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.

Some benzo-iso-a-carbolines were synthesized by modification of the Graebe-Ullmann reaction and examined for antineoplastic activity. The liTumorhemmende Substanzen, 6. Mitt.: Synthese und antineoplastische Eiaenschaften einiger Benzo-iso-a-carboline near, tetracyclic 5,11 -dirnethyl-5H-indolol2,3-blqu~noiine 136, that is related to ellipticine, showed significant antitumor activity against mice P 388 and L 1210 leukemias and against melanoma B 16. --Einige Benzo-iso-a-carboline wurden mittels einer modifizierten GraebeUNmann-Reaktion synthetisiert und auf tumorhemmende Wirkung georuft. Die dem Ellioticin strukturverwandte tetracvclische Verbindung In continuation of our study on the chemistry and biological activity of fused nitrogen heteroaromatic compounds we recently reported on the synthesis of 9H-pyrido[2,3-blindoles (a-carbolines) 12) and 1H-pyrido [2,3-b] indoles (iso-a-carbolines) z3):These compounds can be considered as "tricyclic analogues" of ellipticine 34). They showed, probably because they belong as planar aromatic ring systems to the general group of DNA intercalators, significant activity in vivo against mice Sarcoma Sa 1805) or in vitro against KB tumor cells3).In this paper we report on the synthesis and antitumor properties of the tetra-and pentacyclic benzo-iso-a-carboline systems 8, 13, 16, 23, and 29.The key-intermediates, 1-substituted benzo-and naphthotriazoles 6, 11 and 14, were obtained by heating directly 2-bromopyridine (4) or 2-chloroquinolines 9 with the corresponding naphtho-or benzotriazoles 5 or 10. The required triazoles 6, 11 and 14 were easily separated from the reaction mixture containing also 2-substituted isomers by crystallization.Thermal decomposition of 6, 11, and 14 in polyphosphoric acid (PPA) afforded compounds 7,12, and 15, respectively, which, after quaternization with methyl iodide and basification, gave the final benzo-iso-a-carbolines 8, 13, and 16.Another synthetic way, given on Scheme 2, was used for the 1 1 H-Benzo[i]-a-carboline 22 and 7H-benzo[gl-a-carboline 29 derivatives.The triazoles 21 and 27 were synthesized according to the procedure described earlier2). The thermal decomposition of triazoles 2 1 in PPA yielded benzo-a-carbolines 22, whereas the decomposition of triazole 27 afforded a mixture of products. The required benzo-a-carboline 28 was separated by column chromatography and its structure was confirmed by the 'H-NMR spectrum. The obtained benzo-a-carbolines 22 and 28 were then quaternized with methyl iodide and basified to give the desired benzo-iso-a-carbolines 23 and 29. Pharmacological Results ChemistryFor the synthesis of benzo-a-carbolines, modifications of the Graebe-Ullmann reaction were applied. The synthetic route to 1H-benzo[h]-a-carboline 8,5H-indolo[2,3-bIquinoline 13 and 5H-benzo [5,6]indolo[ 2,3-blquinoline 16 derivatives is depicted in Scheme 1:Compounds 8, 13, 16, 23, and 29 were tested in vitro on KB tumor cells and in vivo in mice bearing P 388 leukemia6! The cytotoxicity in vitro IC50 of the tested compounds is presented in T...

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