Divergent Synthesis and Evaluation of the in vitro Cytotoxicity Profiles of 3,4‐Ethylenedioxythiophenyl‐2‐propen‐1‐one Analogues

Abstract

A new series of 3,4‐ethylenedioxythiophene (EDOT)‐appended propenones were prepared by condensation reaction and their in vitro cytotoxicity effects were evaluated against five human cancer cell lines. Preliminary structure–activity relationships of EDOT‐incorporated 2‐propenone derivatives were also established. The EDOT‐appended enones demonstrated significant cytotoxicity against human cancer cell lines. The most active analogue, (E)‐3‐(2,3‐dihydrothieno[3,4‐b][1,4]dioxin‐5‐yl)‐1‐(3,4,5‐trimethoxyphenyl)prop‐2‐en‐1‐one (3 p, GI50=110 nm), severely inhibited the clonogenic potential of cancer cells, and induced cell‐cycle arrest in the G2/M phase and caused an accumulation of HCT116 colon cancer cells with >4 N DNA content. Also, 3 p exhibited weak inhibition of the enzymatic activity of human topoisomerase I. Molecular docking studies indicated preferential binding of the compounds to the ATP‐binding pocket of the human checkpoint 2 kinase (Chk2) catalytic domain, thus, identifying a novel diaryl 2‐propenone chemotype for the development of potent inhibitors of Chk2.

Novel Thienyl-Based Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma

“…Various reports have described the promising anti-tumor activities of thiophene-based compounds [ 19 , 20 ]. Recently, we identified some E -2-(2-thienyl)-3-acrylonitrile derivatives with high anti-tumor efficacy in p53 wild-type HepG2 hepatoblastoma cells which were more active than the clinically applied multi-kinase inhibitor sorafenib [ 21 ].…”

New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells

“…Among the sulfur-containing heterocycles, the heteroaromatic thiophene (C 4 H 4 S, from Greek "theion", "sulfur" and "phaino", "shining") has emerged as a promising structural scaffold for the design of new pharmacologically active compounds [10]. Disclosed examples of antitumor active thiophenes comprise chalcones and thienopyrimidines [11][12][13][14]. The Knoevenagel reaction is a straightforward method to form C=C bonds and aryl-substituted acrylonitriles can be easily prepared by Knoevenagel reaction from aryl acetonitriles and aryl aldehydes [15,16].…”