Of rebeccamycin

Using the same enzyme, a library of antitumor indolocarbazoles was generated in a combinatorial fashion in vivo upon halogenation and glycosylation, producing halogenated analogs of rebeccamycin (Scheme 7.14) [54]. 

The UV spectrum [7max 238, 256 (sh), 293 (sh), 314, 362 (sh), and 390 (sh) nm] of rebeccamycin (337) indicated the presence of an indolo[2,3-fl]pyrrolo[3,4-c]carbazole-5,7(6H)-dione framework. This was also discernible from its IR spectrum. The H-NMR spectrum indicated the presence of an amide NH at 8 11.37 and an indole NH at 6 10.30, in addition to signals for aromatic protons and a sugar moiety. Unlike (+)-staurosporine (295) (see Scheme 2.74), where the lactam function deshielded only the ortho C-4 proton, the C-4 and C-8 aromatic protons in rebeccamycin are both deshielded due to the anisotropic deshielding effect of the phthalimide function. 

Prudhomme M (2000) Recent Developments of Rebeccamycin Analogues as Topoisomer-ase I Inhibitors and Antitumor Agents. Curr Med Chem 7 1189... 

Hussain M, Vaishampayan U, Heilbrun LK, Jain V, LoRusso PM, Ivy P, Flaherty L (2003) A Phase II Study of Rebeccamycin Analog (NSC-655649) in Metastatic Renal Cell Cancer. Invest New Drugs 21 465... 

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... 

Similar application to the construction of bisindole system was reported by Faul and co-workers. That is, the core structure (indole[2,3-a]carbazoles) (165) of rebeccamycin (61), which possesses potent antitumor and protein kinase C inhibitory properties, was synthesized by intramolecular coupling reaction of bisindolylmaleimides (164) with PIFA-BF3 Et20 [127] (Scheme 34). 

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]. 

Fig. 20.1 Gene clusters for biosynthesis of rebeccamycin, staurosporine, and AT2433.

As shown in Scheme 36, a Heck polyannulation reaction was realized between dibromo(indolyl)maleimide 209 and diacetylenyl trifluoroacetanilide 210 to assemble indolo[2.3-a]carbazole 211, the Af-prolecied aglycone of rebeccamycin (25). Four bonds were formed in one step from a single monocyclic 1,3-diacetylene precursor [101] and the trifluoroacetyl protecting groups were readily cleaved during the workup. 

Cycloadditions. An intramolecular [2+3]-cycloaddition involving a methylene-cyclopropane unit and a conjugated ester proceeds without stereochemical scrambling. A formal Diels-Alder reaction to rapidly build up the skeleton of rebeccamycin is reported. 

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

Nettleton, D.E., T.W. Doyle, B. Krishnan, G.K. Matsumoto, and J. Clardy Isolation and Structure of Rebeccamycin - A New Antitumor Antibiotic from Nocar dia aerocoligenes. Tetrahedron Letters 26, 4011 (1985). 

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