Molecular design, synthesis and biological characterization of novel Resveratrol derivative as potential anticancer agent targeting NF-κB.

Resveratrol (RESV), an anticancer nutraceutical compound, is known to show poor bioavailability inside the human body. Therefore, this study has designed multiple chemical analogs of RESV compound for improving its pharmacokinetic as well as its anti-cancer properties. Initially, the drug likeliness and ADME-toxicity properties of these new chemical analogs were tested with the help of diverse computational approaches. Then the best predicted RESV derivative is synthesized by the organic method, and its NF-κB mediated anti-tumor activity assessed on histiocytic lymphoma U-937 cells. The new synthetic RESV analog, i.e. (E)-3-(prop-2-yn-1-yloxy)-5-(4-(prop-2-yn-1-yloxy) styryl) phenol has shown a rapid, persistent and better dose-dependent (IC50 of 7.25 μM) decrease in the viability of U937 cells than the native (IC50 of 30 μM) RESV compound. This analog has also demonstrated its potential ability in inducing apoptosis through DNA ladder formation. At 10 µg/ml concentration, this chemical derivative has shown a better NF-κB inhibition (IC50 is 2.45) compared to the native RESV compound (IC50 is 1.95). Molecular docking analysis found that this analog exerts its anti- NF-κB activity (binding energy of -6.78 kcal/mol and Ki 10 µM) by interacting with DNA binding residues (Arg246, Lys444, and Gln606) of p50 chain NF-κB. This study presents a novel RESV analog that could further develop as a potential anti-NF-κB mediated tumor inhibitor.