title: Poly-Electrophilic Sesquiterpene Lactones from Vernonia amygdalina: New Members and Differences in Their Mechanism of Thiol Trapping and in Bioactivity.
abstract: In addition to known compounds, the leaves of Vernonia amygdalina afforded the new sesquiterpene lactones 14-O-methylvernolide (2), 3'-deoxyvernodalol (6), and vernomygdalin (8). These and related compounds were evaluated for modulation of a series of thiol trapping-sensitive transcription factors (NF-κB, STAT3, and Nrf2), involved in the maintenance of the chronic inflammatory condition typical of human degenerative diseases. Vernolide (1) emerged as a potent inhibitor of STAT3 and NF-κB and showed cytostatic activity toward the prostate cancer cell line DU45, arresting the cell cycle at the S phase. The exomethylene lactones are characterized by multiple Michael acceptor sites, as exemplified by vernolide (1) and vernodalol (5). By using the nuclear magnetic resonance-based cysteamine assay, the most reactive thiophilic site could be identified in both compounds, and competitive experiments qualified vernolide (1) as being more thiophilic than vernodalol (5), in agreement with the results of the pharmacological assays.
authors.affiliation: †Dipartimento di Farmacia, Università di Napoli Federico II, Via Montesano 49, 80131 Napoli, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Sinisi
authors.affiliation: ‡Maimónides Institute for Research in Biomedicine of Córdoba, Reina Sofía University Hospital, University of Córdoba, Avda Menéndez Pidal s/n, 14004 Córdoba, Spain.
authors.forename: Estrella
authors.initials: E
authors.lastname: Millán
authors.affiliation: §School of Pharmacy, University of Camerino, Piazza dei Costanti, 62032 Camerino, MC, Italy.|⊥School of Medicine, College of Health Sciences, Addis Ababa University, 62212 Addis Ababa, Ethiopia.
authors.forename: Solomon M
authors.initials: SM
authors.lastname: Abay
authors.affiliation: §School of Pharmacy, University of Camerino, Piazza dei Costanti, 62032 Camerino, MC, Italy.
authors.forename: Annette
authors.initials: A
authors.lastname: Habluetzel
authors.affiliation: ∥Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonete Orientale, Via Bovio 6, 28100 Novara, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
authors.affiliation: ‡Maimónides Institute for Research in Biomedicine of Córdoba, Reina Sofía University Hospital, University of Córdoba, Avda Menéndez Pidal s/n, 14004 Córdoba, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
authors.affiliation: †Dipartimento di Farmacia, Università di Napoli Federico II, Via Montesano 49, 80131 Napoli, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Taglialatela-Scafati
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D003543:Cysteamine / Q000737:chemistry; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D015394:Molecular Structure; D051267:NF-E2-Related Factor 2 / Q000187:drug effects; D016328:NF-kappa B / Q000187:drug effects; D018515:Plant Leaves / Q000737:chemistry; D050796:STAT3 Transcription Factor / Q000187:drug effects; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000494:pharmacology; D035741:Vernonia / Q000737:chemistry*
chemical_list: D007783:Lactones; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D050796:STAT3 Transcription Factor; D012717:Sesquiterpenes; D013438:Sulfhydryl Compounds; C000602211:vernodalol; C465363:vernolide; D003543:Cysteamine