Functionalized and [a]-anellated carbazoles as potential B-DNA ligands: experimental studies of DNA binding and molecular modeling of intercalation complexes.
Three synthetically available carbazole derivatives 3-5 were investigated for DNA binding (ethidium bromide displacement assay, DNA unwinding assay), for inhibition of topoisomerase I and for cell cytotoxicity (antitumour cell lines). In addition molecular modeling studies of DNA complexes were performed by semiempirical quantum chemistry, force field calculations and molecular dynamics calculations. In summary, combining the results from experiments and molecular modeling, the naphthoquinone anellated carbazole 4 emerges as a promising antitumour active candidate for further drug design studies in carbazole chemistry.
Pindur
U
U
Institut für Pharmazie, Fachbereich Chemie und Pharmazie, Johannes-Gutenberg-Universität, Mainz, Germany. pindur@mail.uni-mainz.de
Marotto
A
A
Schulze
E
E
Fischer
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000187:drug effects*; D004265:DNA Helicases / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004996:Ethidium; D005456:Fluorescent Dyes; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007928:Lethal Dose 50; D008024:Ligands; D008958:Models, Molecular; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002227:Carbazoles; D005456:Fluorescent Dyes; D007364:Intercalating Agents; D008024:Ligands; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004265:DNA Helicases; D004996:Ethidium