Pyrrolo carbazole alkaloids

Indolocarbazole glycosides have attracted considerable interest over the years, as most indolo[2,3-fl]pyrrolo[3,4-c]carbazole alkaloids possess this structural feature. These systems are beyond the scope of this review however, there are several studies where glycosides of the parent system 1 have been investigated, in some... 

The UV spectrum (/Imax 229, 288, 324, 391, and 475 nm) of the pyrrolo[2,3-c]carbazole alkaloid 290 showed the presence of a pyrrolo[2,3-c]carbazole framework with a spirolactone structure. The H-NMR spectrum indicated the presence of two... 

The UV spectrum (/Imax 229, 289, 324, 391, and 475 nm) of the pyrrolo[2,3-c]carbazole alkaloid 291 was identical to that of 290, indicating the presence of a similar pyrrolo[2,3-c]carbazole spirolactone framework. Comparison of the spectral data of this isolate with those of the pyrrolo[2,3-c]carbazole alkaloid 290 indicated it to be an acid form of 290. This was further established by the chemical conversion of 291 to the corresponding 7-hydroxy derivative. Based on these spectral data, and the close structural similarity to 290, the structure 291 was assigned to this compound (250) (Scheme 2.72). 

Previously in the literature, for simplicity, under indolo[2,3-fl]carbazole natural products, only the indolo[2,3-fl]carbazoles with and without the pyrrolo[3,4-c]ring were considered. The recent past has witnessed an explosive growth of these natural products. Due to this, and the difference in the aglycon framework, in this article we have classified the indolo[2,3-fl]carbazoles with a pyrrolo[3,4-c]ring as indolo[2,3-fl]pyrrolo[3,4-c]carbazole alkaloids, and the indolo[2,3-fl]carbazoles without a pyrrolo[3,4-c]ring as simple indolo[2,3-fl]carbazole alkaloids. 

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). 

Pyrrolo[2,3-c]carbazole alkaloids (see Schemes 2.70-2.72) isolated from the dark green marine sponge, Dictyodendrilla sp., showed inhibitory activity against bovine lens aldose reductase catalyzing the reduction of aldoses to polyols which, on accumulation in cells, may result in diabetes. These alkaloids could provide prevention from such ailments (250). 

Until now, this relatively new class of imidazo[4,5-fl]pyrrolo[3,4-c]carbazole alkaloids includes only three natural products. These natural products showed G2 check point inhibitor activity, and thus represent a promising target for the development of new chemotherapeutic anticancer agents. Due to this fact, a wide range of analogs of imidazo[4,5-fl]pyrrolo[3,4-c]carbazole alkaloids were reported for structure activity studies. 

Funk and Huntley converted divinylpyrrolidine 10 to diene 11, and thence to an indole precursor 12 of )-cis-trikentrin B. A similar sequence was used to synthesize ( )-ci5 -trikentrin B. Dihydropyrrole 10 was assembled in five steps from A-Boc-2-pyrrolidinone. Fiirstner and coworkers synthesized several pyrrolo[2,3-c]carbazole alkaloids, the dictyodendrins B, C, and E, that featured a photochemical 6it-elecirocyclization and in situ dehydrogenation (equation 2) [21], Danheiser and colleagues effected an intramolecular benzyne generation and cycloaddition onto an alkynylpyrrole to afford a polycyclic indole (equation 3) [22],... 

The intramolecular amine-halogen copper-promoted indohzation was applied to the synthesis of more-complex indoles (Scheme , equations 1 ) [58-61]. Other examples in this category of copper-catalyzed amination are syntheses of the carbazole alkaloids murrayaquinone-A and ( )-bis-murrayaquinone-A [62], 3-aryl p-carbolin-l-ones [63, 64], carbazoles from donble C-N cyclization [65], pyrrolo[2,3-c]... 

The interest in indolocarbazoles began in the early 1950s with the first rational synthetic approaches. Since then, this interest has escalated dramatically as numerous derivatives of indolo[2,3-a]carbazole (1) have been isolated from various natural sources. These derivatives were demonstrated to possess highly potent and diverse biological effects, prompting novel efforts in the area. In particular, derivatives of indolo[2,3-n]pyrrolo[3,4-c]carbazole, such as the alkaloid staurosporine (8), have attracted much attention. 

Indolo[3,2-fl]pyrrolo[3,4-c]carbazoles 120 have been obtained in one step from indole and the corresponding maleimides in acetic acid, with coformation of the Michael adducts 121 (Scheme 15). This reactitai required careful temperature control in order to obtain the desired product ratios. An alternative independent synthesis of compounds 120 could also be accompKshed from 2,3 -biindolyl (115) andsuitable maleimides in hot acetic acid (99T2363). The system 120 where R = H has also been reported as a minor product during studies toward a synthesis of the alkaloid arcyriaflavin A (95TL2689). 

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). 

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