Synthesis, antiproliferative, cell cytotoxicity activity, DNA binding features and molecular d ocking study of novel enamine derivatives.

: Novel enamine derivatives (7a-o) were synthesized from the reaction of lactone (6) and chalcones (3a-o) and their antiproliferative and cell cytotoxicity activities against six cancer cell lines (e.g., HeLa, HT29, A549, MCF7, PC3 and Hep3B) and one normal cell line (e.g., FL) were investigated along with their mode of interactions with CT-DNA. Most of the enamine derivatives (7a-o) with 86-168 µM IC50 values demonstrated much stronger antiproliferative activity than the starting molecules (3a-o) against the cancer cells. While, among the enamine derivatives, the compounds 7e, 7f, 7k and 7l displayed higher cytotoxic potency than the control drugs (5-fluorouracil and cisplatin) against the Hep3B cell line, these compounds did not exhibit any significant toxicity against normal cells, FL. The UV-Vis spectral data suggest that the compounds 7c, 7e, 7i, 7l, 7m, 3d, 3i and 3o cause hypochromism with a slight bathochromic shift (~6 nm), indicating that they bind to the DNA by way of an intercalative or minor groove binding mode. The binding constants of the compounds are in the range of 0.1 × 103 M-1-2.3 × 104 M-1. The antiproliferative activity of studied enamine derivatives could possibly be due to their DNA binding as well as their cytotoxic properties. In addition to these assays, compounds 3a-3o and 7a-7o were investigated by molecular docking to calculate the synergistic effect of antiproliferative activities against six human cancer cell lines.