Covering: up to June 2006 The indolocarbazole family of natural products, including the biosynthetically related bisindolylmaleimides, is reviewed (with 316 references cited). The isolation of indolocarbazoles from natural sources and the biosynthesis of this class of compounds are thoroughly reviewed, including recent developments in molecular genetics, enzymology and metabolic engineering. The biological activities and underlying modes of action displayed by natural and synthetic indolocarbazoles is also presented, with an emphasis on the development of analogs that have entered clinical trials for its future use against cancer or other diseases.

Chemotherapy is one of the main treatments used to combat cancer. A great number of antitumor compounds are natural products or their derivatives, mainly produced by microorganisms. In particular, actinomycetes are the producers of a large number of natural products with different biological activities, including antitumor properties. These antitumor compounds belong to several structural classes such as anthracyclines, enediynes, indolocarbazoles, isoprenoides, macrolides, non-ribosomal peptides and others, and they exert antitumor activity by inducing apoptosis through DNA cleavage mediated by topoisomerase I or II inhibition, mitochondria permeabilization, inhibition of key enzymes involved in signal transduction like proteases, or cellular metabolism and in some cases by inhibiting tumor-induced angiogenesis. Marine organisms have attracted special attention in the last years for their ability to produce interesting pharmacological lead compounds.

Rebeccamycin and staurosporine are natural products with antitumor properties, which belong to the family of indolocarbazole alkaloids. An intense effort currently exists for the generation of indolocarbazole derivatives for the treatment of several diseases, including cancer and neurodegenerative disorders. Here, we report a biological process based on combinatorial biosynthesis for the production of indolocarbazole compounds (or their precursors) in engineered microorganisms as a complementary approach to chemical synthesis. We have dissected and reconstituted the entire biosynthetic pathway for rebeccamycin in a convenient actinomycete host, Streptomyces albus. This task was achieved by coexpressing different combinations of genes isolated from the rebeccamycin-producing microorganism. Also, a gene ( staC ) was identified in staurosporine-producing microbes and was shown to have a key role to differentiate the biosynthetic pathways for the two indolocarbazoles. Last, incorporation of the pyrH and thal genes, encoding halogenases from different microorganisms, resulted in production of derivatives with chlorine atoms at novel positions. We produced >30 different compounds by using the recombinant strains generated in this work.