1-Methoxy-Canthin-6-One and Related β-Carbolines: From Natural Compound to Synthesis and Biological Activities

Abstract Ailanthus altissima Swingle (Simaroubaceae) is a medicinal plant used in traditional medicine as an antiviral and an antitumoral drug . Its roots have been successively extracted, at room temperature, with solvents of increasing polarity. The extracts were tested for their antiproliferative activity on HeLa (human cervical carcinoma cell line), at a dose of 10 μg/mL. The chloroform extract, the most active in biological assays, was fractionated on a silica-gel column: the fractions obtained were assayed on the proliferation of the same cellular line, at a dose of 10 mg/mL. The most active fraction (100% of cytotoxic activity) demonstrated to contain a single substance. The identification of this active substance, recognized as 1-methoxy-canthin-6-one, was performed by NMR methods. This indole alkaloid has shown antiproliferative and proapoptotic effects on several tumoral cell lines. In particular, it provoked mitochondrial membrane depolarization, mitochondrial release of cytochrome c and Smac/DIABLO, and caspase 3 activation on Jurkat cells (human leukemia cell line). The compound was active also on other tumor cell lines, HuH7 (hepatocellular carcinoma), NPA (human papillary carcinoma), and ARO (anaplastic thyroid cell line): the apoptosis-inducing activity was evident at a concentration of In vitro cytotoxic activities of these compounds were studied in a human tumor cell line panel. Almost all compounds demonstrated antiproliferative effects, in particular against prostate cancer cells PC-3, with an IC 50 values ranging between 60 and 8 μM. The most active derivatives were tested to evaluate the possible interaction with DNA and inhibition of topoisomerase I. None of these compounds were observed to stabilize the DNA–Topo I complex, thereby poisoning the reaction. In particular, 3-benzyl-1-methoxy-canthin-6-onium bromide exhibited strong inhibition of Topo I, with IC 50 of 17.77 μM.