Design and Synthesis of Novel 4’-Amino Substituted Flavone Derivatives as Anti-Cancer Agents

Abstract

Natural products are of great interest in the process of drug discovery due to their large diversity in nature, they permit the identification of leading molecules of interest for the development of new therapeutic agents. Flavonoids; naturally occurring polyphenols, are phenylbenzo-γ-pyrones derivatives and they possess a remarkable spectrum of biological activity among which Anti-cancer is the most promising one. Tankyrase inhibition is a novel mean of developing newer anticancer agents as it has the critical role in telomere homeostasis, mitotic spindle formation, vesicle transport linked to glucose metabolism, Wnt–b-catenin signaling, and viral replication. 4’- cholro flavone molecule was deemed to be having potential binding interaction towards TNKS2 enzyme’s nicotinamide binding site; due to this binding interaction 4’-chloro flavone shows good selectivity towards TNKS2 over ARTD. Based on above observations various 4’-aminosubstituted flavonoid derivatives have been designed which shows exactly the same interaction as that of 4’-chloro flavone i.e. Gly 1032 (H-bond) and Tyr 1071 (π-π stacking). These designed molecules were docked on TNKS2 enzyme among which MG-h3 and MG-h8 shows better docking score than reference 4’-chloro flavone and standard ligand nicotinamide. As per the docking results various 4’-aminosubstituted flavonoid derivatives were synthesized using baker-venkatraman rearrangement reaction. Which include acylation of 2- hydroxyacetophenone to give 2-acetylphenyl 4-chlorobenzoate which then undergoes baker-venkatraman rearrangement to give 3-(4-chlorophenyl)-1-(2- hydroxyphenyl)prop-2-en-1-one; which is cyclised to 4’-chloro flavone using glacial acetic acid. Cl group is then substituted with different amines to yield 4’-amino substituted flavone derivatives. Further synthesized and purified compounds were established by IR, Mass and H-NMR spectral data. The compounds which gave the highest docking scores and interaction might be further evaluated for anti-cancer activity.