2-Morpholinoisoflav-3-enes as flexible intermediates in the synthesis of phenoxodiol, isophenoxodiol, equol and analogues: Vasorelaxant properties, estrogen receptor binding and Rho/RhoA kinase pathway inhibition

Tilley, A, Zanatta, S, Qin, C, In-Kyeom, K, Seok, Y, Stewart, A, Woodman, O and Williams, S 2012, '2-Morpholinoisoflav-3-enes as flexible intermediates in the synthesis of phenoxodiol, isophenoxodiol, equol and analogues: Vasorelaxant properties, estrogen receptor binding and Rho/RhoA kinase pathway inhibition', Bioorganic & Medicinal Chemistry: the tetrahedron journal for research at the interface of chemistry and biology, vol. 20, no. 7, pp. 2353-2361.


Document type: Journal Article
Collection: Journal Articles

Title 2-Morpholinoisoflav-3-enes as flexible intermediates in the synthesis of phenoxodiol, isophenoxodiol, equol and analogues: Vasorelaxant properties, estrogen receptor binding and Rho/RhoA kinase pathway inhibition
Author(s) Tilley, A
Zanatta, S
Qin, C
In-Kyeom, K
Seok, Y
Stewart, A
Woodman, O
Williams, S
Year 2012
Journal name Bioorganic & Medicinal Chemistry: the tetrahedron journal for research at the interface of chemistry and biology
Volume number 20
Issue number 7
Start page 2353
End page 2361
Total pages 9
Publisher Pergamon
Abstract Isoflavone consumption correlates with reduced rates of cardiovascular disease. Epidemiological studies and clinical data provide evidence that isoflavone metabolites, such as the isoflavan equol, contribute to these beneficial effects. In this study we developed a new route to isoflavans and isoflavenes via 2-morpholinoisoflavenes derived from a condensation reaction of phenylacetaldehydes, salicylaldehydes and morpholine. We report the synthesis of the isoflavans equol and deoxygenated analogues, and the isoflavenes 7,4'-dihydroxyisoflav-3-ene (phenoxodiol, haganin E) and 7,4'-dihydroxyisoflav-2-ene (isophenoxodiol). Vascular pharmacology studies reveal that all oxygenated isoflavans and isoflavenes can attenuate phenylephrine-induced vasoconstriction, which was unaffected by the estrogen receptor antagonist ICI 182,780. Furthermore, the compounds inhibited U46619 (a thromboxane A 2 analogue) induced vasoconstriction in endothelium-denuded rat aortae, and reduced the formation of GTP RhoA, with the effects being greatest for equol and phenoxodiol. Ligand displacement studies of rat uterine cytosol estrogen receptor revealed the compounds to be generally weak binders. These data are consistent with the vasorelaxation activity of equol and phenoxodiol deriving at least in part by inhibition of the RhoA/Rho-kinase pathway, and along with the limited estrogen receptor affinity supports a role for equol and phenoxodiol as useful agents for maintaining cardiovascular function with limited estrogenic effects.
Subject Pharmacology and Pharmaceutical Sciences not elsewhere classified
Medicinal and Biomolecular Chemistry not elsewhere classified
Keyword(s) Kinase inhibitor
Phytoestrogens
Polyphenols
Vascular pharmacology
DOI - identifier 10.1016/j.bmc.2012.02.008
Copyright notice © 2012 Elsevier Ltd. All rights reserved.
ISSN 0968-0896
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