Resveratrol Analogues as Selective Estrogen Signaling Pathway Modulators: Structure–Activity Relationship

Abstract

Resveratrol is a plant-derived phytoalexin found in grapes, red wine and many other plants used in Asian folk medicine. It is extensively studied for pleiotropic biological activity. The most crucial are anticancer and chemopreventive properties. Resveratrol has also been reported to be an antioxidant and phytoestrogen. The phytoestrogenic activity of resveratrol was assayed in different in vitro and in vivo models. Although these works brought some, on the first look, conflicting results, it is commonly accepted that resveratrol interacts with estrogen receptors and functions as a mixed agonist/antagonist. It is widely accepted that the hydroxyl groups are crucial for resveratrol’s cytotoxic and antioxidative activity and are responsible for binding estrogen receptors. In this work, we assayed 11 resveratrol analogues, seven barring methoxy groups and six hydroxylated analogues in different combinations at positions 3, 4, 5 and 3′,4′,5′. For this purpose, recombined estrogen receptors and estrogen-dependent MCF-7 and Ishikawa cells were used. Our study was supported by in silico docking studies. We have shown that, resveratrol and 3,4,4′5′-tetrahydroxystilbene, 3,3′,4,5,5′-pentahydroxystilbene and 3,3′,4,4′,5,5′-hexahydroxystilbene may act as selective estrogen receptor modulators.

Natural resveratrol analogs differentially target endometriotic cells into apoptosis pathways

“…Pterostilbene, which exhibits estrogenic activity, mediated neuroprotective potential via mainly ER-α receptor, which activated the BCL-2 expression presumably through genomic estrogen signaling 42 . The distribution of hydroxyl groups in aromatic rings in the stilbenes makes them similar in chemical structure to endogenous and synthetic estrogens such as 17β-estradiol (E2) or diethylstilbestrol 43 . One early identified biological target of resveratrol was the estrogen receptor (ER), and the compound was classified as a phytoestrogen.…”

Steroidogenic activity of liposomal methylated resveratrol analog 3,4,5,4′-tetramethoxystilbene (DMU-212) in human luteinized granulosa cells in a primary three-dimensional in vitro model

“…Despite various conflicting results, resveratrol is known as an estrogen mixed agonist/antagonist [ 35 , 36 ]. Recently, Kobylka et al have studied the ability of several methoxy- and hydroxy- resveratrol analogs to bind to the estrogen receptors [ 37 ]. Interestingly, the study revealed that DMU-212 does not exert binding affinity to ERα and Erβ [ 37 ].…”

“…Recently, Kobylka et al have studied the ability of several methoxy- and hydroxy- resveratrol analogs to bind to the estrogen receptors [ 37 ]. Interestingly, the study revealed that DMU-212 does not exert binding affinity to ERα and Erβ [ 37 ]. The possible explanation of these results may be the lack of hydroxy groups in the structure of DMU-212 as -OH groups are suggested to possibly be responsible for binding estrogen receptors [ 38 ].…”

Estradiol as the Trigger of Sirtuin-1-Dependent Cell Signaling with a Potential Utility in Anti-Aging Therapies

“…Despite some doubts, it has been already shown that the activation of SIRT1 by resveratrol protects the tibialis anterior muscle against age-associated sarcopenia via the preservation of normal autophagic flux [ 94 ]. Estradiol, as an endogenous activator of SIRT1, may hypothetically exhibit a very similar action, especially since resveratrol and estradiol share many molecular pathways [ 95 , 96 ].…”