5-OH-Eq), and, for the first time, 5-hydroxydehydroequol (5-OH-DEq), and their direct radical-scavenging activities, reaction mechanisms, radical-scavenging capacities, and DNA protective effects were systematically evaluated. Introduction of a C-ring double bond markedly enhanced direct radical-scavenging activity, whereas the parent isoflavones and their reduced metabolites exhibited little or no activity. Among the compounds examined, 5-OH-DEq exhibited the highest antioxidant activity, scavenging radicals predominantly through hydrogen atom transfer, with a second-order rate constant of 1.44 × 10³ M⁻¹ s⁻¹, exceeding that of Trolox and a radical-scavenging capacity of approximately three radical equivalents per molecule. Moreover, 5-OH-DEq protected plasmid DNA against radiation-induced oxidative damage. These findings demonstrate that intestinal microbial metabolism can function as a form of metabolic activation, converting dietary isoflavones into potent direct antioxidants. 5-OH-DEq was identified as a previously unexplored antioxidant metabolite and a promising lead scaffold for further development of next-generation phenolic antioxidants.
SN - 2076-3921
ER -