Biological evaluation of ω-(dialkylamino)alkyl derivatives of 6H-indolo[2,3-b]quinoline- novel cytotoxic DNA topoisomerase II inhibitors
2005
A series of novel 6H-indolo(2,3-b)quinoline derivatives, substituted at C-2, C-9 or N-6 position with dialkyl(alkylamino)alkyl chains differing in the number of methylene groups, was prepared. These compounds were evaluated in vitro for their antimicrobial and cytotoxic activity against several cell lines of different origin and tested for their ability to influence the cell cycle and inhibit topoisomerase II activity. Liphophilic and calf thymus DNA-binding properties of these compounds were also investigated. All the compounds tested inhibited the growth of Gram-positive bacteria and fungi at MIC values ranging between 0.25 and 1 mM. They also showed cytotoxic activity against KB (human cervix carcinoma) cells (ID50 varied from 2.1 to 9.0 IM) and were able to overcome multidrug resistance in colorectal adenocarcinoma LoVo/DX, uterine sarcoma MES-SA/DX5 and promyelocytic leukemia HL-60/MX2 cells (the values of the resistance index RI fell between 0.54 and 2.4). The compounds induced G2M-phase cell cycle arrest in Jurkat T-cell leukemia cells, revealed DNA-binding properties and inhibited topoisomerase II activity. Indolo(2,3-b)quinolines are a group of synthetically obtained analogues of the natural alkaloid, neocryptolepine. They share many biological properties with this compound, including the ability to interact with DNA as intercalators and to inhibit topoisomerase II activity. The indolo(2,3- b)quinoline derivatives also revealed antimicrobial and cytotoxic potential (17-19). Our previous research on 6H-indolo(2,3-b)quinolines was directed towards the synthesis and characterization of derivatives bearing three kinds of substituents: alkyl-, (alkylamino) alkyl- and 4-(3-chlorophenyl) piperazi-1-yl- propyl at the N-6 position. We found that only the presence of an (alkylamino) alkyl chain introduced into the indolo(2,3-b)quinoline core would be a suitable structural requirement for cytotoxic activity, antimicrobial properties and topoisomerase II inhibition (1). As a part of our programme, which aimed at exploring the effect of the introduction of (alkylamino) alkyl chains of different length, we synthesized novel 6H-indolo(2,3- b)quinoline derivatives bearing (alkylamino) alkyl substituents at the C-2, C-9 or N-6 positions. The obtained compounds were evaluated in vitro for their cytotoxicity against the KB cervical cancer cell line, as well as against three other cancer cell lines and their drug-resistant sublines: human colorectal adenocarcinoma LoVo and doxorubicin-resistant LoVo/Dx (P-gp-dependent 1 -, MRP 2 -, LRP 3 -dependent multidrug resistance), human uterine sarcoma MES-SA and
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