title: Erythroidine alkaloids: a novel class of phytoestrogens.
abstract: Erythrina poeppigiana is a medicinal plant which is widely used in Asia, Latin America, and Africa in traditional remedies for gynecological complications and maladies. In continuation of studies for the discovery of novel phytoestrogens, four erythroidine alkaloids, namely α-erythroidine, β-erythroidine, and their oxo-derivatives 8-oxo-α-erythroidine and 8-oxo-β-erythroidine, were isolated and structurally characterized from the methanolic extract of the stem bark of E. poeppigiana. Due to the high amounts of erythroidines in the extract and considering the widespread utilization of Erythrina preparations in traditional medicine, the exploration of their estrogenic properties was performed. The estrogenicity of the isolated erythroidines was assayed in various estrogen receptor-(ER)-dependent test systems, including receptor binding affinity, cell culture based ER-dependent reporter gene assays, and gene expression studies in cultured cells using reverse transcription polymerase chain reaction techniques. α-Erythroidine and β-erythroidine showed binding affinity values for ERα of 0.015 ± 0.010% and 0.005 ± 0.010%, respectively, whereas only β-erythroidine bound to ERβ (0.006 ± 0.010%). In reporter gene assays, both erythroidines exhibited a significant dose-dependent estrogenic stimulation of ER-dependent reporter gene activity in osteosarcoma cells detectable already at 10 nM. Results were confirmed in the MVLN cells, a bioluminescent variant of MCF-7 breast cancer cells. Further, α-erythroidine and β-erythroidine both induced the enhanced expression of the specific ERα-dependent genes trefoil factor-1 and serum/glucocorticoid regulated kinase 3 in MCF-7 cells, confirming estrogenicity. Additionally, using molecular docking simulations, a potential mode of binding on ERα, is proposed, supporting the experimental evidences. This is the first time that an estrogenic profile is reported for erythroidine alkaloids, potentially a new class of phytoestrogens.
authors.affiliation: Division of Pharmacognosy & Natural Products Chemistry, Department of Pharmacy, University of Athens, Athens, Greece.
authors.forename: Sefirin
authors.initials: S
authors.lastname: Djiogue
authors.affiliation: Division of Pharmacognosy & Natural Products Chemistry, Department of Pharmacy, University of Athens, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Halabalaki
authors.affiliation: Laboratory of Animal Physiology, Department of Animal Biology and Physiology, University of Yaoundé 1, Yaounde, Cameroon.
authors.forename: Dieudonné
authors.initials: D
authors.lastname: Njamen
authors.affiliation: Molecular Cell Physiology & Endocrinology, Technische Universität, Dresden, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Kretzschmar
authors.affiliation: Division of Pharmaceutical Chemistry, Department of Pharmacy, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Lambrinidis
authors.affiliation: Molecular Cell Physiology & Endocrinology, Technische Universität, Dresden, Germany.
authors.forename: Josephine
authors.initials: J
authors.lastname: Hoepping
authors.affiliation: Molecular Cell Physiology & Endocrinology, Technische Universität, Dresden, Germany.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Raffaelli
authors.affiliation: Division of Pharmaceutical Chemistry, Department of Pharmacy, Athens, Greece.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mikros
authors.affiliation: Division of Pharmacognosy & Natural Products Chemistry, Department of Pharmacy, University of Athens, Athens, Greece.
authors.forename: Alexios-Leandros
authors.initials: AL
authors.lastname: Skaltsounis
authors.affiliation: Molecular Cell Physiology & Endocrinology, Technische Universität, Dresden, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Vollmer
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D002460:Cell Line; D004079:Dihydro-beta-Erythroidine / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D004895:Erythrina / Q000737:chemistry*; D047628:Estrogen Receptor alpha / Q000187:drug effects; D047629:Estrogen Receptor beta / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D015394:Molecular Structure; D048789:Phytoestrogens / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D024301:Plant Bark / Q000737:chemistry; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D018547:Plant Stems / Q000737:chemistry; D010946:Plants, Medicinal; D011994:Recombinant Proteins
chemical_list: D000470:Alkaloids; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D048789:Phytoestrogens; D010936:Plant Extracts; D011994:Recombinant Proteins; D004079:Dihydro-beta-Erythroidine; C004873:beta-erythroidine