Publication

Abstract : 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.