Cancerostatics, VI. Synthesis and Antineoplastic Properties of Some Benzo‐iso‐α‐carbolines

Abstract

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...

Membrane Perturbations Induced by New Analogs of Neocryptolepine

“…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.…”

“…All these parameters are very important in predicting indoloquinoline behavior in biological environments. (2) were synthesized in the Pharmaceutical Research Institute (Warsaw, Poland) as described previously (DIMIQ- 28) ; 1, 2-Kaczmarek, unpublished data). Dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC) and the sodium salt of dimyristoylphosphatidylglycerol (DMPG) were purchased from Avanti Polar Lipids (Alabaster, AL, U.S.A.).…”

Schistosomicidal and molluscicidal activities of aminoalkylamino substituted neo- and norneocryptolepine derivatives

“…The synthetic strategy of neocryptolepine and norneocryptolepine compounds was based on the amination of chlorosubstituted compounds obtained through Graebe-Ullman condensation (Peczynska-Czoch et al, 1994;Kaczmarek et al, 1988). This method was used for -diethyl-1,4-pentanediamine was firstly used as basic side chain.…”

Synthesis and Cytostatic Properties of Some 6H‐Indolo[2, 3‐b][1, 8]naphthyridine Derivatives

“…The ellipticine isomer 5,11-dimethyl-5H-indolo[2,3-b]-quinoline ( Figure 2) showed strong cytotoxic properties in vitro, and other derivatives of this ring system have been found active against KB tumor cells [2].…”