Design and synthesis of dithiocarbamate linked β-carboline derivatives: DNA topoisomerase II inhibition with DNA binding and apoptosis inducing ability

Article abstract of DOI:10.1016/j.bmc.2015.07.037

A series of new β-carboline-dithiocarbamate derivatives bearing phenyl, dithiocarbamate and H/methyl substitutions at position-1, 3 and 9, respectively, were designed and synthesized. These derivatives 8a-l and 13a-l and their starting precursors (7a-d and 12a-d) have been evaluated for their in vitro cytotoxic activity on selected human cancer cell lines. Among the derivatives tested, 7c, 12c, 8a, 8d, 8i, 8j, 8k, 8l and 13d-l exhibited considerable cytotoxicity against most of the tested cancer cell lines (IC₅₀ <10 μM). Interestingly, most of the derivatives (8a-l and 13a-l) exhibited enhanced activity than their precursors (7a-d and 12a-d), which indicates that the combination of dithiocarbamate with β-carboline enhances the cytotoxicity of 8a-l and 13a-l. Moreover, the derivatives 8j and 13g exhibited significant cytotoxic activity with IC₅₀ values of 1.34 μM and 0.79 μM on DU-145 cancer cells, respectively. Further, the induction of apoptosis by these derivatives was confirmed by Annexin V-FITC and Hoechst staining assays. However, both biophysical as well as molecular docking studies suggested a combilexin-type of interaction between these derivatives and DNA, unlike simple β-carbolines. With a view to understand their mechanism of action, DNA topoisomerase II (topo II) inhibition assay was also performed. Overall, the present study emphasizes the importance of linking a dithiocarbamate moiety to the β-carboline scaffold for exhibiting profound activity.