Of indolocarbazole alkaloid

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). 

Only a few methodologies have been developed for S3mthesizing complex carbohydrate intermediates for use in the total s)mthesis of indolocarbazole alkaloids such as staurosporine (1). Some of those strategies are summarized in the succeeding sections ... 

Mohankrishnan et al s)mthesized staurosporine aglycon and its analogues with 28-36% overall yield, using 2-methylindole (110) as synthetic precursor [50]. The key steps for the s)mthesis of indolocarbazole alkaloids involved electrocychzation and nitrene insertion reactions as depicted in Schemes 16 and 17. 

Fig. 4.40 Intramolecular cross-linking of two indole chrome P450-catalyzed generation of a radical on each of units in the biosynthesis of indolocarbazole alkaloids, the two indole rings, as shown Dimerization is most reasonably explained by the cyto-...

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 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). 

Some selected alkaloids are readily accessible via the corresponding chromium carbenes. A versatile synthesis of indolocarbazoles 133 and 134, bioactive natural products with interesting protein kinase C inhibiting properties, is based on photobenzannulation. Depending on the nature of the Cj-synthon, dioxy and oxyamino derivatives have been synthesized in good to very good yields (Scheme 46) [96]. 

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. 

The earliest application of inverse-detected 2D NMR techniques to a terrestrial alkaloid of which we are aware was the assignment of the H and NMR spectra of the indolocarbazole alkaloid staurosporine (7) reported by Meksuriyeri and Cordell (1988). Later in 1988, Edwards et al. utilized HMQC in the elucidation of the structure of pumiliotoxin-A (10) and related indolizine alkaloids isolated from Panamanian poison frogs. These were the only applications of inverse-detected 2D NMR techniques in alkaloid to appear in 1988. We will thus begin with staurosporine (7) and proceed to related carbazole-based alkaloids before continuing to pumiliotoxin-A (10) and other terrestrial alkaloids. 

Recently still another class of compounds of fused carbazole alkaloids has been recognized. Two particulary interesting members of this class are staurosporine (8a) and its aglycon (8b), both potent inhibitors of protein kinase C. The chemistry of the indolocarbazole alkaloids ha recently been thouroughly reviewed " and will therefore not be discussed in this treatise. 

Strategies Towards the Synthesis of Staurosporine Indolocarbazole Alkaloid and Its Analogues... 

Knolker and Reddy reviewed the s)mthesis and biological activity of carbazole alkaloids, depicted in Figure 2, where different S3mthetic strategies for indolocarbazole alkaloids were discussed [15]. 

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