The Synthesis of Biologically Active Indolocarbazole Natural Products Cite This: DOI: 10.1039/D0np00096e George E
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Natural Product Reports View Article Online REVIEW View Journal The synthesis of biologically active indolocarbazole natural products Cite this: DOI: 10.1039/d0np00096e George E. Chambers, a A. Emre Sayan b and Richard C. D. Brown *a Covering: up to 2020 The indolocarbazoles, in particular indolo[2,3-a]pyrrolo[3,4-c]carbazole derivatives, are an important class of natural products that exhibit a wide range of biological activities. There has been a plethora of synthetic approaches to this family of natural products, leading to advances in chemical methodology, as well as affording access to molecular scaffolds central to protein kinase drug discovery programmes. In this review, we compile and summarise the synthetic approaches to the indolo[2,3-a]pyrrolo[3,4-c]carbazole Received 16th December 2020 derivatives, spanning the period from their isolation in 1980 up to 2020. The selected natural products DOI: 10.1039/d0np00096e Creative Commons Attribution-NonCommercial 3.0 Unported Licence. include indolocarbazoles not functionalised at indolic nitrogen, pyranosylated indolocarbazoles, rsc.li/npr furanosylated indolocarbazoles and disaccharideindolocarbazoles. 1 Introduction nitrogen-containing ring (Fig. 1). There are several indolocarbazole 1.1 The indolocarbazoles isomers, of which the ve most commonly isolated are the 11,12- 1.2 The indolocarbazole alkaloids and their discovery dihydroindolo[2,3-a]-carbazole (1), 5,7-dihydroindolo[2,3-b]carba- 2 Syntheses of indolocarbazoles not functionalised at zole (2), 5,8-dihydroindolo[2,3-c]carbazole (3), 5,12-dihydroindolo indolic nitrogen [3,2-a]carbazole (4) and the 5,11-dihydroindolo[3,2-b]carbazole (5). This article is licensed under a 2.1 Staurosporine aglycone (staurosporinone, 10) The indolocarbazoles have been the subject of several extensive 2.2 Arcyriaavin A (45) 2.3 Arcyriaavins B–D 3 Pyranosylated indolocarbazoles Open Access Article. Published on 05 March 2021. Downloaded 10/1/2021 11:57:17 PM. 3.1 Staurosporine (7) 3.2 Rebeccamycin (8) 3.3 Syntheses of (+)-RK-286c (268), (À)-TAN-1030a (271) and (+)-MLR-52 (272) 4 Furanosylated indolocarbazoles 4.1 K252a (9) 5 Disaccharide indolocarbazoles 6 Conclusions 7 Author contributions 8 Conicts of interest 9 Acknowledgements 10 Notes and references 1 Introduction 1.1 The indolocarbazoles The indolocarbazoles are a family of heterocyclic natural products consisting of a carbazole core fused to an indole system through its aSchool of Chemistry, University of Southampton, Southampton SO17 1BJ, UK. E-mail: [email protected] bUniversity of Southampton Cancer Sciences Division, University of Southampton, Southampton SO17 1BJ, UK Fig. 1 Indolocarbazole isomers. This journal is © The Royal Society of Chemistry 2021 Nat. Prod. Rep. View Article Online Natural Product Reports Review reviews covering their chemistry, properties and biological activity.1–5 Of the indolocarbazole isomers described, the most rigor- ously studied is 11,12-dihydroindolo[2,3-a]-carbazole (1). In particular, a sub-family known as the indolo[2,3-a]pyrrolo[3,4-c] carbazole derivatives (6) ascended to prominence in the early 90 s aer discovery of interesting biological activities associated a c with these compounds, in particular their nanomolar inhibition Fig. 2 An isomer of indolo[2,3- ]pyrrolo[3,4- ]carbazole. of protein kinase C (PKC) (Fig. 2). This broad sub-family of natural products includes compounds both with and without indolic functionalisation, and for convenience throughout this 1.2 The indolocarbazole alkaloids and their discovery review they will be referred to as indolocarbazole natural In 1977, Omura and co-workers isolated a novel alkaloid they products. These natural products have been reviewed previously named AM-2282, from the bacterium Streptomyces staur- 6–8 from a broader perspective, as well as on more speci c osporeus.13 Preliminary testing of the alkaloid revealed strong 4,5,9 10 aspects such as their biological activity, biosynthesis and hypotensive activity as well as antimicrobial activity against 7,11,12 therapeutic application. The primary focus of the present fungi and yeast.13 Much effort was devoted to elucidate the review is on synthetic approaches to the indolocarbazole alkaloid's structure, which was later conrmed by X-ray crys- natural products. tallography, as an indolocarbazole core bearing two glycosyl linkages at the indolic nitrogens. AM-2282 was subsequently renamed staurosporine (7, Fig. 3).14,15 In 1985, Clardy and co-workers isolated rebeccamycin (8),16 and later that year Sezaki and co-workers reported the discovery George Chambers grew up in Creative Commons Attribution-NonCommercial 3.0 Unported Licence. of another