Indolocarbazole alkaloids

Structure 1 by means of X-ray crystallographic analysis of 4 -A/ -methylstaurosporine methiodide. Since the isolation of staurosporine, approximately 60 members of this class of compounds have been isolated from varions soil organisms, bine-green algae and slime molds. 

TAN-999 (2) and TAN-1030a (10) are produced by Nocardiopsis dassomillei C-71425 and Streptomyces sp. C-71799, respectively. They exhibited macrophage-activating 

Syntheses of staurosporine (1) and its analognes from non-carbohydrates have received much attention during the last two decades. It is apparent that carbohydrates are incorporated in such a ring system. 

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Batcho indole synthesis is a useful tool for synthesis of naniral products. As oudined in Scheme 10.6, the Batcho indole synthesis is used for total synthesis of the slime mold alkaloid arcyriacyanin. Such indolocarbazole alkaloids represent a growing number of naniral products isolated from soil organism, slime molds, and marine sources. They are important as andnimor compounds and protein kinase C and topoisomerase inhibitors. 

The majority of indolocarbazole alkaloids, isolated so far from nature, are derivatives of the indolo[2,3-fl]pyrrolo[3,4-c]carbazole ring system 292. They have been isolated from soil organisms, slime molds, and marine sources (3,7,8,252-255), and have shown a broad range of potent biological activities, such as antifungal, antimicrobial, antitumor, and antihypertensive activity (3,7,256-260,267-270). Their activity as potent inhibitors of protein kinase C (PKC) has received special attention, and was the focus of several investigations (8,257,258,271-280). The history of these natural products dates back about 30 years (Scheme 2.73). 

The anticancer indolocarbazole alkaloid rebeccamycin has been the subject of several biosynthetic studies (1439-1441, 2416), which is also proposed to involve the chlorination of tryptophan (Scheme 4.9). 

Engineering Biosynthetic Pathways to Generate Indolocarbazole Alkaloids in Microorganisms... 

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]. 

Two new indolocarbazole alkaloids, 4 -A -Methyl-5 -hydroxystaurosporine 12 and 5 -hydroxystaurosporine 13, were isolated from the culture broth of a marine Micromonospora sp. (strain L-31-CLCO-002) both showed cytotoxic activities against various tumor cell lines. 

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