Carbazole scaffolds in cancer therapy: a review from 2012 to 2018

Abstract

For over half a century, the carbazole skeleton has been the key structural motif of many biologically active compounds including natural and synthetic products. Carbazoles have taken an important part in all the existing anti-cancer drugs because of their discovery from a large variety of organisms, including bacteria, fungi, plants, and animals. In this article, we specifically explored the literature from 2012 to 2018 on the anti-tumour activities reported to carbazole derivatives and we have critically collected the most significant data. The most described carbazole anti-tumour agents were classified according to their structure, starting from the tricyclic-carbazole motif to fused tetra-, penta-, hexa- and heptacyclic carbazoles. To date, three derivatives are available on the market and approved in cancer therapy.

Keywords: Carbazole; cancer; cytotoxicity; enzyme inhibitors; targeted therapy.

Figure 1.

Chemical structures of ellipticine, elliptinium acetate (Celiptium^®) and a 6-bromo derivative of carbazole.

Figure 2.

Chemical structure of alectinib, an ALK inhibitor.

Figure 3.

Chemical structure of midostaurin, an FLT3 inhibitor.

Figure 4.

Main frameworks of biologically active carbazole alkaloids.

Figure 5.

Chemical structure of a ferrocenyl–terpyridine platinum(II) complex 1.

Figure 6.

Chemical structures of N-acyl carbazole derivatives 2a and 2b.

Figure 7.

Chemical structure of tetrahydrocarbazole 3.

Figure 8.

Chemical structures of N-{3-[3–(9-methyl-9H-carbazol-3-yl)-acryloyl]-phenyl}-benzamide derivatives 4a–j.

Figure 9.

Chemical structure of BMVC or compound 5.

Figure 10.

Chemical structures of benzopsoralen and (E)-ethyl-3-(3-hydroxy-9H-carbazol-9-yl)acrylate 6.

Figure 11.

Chemical structure of MHY407.

Figure 12.

Chemical structures of amide containing carbazole derivatives 7a–d and 8.

Figure 13.

Chemical structure of murrayafoline A.

Figure 14.

Chemical structure of clauszoline-I.

Figure 15.

Chemical structures of N-alkylcarbazole derivatives 9a–c.

Figure 16.

Chemical structure of excavatine A.

Figure 17.

Chemical structure of clausenawalline F.

Figure 18.

Chemical structures of compounds 10, 11 and 12.

Figure 19.

Chemical structures of EHop-016 and compounds 13a and 13b.

Figure 20.

Chemical structures of carbazole-3,6-diamine derivatives 14a and 14b.

Figure 21.

Chemical structures of compounds IG-105 and SL-3-19.

Figure 22.

Chemical structures of 1,4-dimethylcarbazole derivatives 15 and 16.

Figure 23.

Chemical structures of guanidinocarbazole compounds 17a–c.

Figure 24.

SAR of tricyclic carbazoles.

Figure 25.

Chemical structure of cyclopenta[c]carbazole 18.

Figure 26.

Chemical structure of mafaicheenamine E.

Figure 27.

Chemical structures of N-10-substituted pyrrolo[2,3-a]carbazole derivatives 19a–g.

Figure 28.

Chemical structures of N₁,N₁₀-bridged pyrrolo[2,3-a]carbazole-3-carbaldehydes 20a and 20b.

Figure 29.

Chemical structure of pyrrolo[2,3-a]carbazole 21.

Figure 30.

Chemical structures of Chk1 inhibitors 22 and 23.

Figure 31.

Chemical structures of pyrazolo[3,4-c]carbazole 24 and pyrazolo[4,3-c]carbazole 25.

Figure 32.

Chemical structure of the isoxazolocarbazole derivative 26.

Figure 33.

SAR study of tetracyclic carbazoles containing a 5-membered ring.

Figure 34.

Chemical structures of compounds 27a–d as ALK inhibitors.

Figure 35.

Chemical structures of crizotinib (Xalkori^®), a second generation of ALK inhibitors.

Figure 36.

Chemical structures of 2–(4-amino-benzosulfonyl)-5H-benzo[b]carbazole-6,11-diones 28 and 29a,b.

Figure 37.

Chemical structure of girinimbine.

Figure 38.

Chemical structures of some pyrano[3,2-c]carbazole derivatives 30a–d.

Figure 39.

Chemical structure of mahanine.

Figure 40.

Chemical structure of the pyridocarbazole 31.

Figure 41.

Chemical structures of olivacine and derivatives 32a–i used for 2 D QSAR analysis.

Figure 42.

Chemical structure of hetero annulated carbazole compound 33.

Figure 43.

Chemical structure of the pyridocarbazole 34.

Figure 44.

Chemical structure of pyridocarbazole 35.

Figure 45.

Chemical structure of ditercalinium.

Figure 46.

Chemical structures of pyrimido[4,5-a]carbazole derivatives 36a–d.

Figure 47.

Chemical structures of oxazinocarbazole derivatives 37a–c.

Figure 48.

Chemical structures of the tetracyclic carbazoles 38, 39, and 40.

Figure 49.

SAR of tetracyclic carbazoles containing a 6-membered ring.

Figure 50.

Chemical structures of the 1,4-thiazepan-3-ones fused with carbazoles 41a–f.

Figure 51.

Chemical structures of 3-substituted-pyrrolocarbazole analogs 42a and 42b.

Figure 52.

Chemical structure of tetrahydroindolocarbazole 43.

Figure 53.

Chemical structure of pyridocarbazole-rhodium complex 44.

Figure 54.

Chemical structures of iridium complex 45a and its N-methylated derivative 45b.

Figure 55.

Chemical structure of DBC and B[a]P.

Figure 56.

Chemical structure of murrayazolinine.

Figure 57.

Chemical structure of carbazole-amonafide structural hybrid lead candidate 46.

Figure 58.

Chemical structures of K252c the indenopyrrolocarbazole, compound 47.

Figure 59.

Chemical structure of CEP-11981.

Figure 60.

Chemical structures of the synthetic indolocarbazoles in clinical trials.

Figure 61.

Chemical structures of staurosporine, indolocarbazole analogs and compound 48.

Figure 62.

Chemical structures of streptocarbazoles A and B.

Figure 63.

Chemical structures of new indolopyrrolocarbazoles 49a–d.

Figure 64.

From pyrrolocarbazole, a growing approach to design new hexacyclic fused carbazoles as anti-cancer drugs.

Figure 65.

Chemical structures of indolocarbazoles 50 and 51.

Figure 66.

Chemical structures of indolopyrimidocarbazole 52a and azaindolopyrimidocarbazole 52b.

Figure 67.

Pharmacomodulation works by replacement of pyrrole moiety.

Figure 68.

Chemical structures of carbazole derivatives of ursolic acid 53a–f.

Figure 69.

Major anti-tumor activities of carbazole derivatives.