important indolocarbazole alkaloid that subse- south–east England and studied quently became known as (+)-K252a (9) when Kase and co- chemistry at the University of workers isolated several more compounds with the indolo- Southampton, where he received carbazole core including the staurosporine aglycone (10).17–19 An a rst class MChem in 2018. excellent account of the discovery and isolation of members of During his studies, he spent 6 the indolocarbazole family can be found in Knolker¨ and Reddy's months at the University of Syd- review.20 ney working in the group of A pivotal development in the indolocarbazole alkaloid story Associate Prof. Christopher was realisation of their potential as therapeutic agents, or as This article is licensed under a McErlean on the synthesis of leads to develop more selective drugs. In particular, their high trehalose-6-phosphate potency as inhibitors of protein kinase C (PKC) caused great analogues. He then joined the excitement;18,21,22 K252a (9) exhibited nanomolar inhibition of group of Prof. Richard Brown for Open Access Article. Published on 05 March 2021. Downloaded 10/1/2021 11:57:17 PM. PKC (IC ¼ 32 nM) whilst staurosporine (7) displayed the his PhD where he is currently working on the total synthesis of 50 greatest inhibitory power (IC ¼ 2.7 nM).4,18,23 The PKC family indolocarbazole alkaloids. 50 Emre Sayan was born in Ankara, Richard Brown was born in Turkey, in 1972. He completed Canterbury, UK, in 1968. his BSc degree in Bogazici Following undergraduate and University, followed by MSc and postgraduate studies at the PhD degrees (2002) in Bilkent University of Southampton, UK University, department of (PhD 1994, supervisor Prof. Molecular Biology and Genetics. Philip J. Kocienski), he took up He worked in INSERM (Paris), a NATO postdoctoral fellowship MRC Toxicology Unit (Leicester, at UC Berkeley (Prof. Clayton H. UK) and University of Leicester Heathcock). He returned to the (UK) as postdoctoral and career University of Southampton in development fellow between 1996 as a Royal Society Univer- 2002–2010. He was appointed sity Research Fellow, and was as a Lecturer in University of Southampton, UK (2010). His promoted to Professor in 2010. His group's research includes research group's interests include biomarker discovery and drug natural product total synthesis, oxidative cyclisation methodology development for metastatic cancers. He has a fascination for and electro-organic synthesis using ow reactors. Natural products natural products and he always takes lessons from nature. provide a major inspiration for his research, with current synthetic targets including bioactive alkaloids. Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2021 View Article Online Review Natural Product Reports Fig. 3 Structures of indolocarbazole alkaloids. Creative Commons Attribution-NonCommercial 3.0 Unported Licence. of enzymes has an important role in regulation of cellular responses, which include gene expression, cell proliferation, and inammatory response. Consequently, PKC's have been under intense investigation over many decades in order to understand their structure, molecular mechanisms and impact upon cellular function. The discovery that inhibition of PKC can lead to cancer cell apoptosis stimulated huge interest in the Scheme 1 Winterfeldt and co-workers' synthesis of staurosporine aglycone (10). search for new classes of anti-cancer drugs.6,23,24 This exciting This article is licensed under a biological activity clearly heightened interest in indolocarba- zoles, stimulating many synthetic endeavours that extend over Discovery of important biological activity exhibited by these four decades. natural products sparked a dramatic upsurge in synthetic Open Access Article. Published on 05 March 2021. Downloaded 10/1/2021 11:57:17 PM. interest.6 In 1983, Raphael and co-workers developed a Diels– 2 Syntheses of indolocarbazoles not Alder/nitrene insertion approach to aglycone 10 (Scheme 2). Frustratingly, an initial attempt was thwarted by failure to functionalised at indolic nitrogen cleave N-benzyl protection from the aglycone.27 However, 2.1 Staurosporine aglycone (staurosporinone, 10) a synthesis of the unprotected aglycone 10 was ultimately 28 The rst indolocarbazoles covered herein are the natural published in 1990, commencing with a Wittig reaction products devoid of functionalisation at indolic nitrogen. One of between 2-nitrocinnamaldehyde (18) and phosphonium salt 19 – the most important is the staurosporine aglycone (10), also to give butadiene 20. The ensuing Diels Alder reaction with commonly referred to as K252c and staurosporinone. The rst dimethyl acetylenedicarboxylate gave 1,4-cyclohexadiene 21, synthesis was described in 1983 by Winterfeldt and co-workers which was subjected to dehydrogenative aromatisation and (Scheme 1).25 The synthesis