A structure-function study of nucleic acid-fluorenone complexes

Several 2,7-bis-[(dialkylamino)-acetylamino]-fluoren-9-one derivatives (flu oramides) were synthesized as analogues of the DNA binding compound tiloron e (2,7-bis[(diethylamino)-ethoxy]-fluoren-9-one). Previous studies showed t he drugs to induce cytokines and inhibit reverse transcription. Here, their binding to DNA was evaluated using UV and circular dichroism studies. Like tilorone, the fluoramides derivatives also intercalate resulting in in creased T-m values and new CD signatures. A preference to alternating A-T a nd G-C sequences was detected; only minor interaction to homologous sequenc es was observed. Moreover, no upper limit in the drug/DNA ratio was found, testing limit being the precipitation of the drug. However, surface plasmon resonance (SPR) studies of tilorone and 2,7-bis- [(dipropylamino)-acetyl-a mino]-fluoren-9-one, indicate an astonishing drug/base pair ratio (r > 1), which point to a multitude of interactions under SPR conditions. Molecular modeling calculations, where the geometries of the complexes optimized unde r the assumption of intercalative and multitude of suprahelical arrangement s, rationalize the observations. Based on the thermodynamic and biological studies, a structure-function model is proposed.