From tryptophan to novel mitochondria-disruptive agent, synthesis and biological evaluation of 1,2,3,6-tetrasubstituted carbazoles

Mitochondrial targeting plays an important role in anticancer therapy. The Mn(III)-promoted cyclization of 5-(1H-indol-3-yl)-3-oxopentanoic acid allow to obtain novel substituted carbazole derivatives that can act as mitochondria-disruptive agents. The starting materials used for the synthesis of these new aminocarbazoles are oxopentanoate derivatives of tryptophan. The scope and limitation of this method of synthesis are determined by a series of experiments. The prepared carbazole derivatives are screened for their in vitro anticancer activity against a broad panel of human cancer cells and normal cell lines. Among the tested compounds, the most active ones are examined further against human colon cancer cells (HCT-116) and human bone osteosarcoma (U-2 OS), in complex in vitro cellular assays, including studies on cell cycle distribution, intracellular compartmentalization, antimigratory properties, mitochondrial generation of reactive oxygen species, DNA damage, and type of cellular death. The results reveal that the synthesized compounds display potent oxidative activity inducing massive accumulation of DNA double-strand breaks, which lead to a parallel change in the assembly of mitochondria causing their dysfunction. These findings provide new leads for the treatment of colon cancer and osteosarcoma. [Display omitted] •Tryptophans cyclize to substituted carbazoles.•Oxidative activity induced massive accumulation of DNA double-strand breaks.•Carbazoles induced intense senescence in both HCT-116 and U-2 OS cell lines.