A C-ring regioisomer of the marine alkaloid meridine exhibits selective in vitro cytotoxicity for solid tumours.
9-Hydroxybenzo[b]pyrido[4,3,2-de](1,10)-phenantrolin-8-one (1), a regioisomer of the marine alkaloid meridine, was synthesized from 5,8-dimethoxy-6-nitro-4(1H)-quinolinone in eight steps and 23% overall yield. A shorter route was also investigated, based on the hetero Diels-Alder reaction between o-nitrocinnamaldehyde dimethylhydrazone and 4-halogen-6-bromo-5,8-quinolinequinones followed by reductive cyclization onto the C-5 carbonyl of the quinone. Compound 1 showed a remarkable in vitro cytotoxicity, with a pattern of selectivity towards solid tumours that is not found in the reference alkaloid, the activity against the human lung carcinoma (A-549) being particularly noteworthy. The activities of meridine and compound 1 as inhibitors of topoisomerase II were also significantly different.
Angel de la Fuente
J
J
Instituto Biomar, S.A. Polígono Industrial, Edificio C.E.I., 24231 Onzonilla, León, Spain.
Jesús Martín
M
M
del Mar Blanco
M
M
Pascual-Alfonso
E
E
Avendaño
C
C
Carlos Menéndez
J
J
D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010618:Phenanthrolines / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D017550:Spectroscopy, Fourier Transform Infrared; D014407:Tumor Cells, Cultured
C434786:9-hydroxybenzo(b)pyrido(4,3,2-de)(1,10)-phenantrolin-8-one; D000470:Alkaloids; D000970:Antineoplastic Agents; D010618:Phenanthrolines; D011725:Pyridines; C079196:meridine