Synthesis and Structure-Activity Relationship of Methyl-Substituted Indolo[2,3-b]quinolines: Novel Cytotoxic, DNA Topoisomerase II Inhibitors

Abstract

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 indolo[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 indolo[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) mumol/mL, displayed cytotoxicity against KB cells ID50 in the range 2 x 10(-3) to 9 x 10(-3) mumol/mL, and stimulated the formation of calf thymus topoisomerase II mediated DNA cleavage at concentration between 0.4 and 10 microM. 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 (Tm). The delta Tm 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 Tm of calf thymus DNA. The values of delta Tm reached 19 degrees C and 1.6 degrees C for the most substituted compounds of both series.

Membrane Perturbations Induced by New Analogs of Neocryptolepine

“…In the neutral aqueous solution of this compound there may coexist a mixture of uncharged (neutral) and charged (cationic) forms. 17) The values of pK a obtained for 1 and 2 according to the same method (Jaromin, A., data unpublished) have slightly higher values, 7.72 and 7.65, respectively. It is postulated that the active form is the acidic (cationic) one.…”

“…55,56) It is also worth noting that an analog without a methyl group at N-5 (11-methyl-6H-indolo[2,3-b] quinoline) and an analog with a methyl group at N-6 (6,11-dimethyl-6H-indolo [2,3-b] quinoline) are completely inactive in test conditions (Jaromin, unpublished data). In light of these observations, it is likely that some biological effects of these agents are attributed to N-5 alkylation, 17) similar as for bis-quindolines. 57) Another interesting explanation of this effect is the modulation of AChE activity by the tested compounds by alteration of the distribution and mobility of membrane lipids (fluidity of the membrane).…”

“…This fact caused significant interest for the synthesis of indoloquinoline alkaloid derivatives, because of their potential biomedical and pharmaceutical value. 1,[17][18][19][20][21][22][23][24][25][26][27] Previous studies have indicated that all indolo[2,3-b]-quinolines belonging to the 5H-series possess interesting biological activities, including inhibition of the growth of Gram-positive bacteria and pathogenic fungi, cytotoxicity against KB cells and stimulation of the formation of calf thymus topoisomerase II mediated DNA cleavage. 17) 5,11-Dimethyl-5H-indolo [2,3-b] quinoline (DIMIQ), a benzoiso-α-carboline derivative, is one of the most interesting and active representatives of this group (Fig.…”

“…DIMIQ displayed strong antibacterial, antimycotic and cytotoxic activity in vitro as well as significant antitumor properties in vivo. 17,28,29) The influence of analogs of indolo [2,3-b] quinolines on cell cycle effects and their cytotoxicity have been extensively studied in vitro against several cell lines of different origin. Additionally, their ability to inhibit topoisomerase II activity was also evaluated.…”

Synthesis and Antiproliferative Activity of Novel Neocryptolepine-Hydrazides Hybrids

“…In each case, the compounds were designed to incorporate structural features that might increase DNA binding affinity, cell viability, and cytotoxicity towards the cancer cells. The indoloquinoline scaffold was selected due to its welldocumented DNA binding capability and to its DNA binding interactions through intercalation (Bailly et al, 2000;Guittat et al, 2003;Peczynska−Czoch et al, 1994). Therefore, indoloquinolines may be considered promising scaffolds for the development of novel selective anticancer drugs.…”