Novel Heterocycle-fused Naphthalimides: Design, Synthesis And Evaluation Of Biological Activity

Several series of heterocycle-fused 1,8-naphthalimide derivatives have been designed and synthesized and their spectra properties, DNA intercalative, antitumor and DNA photo-damaging abilities have been evaluated.A series of quino-fused 1,8-naphthalimide derivatives with electron-deficiency characteristics has been designed and synthesized. The Scatchard binding constant reached 10 order, indicating its good DNA intercalative ability. The sites of substituents, especially two peri sites of heterocyclic N atoms, exerted great influence on their topoisomerase I inhibitory, antitumor and DNA photodamaging abilities.A series of mono- and bis-quinolino-fused 1,8-naphthalimide derivatives with electron-deficiency characteristics has been designed and synthesized. Its DNA intercalative constant also reached 105 order. The study on DNA unwinding angles proved that bis- quinolino-fused 1,8-naphthalimide derivatives interacted with CT-DNA through bis-intercalative mode. Mono-substituted compound could photo-damaged DNA through the generation of singlet oxygen. The antitumor activities of bis-naphthalimides showed that the compound with the longest interchromophore chain exhibited the highest antitumor activity.Several series of 1,8-naphthalimide derivatives with chiral chain have been designed and synthesized. The five-member thio-fused naphthalimide compounds exhibited the highest DNA intercalative ability. The compound with S-configuration chiral chain exhibited the higher DNA intercalative ability than either R- enantiomers or racemic compounds, which was in accordance with their DNA photo-damaging properties. No obvious qualitative relationship was found between the structure of chiral compounds and their antitumor activities.A series of mono- and bis-substituted non-heterocylic 1,8-naphthalimide derivatives containing S element has been designed and synthesized. Their DNA intercalative abilities reached 10~4 order, which were lower than those of planar heterocycle-fused derivatives. The mono-substituted compounds exhibited better DNA photo-damaging ability than that with bis-substituted compounds. However, the latter exhibited greater antitumor selectivity than the former.