Synthesis, antitumour and antioxidant activities of novel α,β-unsaturated ketones and related heterocyclic analogues: EGFR inhibition and molecular modelling study

Abstract

New α,β-unsaturated ketones 4a,b; 5a-c; and 6a,b; as well as 4-H pyran 7; pyrazoline 8a,b; isoxazoline 9; pyridine 10-11; and quinoline-4-carboxylic acid 12a,b derivatives were synthesized and evaluated for in vitro antitumour activity against HepG2, MCF-7, HeLa, and PC-3 cancer cell lines. Antioxidant activity was investigated by the ability of these compounds to scavenge the 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS^•+). Compounds 6a, 6b, 7, and 8b exhibited potent antitumour activities against all tested cell lines with [IC₅₀] ≅5.5-18.1 µΜ), in addition to significantly high ABTS^•+ scavenging activities. In vitro EGFR kinase assay for 6a, 6b, 7, and 8b as the most potent antitumour compounds showed that; compounds 6b, and 7 exhibited worthy EGFR inhibition activity with IC₅₀ values of 0.56 and 1.6 µM, respectively, while compounds 6a and 8b showed good inhibition activity with IC₅₀ values of 4.66 and 2.16 µM, respectively, compared with sorafenib reference drug (IC₅₀ = 1.28 µM). Molecular modelling studies for compounds 6b, 7, and 8b were conducted to exhibit the binding mode towards EGFR kinase, which showed similar interaction with erlotinib.

Keywords: EGFR inhibition; antioxidant effect; antitumour activity; molecular docking; α,β-Unsaturated ketone.

Figure 1.

The reported antitumour (A–F) and the designed (G) compounds.

Scheme 1.

Synthesis of the designed α,β-unsaturated ketones and 4-H pyran derivatives.

Scheme 2.

Synthesis of the designed pyrazoline, isoxazoline, cyanopyridine, and quinoline-4-carboxylic acid derivatives.

Figure 2.

The overall correlation between the antioxidant activity (%Inhibition) and the antitumour activity of the synthesized compounds against cancer cell lines (HepG2, MCF-7, HeLa, and PC-3 cells).

Figure 3.

Three-dimensional (3D) interactions of erlotinib (upper panel), compounds 6b (middle left panel), 7 (middle right panel), and 8b (lower panel) with the receptor pocket of EGFR kinase. Hydrogen bonds are shown as green lines and CH–π interactions as dotted lines.