SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP OF METHYL-SUBSTITUTED INDOLE[2,3-B]QUINOLINES - NOVEL CYTOTOXIC, DNA TOPOISOMERASE-II INHIBITORS

In furtherance of our SAR study on the chemistry and antitumor activity of fused nitrogen heteroaromatic compounds, a series of linear, methyl-substituted derivatives of 5H- and 6H-indolo[2,3-b]quinolines were synthesized according to the modified Graebe-Ullmann reaction. To establish the relationship between the physicochemical and biological activities of indole[2,3-b]quinolines, their lipophilic properties, cytotoxic and antimicrobial activity, and ability to induce topoisomerase II dependent pSP65 DNA cleavage in vitro were investigated. We found that the antimicrobial and cytotoxic activity of indolo[2,3-b]quinolines was strongly influenced by the position, and the number of methyl substituents and the presence of methyl group at pyridine nitrogen was essential for the cytotoxicity of these compounds. All indole[2,3-b]quinolines belonging to the 5H series, i.e., bearing a methyl group on the pyridine nitrogen, showed significant activity against procaryotic and eucaryotic organisms. They inhibited the growth of Gram-positive bacteria and pathogenic fungi at MIC range 3 x 10(-2) to 2.5 x 10(-1) mu mol/mL, displayed cytotoxicity against KB cells ID50 in the range 2 x 10(-3) to 9 x 10(-3) mu mol/mL, and stimulated the formation of calf thymus topoisomerase II mediated DNA cleavage at concentration between 0.4 and 10 mu M. None of the indolo[2,3-b]quinolines belonging to the 6H series, i.e., lacking a methyl group on the pyridine nitrogen, was active in analogous tests. Of the investigated compounds, the most active was 2,5,9,11-tetramethyl-5H-indolo-[2,3-b]quinoline, a compound bearing the highest number of symmetrically distributed methyl groups. The interaction of indolo[2,3-b]quinolines with DNA was studied by measuring the increase of calf thymus DNA denaturating temperature (T-m). The Delta T-m values for the 5H series were found to be about 10 times as high as those for the 6H compounds. Indolo[2,3-b]quinolines with the highest number of methyl groups had the greatest contribution to the increase in the T-m of calf thymus DNA. The values of Delta T-m reached 19 degrees C and 1.6 degrees C for the most substituted compounds of both series.