Biosynthetic rebeccamycin

Independently, in 1998, the Cordell (290,379,380) and Pearce (381) groups published some preliminary biosynthetic results on staurosporine and rebeccamycin, typical representative members of the indolo[2,3-fl]pyrrolo[3,4-c]carbazole alkaloids. Cordell s biosynthetic studies on staurosporine were based on feeding experiments with L-tryptophan. These studies showed that two units of L-tryptophan, with the two carbon side-chains intact, were responsible for the biosynthesis of staurosporine aglycone. Further experimental studies are necessary to establish the nature of the intermediate in the biotransformation of L-tryptophan to staurosporine. Although these studies are not complete, they gave for the first time insight into the biosynthesis of staurosporine (379,380). 

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). 

Onaka H, Taniguchi S, Igarashi Y, Furumai T (2003) Characterization of the Biosynthetic Gene cluster of Rebeccamycin from Lechevalieria aerocolonigenes ATCC 39243. Biosci Biotechnol Biochem 67 127... 

The biosynthesis of 1 follows a pattern seen for all bisindoles that have been biosynthetically investigated thus far [17, 163, 164] two molecules of L-tryptophan (123) are oxidized and then dimerized to give an initial bisindole skeleton (Fig. 24). Historically, the biosynthesis of staurosporine (121) has been investigated in parallel with that of rebeccamycin (124), a related bisindole. Both molecules are thought to be biosynthesized through nearly identical routes to give the aglycone... 

That chlorination occurs early in the biosynthesis of rebeccamycin is shown by the identification of two genes in the biosynthetic duster and their ability to chlorinate tryptophan at C-7 as shown in Scheme 19.5 [117]. 

Rebeccamycin is a natural product that inhibits DNA topoisomerase I and has been studied as a potential anticancer agent because of the importance of DNA topoisomerase I in cell growth and proliferation. Rebeccamycin analogues are being used in clinical trials for the treatment of neoplastic tumors,renal cell cancer, and leukemia, " rehO is one of the 11 genes in the rebeccamycin biosynthetic cluster. The protein product, RebO, is an L-amino acid oxidase that contains a noncovalently bound FAD. RebO catalyzes the oxidation of 7-chloro-L-tryptophan in an early step in rebeccamycin biosynthesis (Equation (4)). 

Figure 5.50 Early (a) and revised (b) proposal for the biosynthetic pathway of rebeccamycin.

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