Engineering Biosynthetic Pathways to Generate Indolocarbazole Alkaloids in Microorganisms

Engineering Biosynthetic Pathways to Generate Indolocarbazole Alkaloids in Microorganisms 

Cesar Sanchez, Carmen Mendez, Jose A. Salas 20.1 

The indolocarbazole alkaloids and the biosynthetically related bisindolylmaleiraides constitute an important class of natural products, which have been isolated from actinomycetes, cyanobacteria, slime molds, and marine invertebrates [1-3], They display a wide range of biological activities, including antibacterial, antifungal, antiviral, hypotensive, antitumor, and/or neuroprotective properties. The antitumor and neuroprotective activities of indolocarbazoles are the result of one, or several, of the following mechanisms (a) inhibition of different protein kinases, (b) inhibition of DNA topoisomerases, or (c) direct DNA intercalation [3-6], Hundreds of indolocarbazole derivatives have been produced by chemical synthesis or semisynthesis [1,2,6], and several of them have entered clinical trials for the treatment of diverse types of cancer, Parkinson s disease or diabetic retinopathy [3,7]. 

Structurally, most members of this family are characterized by a core consisting of an indolo[2,3-a]carbazole, which is frequently fused to a pyrrolo[3,4-c] unit. The chromophore is often decorated with a carbohydrate that is attached either through a single N-glycosidic bond, as in rebeccamycin 1 (REB), or through two C-N bonds, as in staurosporine 2 (STA). Another key structural difference between REB and STA resides at the pyrrole moiety, consisting of an imide function in the former but an 

Modem Alkaloids Structure, Isolation, Synthesis and Biology. Edited by E. Eattomsso and O. Taglialatela-Scafati Copyright 2008 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-31521-5 

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I 20 Engineering Biosynthetic Pathways to Generate Indolocarbazole Alkaloids in Microorganisms 20.4.4... 

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