title: Synthesis, and cytotoxic activity of some novel indolo[2,3-b]quinoline derivatives: DNA topoisomerase II inhibitors.
abstract: A series of new 5H-indolo[2,3-b]quinoline derivatives bearing methoxy and methyl groups at C-2 and C-9 was synthesized (according to the modified Graebe-Ullmann reaction). These compounds were evaluated for their antimicrobial and cytotoxic activity and tested as inhibitors of DNA topoisomerase II. Lipophilic and calf thymus DNA binding properties of these compounds were also established. In the SAR studies we used quantum-mechanical methodology to analyze the molecular properties of the drugs. All of the 5H-indolo[2,3-b]quinolines tested were found to inhibit the growth of gram-positive bacteria and pathogenic fungi at MIC ranging between 2.0 and 6.0 microM. They showed also cytotoxic activity in vitro against several human cancer cell lines of different origin (ID50 varied from 0.6 to 1.4 microM), and stimulated the formation of topoisomerase-II-mediated pSP65 DNA cleavage at concentration between 0.2 and 0.5 microM. The most active indolo[2,3-b]quinolines which had the greatest contribution to the increase in the Tm of DNA displayed also the highest DNA binding constants and the highest cytotoxic activity. The differences in DNA binding properties and cytotoxic activity seem to be more related to steric than electrostatic effects.
authors.affiliation: Pharmaceutical Research Institute, Warszawa, Poland.
authors.forename: L
authors.initials: L
authors.lastname: Kaczmarek
authors.forename: W
authors.initials: W
authors.lastname: Peczyńska-Czoch
authors.forename: J
authors.initials: J
authors.lastname: Osiadacz
authors.forename: M
authors.initials: M
authors.lastname: Mordarski
authors.forename: W A
authors.initials: WA
authors.lastname: Sokalski
authors.forename: J
authors.initials: J
authors.lastname: Boratyński
authors.forename: E
authors.initials: E
authors.lastname: Marcinkowska
authors.forename: H
authors.initials: H
authors.lastname: Glazman-Kuśnierczyk
authors.forename: C
authors.initials: C
authors.lastname: Radzikowski
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D007211:Indoles; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; D004247:DNA; D004250:DNA Topoisomerases, Type II