DNA MINOR-GROOVE CLEAVING AGENTS - SYNTHESIS, BINDING AND STRAND CLEAVING PROPERTIES OF ANTHRAQUINONE-OLIGOPYRROLECARBOXAMIDE HYBRIDS

Three 9,10-anthraquinone-oligopyrrolecarboxamide hybrids have been pre pared as potential DNA minor groove cleaving agents. Each conjugate wa s designed to contain a bis- or tris-pyrrolecarboxamide moiety related to netropsin or distamycin covalently linked to a 2-substituted anthr aquinone chromophore capable of triggering photocleavage of DNA. AQ((N C))-Dist, having three pyrrole rings, is related to distamycin. AQ((NC ))-Net and AQ((CN))-Net are related to netropsin; they differ only by the orientation of the amide bond between the anthraquinone and the ne tropsin moiety. The binding properties of these compounds to various n atural DNAs have been studied by footprinting and circular dichroism. The introduction of the chromophore does not abolish the capacity of t he drugs to recognize AT-rich sequences in DNA selectively. There is a pparently little correlation between this property and the ability to trigger photo-induced DNA cleavage. AQ((CN))-Net is almost totally ina ctive in the cleavage assays whereas it manifestly binds selectively t o AT-rich tracts. With AQ((NC))-Net and AQ(Nc)-Dist, complete conversi on of form I to form II of circular DNA is obtained. Moreover, in most cases the cleavage of DNA proved to be non-specific.