lndolocarbazoles as Anti-Cancer Agents

Abstract: Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine protein kinases that plays a key role in signal transduction. Consequently, PKC controls a large variety of cellular processes such as proliferation and differentiation as well as smooth muscle contraction and secretions. The disruption of these processes would have severe implications for many physiological functions. The twelve known PKC isoenzymes show great variations in their substrate specificity and their distribution among different tissues, indicating their specialised role in certain tissue functions. Altered expression of PKC isoenzymes has been reported in a wide range of diseases. DNA topoisomerase I is a nuclear enzyme, involved in replication, transcription and recombination, that modifies and regulates the topological state of DNA. Many microbial metabolites and synthetic compounds possessing an indolocarbazole unit are biologically active products with antitumor properties. Antibiotic indolocarbazoles staurosporine, K-252a, UCN-01 and 02 are known protein kinase C inhibitors while structurally related rebeccamycin and ED-110 are topoisomerase I inhibitors without inhibitory effect against PKC. This review will update efforts made toward the discovery of antitumor indolocarbazoles and their possible mode of action via either PKC or topoisomerase I inhibition. Structure-activity relationship studies in a series of maleamide and maleimide indolocarbazoles bearing or not a sugar moiety linked either to both indole nitrogens such as staurosporine, or to one indole nitrogen such as rebeccamycin, will be reported.