Phytocarbazoles: alkaloids with great structural diversity and pronounced biological activities

Abstract

Carbazole alkaloids characterized by a heterocyclic aromatic basic skeleton are known from different organisms but do not represent a biogenetically homogenous group. The majority, comprising more than 330 derivatives, is derived from 3-methylcarbazole as common precursor and is designated as phytocarbazoles. They are nearly exclusively known from the four closely related plant genera Bergera (part of Murraya s. l.), Clausena, Glycosmis, and Micromelum of the family Rutaceae. Derived from anthranilic acid and malonyl-CoA the tricyclic basic skeleton is formed via a prenylated 2-quinolone intermediate. The following steps are speculated to involve the formation of 2-prenylindole and cyclization of the prenyl side chain to generate 3-methylcarbazole. Apart from different oxygenations and oxidations of the basic skeleton additional prenylations and geranylations contribute to the great structural diversity of phytocarbazoles which are grouped together according to their C₁₃-, C₁₈-, and C₂₃-basic structures. Of taxonomic significance are the different oxidations of the characteristic C-3 methyl group leading to 3-formyl- and 3-carboxyl derivatives particularly accumulated in Clausena and Micromelum species. Predominant prenylation at C-5 is typical for Glycosmis and Micromelum, whereas in Clausena prenylation at different positions can contribute to an infrageneric grouping. Geranylation represents a characteristic biogenetic trend of Bergera. A wide variety of biological activities ranges from significant antimicrobial, antiprotozoal, and insecticidal properties to anti-inflammatory, antioxidative, antiplatelet aggregative, and anti-HIV activities. Of particular interest is the cytotoxicity of phytocarbazoles against various cancer cell lines, where some derivatives turned out to act as cell cycle inhibitors and apoptosis inducers. Especially the C₂₃ derivative mahanine induced different cell-signaling pathways suggesting that it represents a multi-targeted and multi-functional compound that works on an array of different cancer types and has the potential to inhibit tumor growth in vivo.