J Appl Biomed 18:8-17, 2020 | DOI: 10.32725/jab.2020.001

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

Zuhier Awan¹, Hussam Ibrahim Kutbi², Aftab Ahmad³, Rabbani Syed⁴, Faten A. S. Alsulaimany⁵, Noor Ahmad Shaik^6,7,*

¹ King Abdulaziz University, Faculty of Medicine, Department of Clinical Biochemistry, Jeddah, Kingdom of Saudi Arabia

² King Abdulaziz University, Faculty of Pharmacy, Department of Pharmacy Practice, Jeddah, Kingdom of Saudi Arabia

³ King Abdulaziz University, Faculty of Applied Studies, Health Information Technology Department, Jedah, Kingdom of Saudi Arabia

⁴ King Saud University, College of Pharmacy, Department of Pharmaceutics, Riyadh, Kingdom of Saudi Arabia

⁵ King Abdulaziz University, Faculty of Science, Department of Biological Sciences, Jeddah, Kingdom of Saudi Arabia

⁶ King Abdulaziz University, Faculty of Medicine, Department of Genetic Medicine, Jeddah, Kingdom of Saudi Arabia

⁷ King Abdulaziz University, "Princess Al-Jawhara, Al-Brahim Center of Excellence in Research of Hereditary Disorders", Jeddah, Kingdom of Saudi Arabia

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.

Keywords: Apoptosis; Chemical analog; Drug designing; Molecular docking; NF-κB; RESV; U-937 cell lines

Grants and funding:

This project was funded by the Deanship of Scientific Research (DSR) at King Abdulaziz University Saudi Arabia, under Grant no. G-499- 140-1439. The authors, therefore, acknowledge the DSR for technical and financial support.

Conflicts of interest:

Authors declare no conflict of interests for this article.

Received: July 4, 2019; Revised: January 5, 2020; Accepted: January 23, 2020; Prepublished online: February 10, 2020; Published: March 1, 2020  Show citation