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.