title: Synthesis of structurally simplified analogues of aplidinone A, a pro-apoptotic marine thiazinoquinone.
abstract: The synthesis of analogues of aplidinone A (7), a prenylated quinone isolated from the Mediterranean ascidian Aplidium conicum, has been performed. This work not only allowed confirming the structural assignment of aplidinone A, previously made with the support of GIAO shielding calculations, but, above all, made a series of structurally related quinone derivatives (compounds 8-13 and the natural metabolite) available for a screening in vitro for cytotoxic and pro-apoptotic activity and for SAR studies. The study evidenced one of the synthetic analogues (11) as a potent cytotoxic and pro-apoptotic agent against several tumor cell lines which also inhibits the TNFalpha-induced NF-kappaB activation in a human leukemia T cell line. This exemplifies the potential of a natural product to qualify as lead structure for medicinal chemistry campaigns, affording simplified analogues with better bioactivity and easier to synthesize.
authors.affiliation: Dipartimento di Chimica delle Sostanze Naturali, Università degli Studi di Napoli 'Federico II', Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Aiello
authors.forename: Ernesto
authors.initials: E
authors.lastname: Fattorusso
authors.forename: Paolo
authors.initials: P
authors.lastname: Luciano
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Menna
authors.forename: Marco A
authors.initials: MA
authors.lastname: Calzado
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
authors.forename: Francesco
authors.initials: F
authors.lastname: Bonadies
authors.forename: Marcella
authors.initials: M
authors.lastname: Guiso
authors.forename: Maria Filomena
authors.initials: MF
authors.lastname: Sanasi
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Cocco
authors.forename: Rosario
authors.initials: R
authors.lastname: Nicoletti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D011809:Quinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014561:Urochordata / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D011809:Quinones; D014409:Tumor Necrosis Factor-alpha; C548619:aplidinone A