Novel Curcumin Monocarbonyl Analogue-Dithiocarbamate hybrid molecules target human DNA ligase I and show improved activity against colon cancer

Human DNA ligase I (hLigI) plays an important role in the process of DNA replication and repair mechanisms, making it an important target for cancer. This article reports the design, synthesis, and biological activity of a series of 59 curcumin-monocarbonyl-dithiocarbamate hybrid molecules. Many of the synthetic compounds tested in this study showed a significant inhibitory effect on hLig1 activity (>90% inhibition) and demonstrated significant antiproliferative activity against colon cancer cells (DLD-1) at the 10 µM concentrations, with certain compounds showing selective activity against DLD-1 as compared to the normal HEK-293 and VERO cell line. The activity of curcuminoids were compared against Doxorubicin and Bleomycin which were used as positive control compounds with activity towards hLigI. Further, we checked the cytotoxicity of two compounds ( 27 and 49 ) along with positive control Doxorubicin in a concentration-dependent manner against DLD-1, HEK293, and VERO cell lines. Overall, our studies demonstrated that compounds 27 and 49 have significantly better hLigI inhibition and targeted cytotoxic activities than the previously reported monocarbonyl-curcumin hybrid compound 23 *. This study brings us a step closer towards our quest to explore the molecular space for novel hLig1 inhibitors that will be suitable for clinical trials in cancer patients. Graphical abstract