CHROMOPHORE-MODIFIED BIS-NAPHTHALIMIDES - SYNTHESIS AND ANTITUMOR-ACTIVITY OF BIS-DIBENZ[DE,H]ISOQUINOLINE-1,3-DIONES

The bis-dibenz[de,h]isoquinoline-1,3-diones are a new series of antitu mor agents that consist of two chromophores bridged by an alkylamino l inker. In the present study we have explored the effect produced by th e presence of two dibenz[de,h]isoquinoline-1,3-dione moieties with dif ferent polyamine chains on cellular cytotoxicity. Bis-dibenz[de JE]iso quinoline-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, al tered DNA mobility and topoisomerase I and II activity at approximatel y 5 mu M. When tested in vivo, compound 16 increased the median surviv al time of mice implanted with M5076 with an optimum %T/C of 154% and produced cures in 50% of mice implanted with Lox melanoma.