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

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 33; no. 1; pp. 507 - 518
• Main Authors: El-Husseiny, Walaa M., El-Sayed, Magda A.-A., Abdel-Aziz, Naglaa I., El-Azab, Adel S., Ahmed, Esam R., Abdel-Aziz, Alaa A.-M.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01-01-2018; Taylor & Francis Group
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antioxidant effect; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; antitumour activity; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; EGFR inhibition; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Humans; Ketones - chemical synthesis; Ketones - chemistry; Ketones - pharmacology; Models, Molecular; molecular docking; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Research Paper; Structure-Activity Relationship; α,β-Unsaturated ketone; EGFR inhibition; molecular docking; antioxidant effect; antitumour activity; α,β-Unsaturated ketone
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2018.1434519

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 [IC
50
] ≅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 IC
50
values of 0.56 and 1.6 µM, respectively, while compounds 6a and 8b showed good inhibition activity with IC
50
values of 4.66 and 2.16 µM, respectively, compared with sorafenib reference drug (IC
50
 = 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.