Isolation, biological activity and synthesis of the natural product ellipticine and related pyridocarbazoles

Abstract

The tetracyclic natural product ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) was first isolated from the plant material of Ochrosia elliptica Labill in 1959. Woodward et al. reported the first synthesis of ellipticine later the same year, and this was followed by many different synthetic strategies in subsequent decades. Investigation of the biological activity of ellipticines uncovered potent anti-cancer properties and several ellipticine derivatives have been the subject of clinical trials. The ellipticine family of compounds exert their biological activity via several modes of action, the most well established of which are intercalation with DNA and topoisomerase II inhibition. In recent times other modes of action have been revealed, including kinase inhibition, interaction with p53 transcription factor, bio-oxidation and adduct formation. The scope of this review covers key features of the biological activity of ellipticine, with emphasis on new modes of action, followed by synthetic routes to ellipticine, including key early syntheses of pyrido[4,3-b]carbazoles and comprehensive coverage of the literature since the late 1980s, along with more recent syntheses of ellipticine analogues and substituted ellipticines.