Irilone

J Nat Prod. 2018 Sep 28;81(9):1962-1967.

Irilone from Red Clover ( Trifolium pratense) Potentiates Progesterone Signaling.[Pubmed: 30199256 ]

The use of botanical dietary supplements is becoming increasingly popular for the alleviation of hormonal-based conditions such as hot flashes, premenstrual syndrome, and fertility. Estrogen and progesterone receptors (ER and PR) play an essential role in these processes. However, despite the fact that many therapies used to alleviate gynecological conditions act through PR-mediated mechanisms, few studies have investigated or identified any herbal natural product components that act on this receptor.
METHODS AND RESULTS:
In the current study, we used a progesterone response element (PRE)-luciferase (Luc) reporter assay to identify four phytoprogestins present in a standardized red clover ( Trifolium pratense) extract. We found that the component Irilone (1) potentiated the effect of progesterone in both endometrial and ovarian cancer cell lines. In these cancers, progesterone action is generally associated with positive outcomes; thus the potentiating effect of 1 may provide entirely new strategies for enhancing progesterone signaling as a means of mitigating conditions such as fibroids and endometriosis. Formononetin (3) and biochanin A (4) exhibited mixed agonist activity, while prunetin (2) acted only as an antagonist.
CONCLUSIONS:
Collectively, these results suggest that the effects of red clover extract repeatedly observed in cultured cells and the inverse correlation between risk of various cancers and flavonoid intake may be due, in part, to altered progesterone signaling.

Bioorg Chem. 2017 Feb;70:192-198.

8-Hydroxyirilone 5-methyl ether and 8-hydroxyirilone, new antioxidant and α-amylase inhibitors isoflavonoids from Iris germanica rhizomes.[Pubmed: 28069265 ]

Iris species are well recognized as wealthy sources of isoflavonoids.
METHODS AND RESULTS:
In the present study, phytochemical investigation of the rhizomes of Iris germanica (Iridaceae) procure the isolation of two new isoflavonoids namely, 8-hydroxyIrilone 5-methyl ether (2) and 8-hydroxyIrilone (3), along with eight known isoflavonoids: Irilone 4'-methyl ether (1), Irilone (4), irisolidone (5), irigenin S (6), irigenin (7), Irilone 4'-O-β-d-glucopyranoside (8), iridin S (9), and iridin (10). The isolated flavonoids were structurally characterized with the assist of comprehensive spectroscopic analyses (UV, IR, 1D and 2D NMR, and HRMS) and comparing with the published data. They were estimated for their antioxidant and antidaibetic capacities using DPPH and α-amylase inhibition assays, respectively.
CONCLUSIONS:
Compounds 2, 3, and 4 exhibited prominent antioxidant activities with IC50 values of 12.92, 9.23, and 10.46μM, respectively compared to propyl gallate (IC50 7.11μM). Moreover, 2-5 possessed highest α-amylase inhibitory activity with % inhibition 66.1, 78.3, 67.3, and 70.1, respectively in comparison to acarbose (reference α-amylase inhibitor). Additionally, their structure-activity relationship has been discussed.

Neurosci Res. 2008 Oct;62(2):123-30.

Protective effect of isoflavones from Trifolium pratense on dopaminergic neurons.[Pubmed: 18675857 ]

In the present study, protective effect of five isoflavones (formononetin, daidzein, pratensein, calycosin and Irilone) from Trifolium pratense on lipopolysaccharide-induced dopaminergic neurodegeneration was studied for the first time.
METHODS AND RESULTS:
The results showed that all five isoflavones attenuated LPS-induced decrease in dopamine uptake and the number of dopaminergic neurons in a dose-dependent manner in rat mesencephalic neuron-glia cultures. Moreover, they also significantly inhibited LPS-induced activation of microglia and production of tumor necrosis factor-alpha, nitric oxide and superoxide in mesencephalic neuron-glia cultures and microglia-enriched cultures. In addition, the rank order of protective potency of five isoflavones was: pratensein>daidzein>calycosin>formononetin>Irilone.
CONCLUSIONS:
This study suggested that all five isoflavones protected dopaminergic neurons against LPS-induced injury through inhibition of microglia activation and proinflammatory factors generation.

Phytother Res. 2009 Mar;23(3):428-33

Immunomodulatory activity of isoflavones isolated from Iris germanica (Iridaceae) on T-lymphocytes and cytokines.[Pubmed: 19003948 ]

The immunomodulatory activities of two isoflavones, 5,7-dihydroxy-6,4'-dimethoxyisoflavone (irisolidone) (1) and 5,4'-dihydroxy-6,7-methylenedioxyisoflavone (Irilone) (2) isolated from Iris germanica (Iridaceae) is reported.
METHODS AND RESULTS:
Their influence on production of T-lymphocytes (CD4+ and CD8+ cells) and T-cell cytokines, namely Th1: IL-2, IFN-gamma and Th2: IL-4 and IL-5 in a dose-dependent manner was studied by flow cytometric method in Balb/c mice. Oral administration of drugs at doses of 0.1-0.8 mg/kg per oral dose showed 1 to possess stimulatory activity on T-cells and Th1 cytokine production, while as 2 acted as an immunosuppressant for both cells and cytokines.
CONCLUSIONS:
The methylated products of 1 and 2 showed a similar trend to that of their parent compounds but their activity was drastically decreased revealing the importance of free phenolic groups for their immunomodulating activities.

Toxicol Lett. 2018 Sep 15;294:27-36.

Drug interaction study of flavonoids toward CYP3A4 and their quantitative structure activity relationship (QSAR) analysis for predicting potential effects.[Pubmed: 29753067 ]

The high risk of herb-drug interactions (HDIs) mediated by the herbal medicines and dietary supplements which containing abundant flavonoids had become more and more frequent in our daily life. In our study, the inhibition activities of 44 different structures of flavonoids toward human CYPs were systemically evaluated for the first time.
METHODS AND RESULTS:
According to our results, a remarkable structure-dependent inhibition behavior toward CYP3A4 was observed in vitro. Some flavonoids such as licoflavone (12) and Irilone (30) exhibited the selective inhibition toward CYP3 A4 rather than other major human CYPs. To illustrate the interaction mechanism, the inhibition kinetics of various compounds was further performed. Sophoranone (1), apigenin (10), baicalein (11), 5,4'-dihydroxy-3,6,7,8,3'-pentamethoxyflavone (15), myricetin (23) and kushenol K (38) remarkably inhibited the CYP3 A4-catalyzed bufalin 5'-hydroxylation reaction, with Ki values of 2.17 ± 0.29, 6.15 ± 0.39, 9.18 ± 3.40, 2.30 ± 0.36, 5.00 ± 2.77 and 1.35 ± 0.25 μM, respectively. Importantly, compounds 1, 11, 15, 23 and 38 could significantly inhibit the metabolism of some clinical drugs in vitro, and these drug-drug interactions (DDIs) of myricetin (23) or kushenol K (38) with clinical drug diazepam were further verified in human primary hepatocytes, respectively. Finally, a quantitative structure-activity relationship (QSAR) of flavonoids with their inhibitory effects toward CYP3 A4 was established using computational methods.
CONCLUSIONS:
Our findings illustrated the high risk of herb-drug interactions (HDIs) caused by flavonoids and revealed the vital structures requirement of natural flavonoids for the HDIs with clinical drugs eliminated by CYP3 A4. Our research provided the useful guidance to safely and rationally use herbal medicines and dietary supplements containing rich natural flavonoids components.