Synthesis and evaluation of resveratrol derivatives as new chemical entities for cancer

Resveratrol has been shown to be active in inhibiting multistage carcinogenesis. The potential use of resveratrol in cancer chemoprevention or chemotherapy settings has been hindered by its short half-life and low bioavailability. Considering the above remarks, using resveratrol as a prototype, we have synthesized two derivatives of resveratrol. Their activity was evaluated using in vitro and in silico analysis. Biological evaluation of resveratrol analogues on U937 cells had shown that two synthesized analogues of resveratrol had higher rates of inhibition than the parental molecule at 10 μM concentration. EMSA conducted for NF-kB revealed that these molecules significantly interfered in the DNA binding ability of NF-kB. It was found that these molecules suppressed the expression of TNFα, TNFR, IL-8, actin and activated the expression of FasL, FasR genes. To understand possible molecular mechanism of the action we performed docking and dynamic studies, using NF-kB as a receptor. Results showed that resveratrol, RA1 and RA2 interacted with the residues involved in DNA binding. Resveratrol analogues by interacting NF-kB might have prevented its translocation and also by interacting with the residues involved in DNA binding might have prevented the binding of NF-kB to DNA. This may be the reason for suppression of NF-kB binding to DNA.

The synthesized analogues of resveratrol were more potent than the parent molecule in inducing anti-proliferative activities. Docking studies showed that they may interact with DNA binding residues of NF-kB for inhibiting its activity.Figure optionsDownload high-quality image (215 K)Download as PowerPoint slideHighlights
► Resveratrol derivatives were synthesized by synthetic manipulations onto resveratrol.
► Resveratrol and its derivatives induced interference the binding of NF-kB to DNA.
► Docking studies showed that NF-kB at its DNA binding domain may accommodate them.
► This might have changed the topology of the protein at its DNA binding site.
► RA1 showed more potent action and is even higher than that of the parental molecule.