ABSTRACT
Bacteria and primitive organisms are important sources of various compounds of biological interest. Among the diversity of bacterial metabolites are maleimido-or maleamido-indolocarbazoles. Some of them do not bear any sugar moiety (arcyriaŸavins, tjipanazole J, K-252c, and BE-13793C), and others have a carbohydrate moiety linked to only one indole nitrogen (rebeccamycin, AT2433-A1, and AT2433-B1) or to both indole nitrogens (staurosporines, K-252a, and K-252b) (Figure 24.1).1-6 Staurosporine was isolated from Streptomyces staurosporeus7,8 in 1977, and three years later, arcyriaŸavins were obtained from the fruiting bodies of slime molds Arcyria denudata.9 Later, more than 30 microbial staurosporine analogs were isolated from bacterial cultures. Indolocarbazoles have attracted considerable interest since the discovery in 1986 of the inhibitory properties of staurosporine toward protein kinase C (PKC), a kinase involved in many signal transduction pathways leading to a variety of cell responses, such as cell proliferation, differentiation, and gene expression.10 K-252a and analogs bearing a œve-membered ring sugar moiety have been isolated from Nocardiopsis and Streptomyces species, and they are also PKC inhibitors.11-13 Stauro sporine is a nonselective adenosine triphosphate (ATP)-competitive kinase inhibitor that inhibits the different PKC isoenzymes,
24.1 Introduction .......................................................................................................................... 647 24.2 Mechanisms of Action ..........................................................................................................649
