Indolocarbazole antitumour compounds by combinatorial biosynthesis

The indolocarbazoles constitute a family of natural products with potential therapeutic applications in the treatment of cancer and neurodegenerative disorders. Members of this family are either potent stabilizers of topoisomerase I-DNA covalent complex or potent inhibitors of protein kinases. Rebeccamycin, staurosporine, AT2433 and K252a are members of this family, which are produced by different actinomycete strains, and whose biosynthesis gene clusters have been isolated and characterized. A number of indolocarbazole derivatives have been generated by applying combinatorial biosynthesis technologies to these clusters either in the producer strain or in the heterologous hosts after expression of part or the entire gene cluster. Combinatorial biosynthesis is therefore providing a new approach for increasing structural diversity in this family of natural products.