Preparation and cytotoxicity toward cancer cells of mono(arylimino) derivatives of beta-lapachone.
A regio- and stereospecific synthesis of monoarylimino o-quinones derived from beta-lapachone (1) was achieved by treatment of the quinone with a slight excess of an arylamine in the presence of an excess of triethylamine/titanium tetrachloride 4:1. Imine formation occurred exclusively at position 6, giving the Z diastereomer, as determined by single-crystal X-ray analysis. In vitro tests for cytotoxicity in 55 human cancer cell cultures showed a substantial loss in activity for the p-nitrophenylimine (5), whereas the phenylimine (2), p-methylphenylimine (3), and p-methoxyphenylimine (4) retained (or bettered) most of the cytotoxicity and selectivity of the parent quinone. Preliminary in vivo testing in hollow fiber assays against a standard panel of 12 human tumor cell lines showed that although beta-lapachone failed, compounds 2 and 3 had good scores with net cell kills.
Di Chenna
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PH
Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, (1428) Buenos Aires, Argentina.
Benedetti-Doctorovich
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V
Baggio
R F
RF
Garland
M T
MT
Burton
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G
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009285:Naphthoquinones / Q000737:chemistry*; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C431688:2,2-dimethyl-6-(4-methylphenylimino)-3,4,5,6-tetrahydro-2H-naphtho(1,2-b)oxin-5-one; C431687:2,2-dimethyl-6-phenylimino-3,4,5,6-tetrahydro-2H-naphtho(1,2-b)oxin-5-one; D000970:Antineoplastic Agents; D007097:Imines; D009281:Naphthalenes; D009285:Naphthoquinones; D011714:Pyrans; C014638:beta-lapachone