Advances in lndolo[2,3-a]carbazole Chemistry: Design and Synthesis of Protein Kinase C and Topoisomerase I Inhibitors

Abstract

lndolo[2,3-a]carbazoles, their pyrrolo[3,4-c]anellated variants and structurally closely related bisindolylmaleimides represent a biologically highly interesting class of natural compounds which are potential anticancer agents. According to the ongoing literature new and efficient synthetic methods yield a great variety of these compounds which have been reported in detail. The biological activities and the inhibitory activities against the target enzymes protein kinase C and topoisomerase I are also discussed including structure activity relationships. A molecular binding model of the protein kinase C inhibitors with the target enzyme at the atomic level is presented and supported by X-ray crystallographic structures and by molecular modelling studies.

Chemistry and Properties of Indolocarbazoles

“…Coverage of the early progress in the synthesis of indolo­[2,3- a ]­carbazoles has been included in several previous accounts. ,,, Many of the synthetic approaches from that time are still widely used, and the discussion in this section will therefore focus on highlighting selected methods for ring synthesis and functionalization, with the aim to illustrate the most general synthetic routes, particularly the most recent advances.…”

“…The indolo­[2,3- a ]­pyrrolo­[3,4- c ]­carbazoles occupy the position as the most intensely studied group of indolocarbazole derivatives and are featured in a multitude of journal articles and patents. Consequently, this subject has been reviewed in much detail over the years, covering topics ranging from natural occurrence and biosynthesis, ,,, chemical synthesis, ,,, to biological effects and therapeutic applications. ,,, Hence, only a selection of representative examples described in scientific journals will be presented, illustrating some directions of research, bearing in mind that a comprehensive account of this intensely researched area (which is particularly evident from the vast patent literature) is beyond the scope of this text.…”

“…The same is true for the antitumor natural product rebeccamycin ( 7 ), − which is one of the most influential indolo­[2,3- a ]­pyrrolo­[3,4- c ]­carbazole derivatives with tremendous impact on subsequent research activities, which rapidly established the indolo­[2,3- a ]­carbazole as the most intensely studied isomer. The indolo­[2,3- a ]­pyrrolo­[3,4- c ]­carbazoles have been reviewed thoroughly over the years, focusing not only on general aspects ,− but also on more specialized topics such as biosynthesis − and development of rebeccamycin analogues as anticancer agents. , …”

One-Pot Access to Benzo[a]carbazoles via Palladium(II)-Catalyzed Hetero- and Carboannulations

“…Carbazoles, prevalent in many naturally occurring alkaloids, have gained considerable attention in recent times due to their diverse biological and unique optical properties . Among the large varieties of carbazoles, aryl/heteroaryl annulated ones are of special interest because of their significant biological and pharmaceutical potential arising out of their special affinity toward DNA . Benzo­[ a ]­carbazoles display a broad range of activities including anti-inflammatory, antiestrogenic, antifungal, and kinase inhibitory and are also utilized in other fields such as development of light-emitting diodes (LEDs), dye-sensitized solar cells (DSSC), and fluorescent reagents .…”

Coupling reactions of indole-3-acetic acid derivatives. Synthesis of arcyriaflavin A

“…The interesting biological activities of indolocarbazole alkaloids, such as the protein kinase C inhibitor staurosporine 1 and the tumour-growth inhibitor rebeccamycin, 2 have stimulated the development of a number of synthetic approaches towards indolo [2,3-a]pyrrolo [3,4-c]carbazoles such as the aglycon of 1, staurosporinone 3, and arcyriaflavin A 4. [3][4][5][6][7] Both staurosporine 1 and rebeccamycin 2 have been shown by labelling experiments to be biosynthetically derived from two tryptophan units. 8, 9 This notion has been used by us 10, 11 and others 12 in the synthetic strategy to this type of compounds.…”