New indolocarbazoles as antitumour active compounds: evaluation of the target by experimental and theoretical studies.
A series of indolocarbazoles was synthesized as congeners of the natural lead compounds rebeccamycin (1) and staurosporine (2) which reduce cell growth by inhibiting topoisomerase I and protein kinase C respectively. Two of the carbazoles (3 and 4) screened at the National Cancer Institute (NCI, USA) showed an interesting cytotoxic activity and were therefore further analysed. The mechanism of action of these two compounds was studied experimentally using different assay to determine the B-DNA binding ability and the inhibition of topoisomerase I and of protein kinase C. Theoretical molecular modelling studies were also performed to describe the possible interactions with protein kinase C and DNA.
Marotto
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A
Institut für Pharmazie, Fachbereich Chemie und Pharmazie der Johannes Gutenberg-Universität Mainz, Germany.
Kim
Y S
YS
Schulze
E
E
Pindur
U
U
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002227:Carbazoles / Q000138:chemical synthesis / Q000494:pharmacology; D004247:DNA / Q000187:drug effects; D004265:DNA Helicases / Q000737:chemistry / Q000187:drug effects; D004587:Electrophoresis, Agar Gel; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004996:Ethidium / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology; D008958:Models, Molecular; D009691:Nucleic Acid Denaturation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D059005:Topoisomerase II Inhibitors; D004247:DNA; D011493:Protein Kinase C; D004265:DNA Helicases; D004996:Ethidium