Biological evaluation of omega-(dialkylamino)alkyl derivatives of 6H-indolo[2,3-b]quinoline--novel cytotoxic DNA topoisomerase II inhibitors.
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 microM) 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.
Godlewska
Joanna
J
Pharmaceutical Research Institute, 8 Rydygiera St., 01-783 Warszawa, Poland.
Luniewski
Wojciech
W
Zagrodzki
Bogdan
B
Kaczmarek
Lukasz
L
Bielawska-Pohl
Aleksandra
A
Dus
Danuta
D
Wietrzyk
Joanna
J
Opolski
Adam
A
Siwko
Magdalena
M
Jaromin
Anna
A
Jakubiak
Anna
A
Kozubek
Arkadiusz
A
Peczyñska-Czoch
Wanda
W
D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007624:KB Cells; D008826:Microbial Sensitivity Tests; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D018736:DNA Adducts; D007211:Indoles; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; D004247:DNA; C427203:calf thymus DNA