Synthesis of structurally simplified analogues of aplidinone A, a pro-apoptotic marine thiazinoquinone.
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.
Aiello
Anna
A
Dipartimento di Chimica delle Sostanze Naturali, Università degli Studi di Napoli 'Federico II', Via D. Montesano 49, 80131 Napoli, Italy.
Fattorusso
Ernesto
E
Luciano
Paolo
P
Menna
Marialuisa
M
Calzado
Marco A
MA
Muñoz
Eduardo
E
Bonadies
Francesco
F
Guiso
Marcella
M
Sanasi
Maria Filomena
MF
Cocco
Gianfranco
G
Nicoletti
Rosario
R
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*
D000970:Antineoplastic Agents; D016328:NF-kappa B; D011809:Quinones; D014409:Tumor Necrosis Factor-alpha; C548619:aplidinone A