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.
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.
authors.affiliation: School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tilley
authors.forename: Shannon D
authors.initials: SD
authors.lastname: Zanatta
authors.forename: Cheng Xue
authors.initials: CX
authors.lastname: Qin
authors.forename: In-Kyeom
authors.initials: IK
authors.lastname: Kim
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Seok
authors.forename: Alastair
authors.initials: A
authors.lastname: Stewart
authors.forename: Owen L
authors.initials: OL
authors.lastname: Woodman
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Williams
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000633:toxicity; D000818:Animals; D060754:Equol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007529:Isoflavones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000737:chemistry; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000737:chemistry* / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007529:Isoflavones; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011960:Receptors, Estrogen; D014665:Vasodilator Agents; D060754:Equol; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C037574:morpholine; C471183:phenoxodiol; D054460:rho-Associated Kinases