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Chromophore-Modified Bis-Naphthalimides: Synthesis and Antitumor Activity of Bis-Dibenz[ de , h ]isoquinoline-1,3-diones

1997; American Chemical Society; Volume: 40; Issue: 4 Linguagem: Inglês

10.1021/jm960295k

1520-4804

M. F. BRANA, José M. Castellano, Denise Perron, Charles A. Maher, Donna Conlon, Peter F. Bousquet, Jinu Jacob George, Xiaoxia Qian, Simon P. Robinson,

Bioactive Compounds and Antitumor Agents

The bis-dibenz[de,h]isoquinoline-1,3-diones are a new series of antitumor agents that consist of two chromophores bridged by an alkylamino linker. In the present study we have explored the effect produced by the presence of two dibenz[de,h]isoquinoline-1,3-dione moieties with different polyamine chains on cellular cytotoxicity. Bis-dibenz[de,h]isoquinoline-1,3-diones with the bridge (CH2)2-NH-(CH2)n-NH-(CH2)2, where n = 2-5, showed optimum cytotoxicity with IC50's around 10 nM. Compound 16, which has the (CH2)2-NH-(CH2)3-NH-(CH2)2 bridge, altered DNA mobility and topoisomerase I and II activity at approximately 5 microM. When tested in vivo, compound 16 increased the median survival time of mice implanted with M5076 with an optimum %T/C of 154% and produced cures in 50% of mice implanted with Lox melanoma.